ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease
Open accessAbstract
As the population ages, neurodegenerative diseases such as Alzheimer's disease (AD) are becoming a significant burden on patients, their families, and health-care systems. Neurodegenerative processes may start up to 15 years before outward signs and symptoms of AD, as evidenced by data from AD patients and mouse models. A major genetic risk factor for late-onset AD is the ɛ4 isoform of apolipoprotein E (ApoE4), which is present in almost 20% of the population. In this review we discuss the contribution of ApoE receptor signaling to the function of each component of the tripartite synapse - the axon terminal, the postsynaptic dendritic spine, and the astrocyte - and examine how these systems fail in the context of ApoE4 and AD.
AI snapshot
Written from the paper’s full text.
TL;DR
This review argues that ApoE receptors (the LDL receptor family) act as central regulators of synaptic function across all three compartments of the tripartite synapse, and that the ApoE4 isoform disrupts these neuromodulatory roles early in Alzheimer's disease. It proposes that ApoE4 drives neuronal dysfunction both by impairing amyloid-beta turnover and by blunting Reelin/ApoE receptor protection of the synapse.
Key findings
- ApoE4 is a major late-onset AD risk factor: one copy roughly triples risk, two copies confer about a 90% lifetime risk, and allele frequency is 15–20%; ApoE2 appears protective and ApoE3 risk-neutral.
- Reelin signaling through Apoer2/Lrp8 and Vldlr phosphorylates Dab1, which boosts NMDAR-mediated calcium influx and LTP while inhibiting GSK3β and tau phosphorylation; Reelin application to hippocampal slices prevents Aβ-induced LTP reduction, and intraventricular Reelin improves learning and memory in mice.
- Aβ oligomers oppose Reelin via calcineurin/STEP-driven NMDAR internalization and via caspase-3/Akt-mediated GSK3β activation, reducing LTP; Reelin-deficient mice overexpressing Aβ are heavily impaired on the Morris Water Maze.
- ApoE4's structural instability (molten globule tendency, aggregation at 37°C) stalls endosomal recycling of ApoE receptors and co-trapped glutamate receptors, producing a state of "Reelin resistance"; ApoE4 targeted-replacement mice and human ApoE4 carriers show reduced dendritic spine complexity.
- Presynaptically, Reelin acting through Apoer2/Vldlr raises intracellular calcium and selectively enhances fusion of VAMP7-containing vesicles; ApoE4 TR mice show decreased glutamate, increased glutamine, and late increases in vglut1.
- Astrocytic Lrp4 mediates agrin-driven ATP release, which is converted to adenosine and suppresses presynaptic glutamate release via A1 receptors; ApoE4 limits astrocytic synaptic pruning and causes the greatest glial activation.
Methods
- Narrative review; no primary data collection or new experiments.
- Synthesizes published human, mouse, and in vitro literature on ApoE, LDL receptor family members, Reelin, and AD pathology.
- Organizes evidence by tripartite synapse compartment (postsynaptic spine, axon terminal, astrocyte) and by signaling pathway (Reelin/Dab1, calcium homeostasis, actin polymerization, endocytic trafficking).
Limitations
- Stated: the authors list unresolved questions, including whether ApoE4 represents gain or loss of function, whether ApoE isoforms affect presynaptic VAMP7-vesicle mobilization, the mechanism by which ApoE influences astrocytic pruning, how Lrp4 increases astrocytic ATP release, and which molecular targets could ameliorate ApoE4's endocytic recycling effects.
- Stated: definitive human evidence that Reelin is protective is largely lacking; the role of Lrp1 in ApoE-isoform effects on pruning "remains to be demonstrated"; the impact of altered presynaptic glutamate production in vivo requires follow-up.
- Evident from the text: as a review it presents no new data, and several mechanistic claims rest on mouse models or slice preparations whose translation to human AD is not established.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 95 cited sources checked · 0 supported · 0 flagged
- Interpretationreasoning
ApoE has a role in neuronal function prior to amyloid deposition.
“indicating a role for ApoE in neuronal function prior to amyloid deposition”
Quote in the paperSubstantial claim - Premisecitation
Some of these ApoE4-related alterations are present much earlier in life.
“some of these changes are present much earlier in life [16]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Dean DC 3rd 2014 Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study JAMA Neurol 71 1 11 22 24276092 PMC4056558 source
Not checked in the free run.
- Premisecitation
Lrp1 interacts with the N-methyl-D-aspartate receptor (NMDAR), promoting endocytosis of NMDAR from the cell surface.
“Lrp1 interacts with the N-methyl-D-aspartate receptor (NMDAR), promoting the endocytosis of NMDAR from the cell surface [19].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Maier W 2013 LRP1 is critical for the surface distribution and internalization of the NR2B NMDA receptor subtype Mol Neurodegener 8 25 23866919 PMC3722104 source
Not checked in the free run.
- Premisecitation
The primary ligand for Apoer2 and Vldlr in the central nervous system is Reelin, not ApoE.
“The primary ligand for these receptors in the CNS is not ApoE, but rather the glycoprotein Reelin [22].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Lee GH D’Arcangelo G 2016 New Insights into Reelin-Mediated Signaling Pathways Front Cell Neurosci 10 122 27242434 PMC4860420 source
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- Premisecitation
ApoE4 hinders the clearance of amyloid-beta (Aβ) significantly more than ApoE3 and ApoE2.
“ApoE4 hindering Aβ clearance significantly over ApoE3 and ApoE2 [14]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Castellano JM 2011 Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance Sci Transl Med 3 89 89ra57 PMC3192364 21715678 source
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- Premisecitation
Apoer2/Lrp8 and Vldlr form a complex with scaffolding proteins such as PSD-95 and glutamate receptors.
“the ApoE receptors Apoer2/Lrp8 and Vldlr form a complex with scaffolding proteins, such as PSD-95, and the glutamate receptors [21].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Beffert U 2005 Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2 Neuron 47 4 567 79 16102539 source
Not checked in the free run.
- Premisecitation
The ε4 isoform of apolipoprotein E (ApoE4) is a major genetic risk factor for late-onset Alzheimer's disease (AD).
“A major genetic risk factor for late-onset (AD) is the ε4 isoform of apolipoprotein E (ApoE4)”
- Also stated in: § ApoE, ApoE Receptors, and Alzheimer’s Disease · plain
“Over two decades ago, the ε4 isoform of ApoE (ApoE4) was identified as a major genetic risk factor for late-onset AD (i.e., after 60 years of age) [12].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Lutz MW 2016 A Genetics-based Biomarker Risk Algorithm for Predicting Risk of Alzheimer’s Disease Alzheimers Dement (N Y) 2 1 30 44 27047990 PMC4817110 source
Not checked in the free run.
- Also stated in: § ApoE, ApoE Receptors, and Alzheimer’s Disease · plain
- Interpretationreasoning
ApoE4's hindrance of Aβ clearance directly increases amyloid pathology.
“and thus directly increasing amyloid pathology”
Quote in the paperNot a substantial claim - Premisecitation
Older individuals who are ApoE4 carriers have structural and functional alterations in AD-affected areas in the absence of cognitive dysfunction.
“older individuals who are ApoE4 carriers have structural and functional alterations in AD affected areas in the absence of cognitive dysfunction [15]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Chen Y 2015 Disrupted functional and structural networks in cognitively normal elderly subjects with the APOE varepsilon4 allele Neuropsychopharmacology 40 5 1181 91 25403724 PMC4367462 source
Not checked in the free run.
- Premisecitation
Loss of Lrp1 hinders some elements of NMDAR signaling, including internalization of GluA1 and degradation of PSD-95.
“loss of Lrp1 hinders some elements of NMDAR signaling, such as internalization of GluA1 and degradation of PSD-95 [20].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Nakajima C 2013 Low density lipoprotein receptor-related protein 1 (LRP1) modulates N-methyl-D-aspartate (NMDA) receptor-dependent intracellular signaling and NMDA-induced regulation of postsynaptic protein complexes J Biol Chem 288 30 21909 23 23760271 PMC3724646 source
Not checked in the free run.
- Premisecitation
When Reelin is applied to hippocampal slices, greater Ca2+ influx through opened NMDARs leads to increased long-term potentiation (LTP).
“when Reelin is applied to hippocampal slices, greater Ca2+ influx through opened NMDARs leads to increased long-term potentiation [29].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Weeber EJ 2002 Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning J Biol Chem 277 42 39944 52 12167620 source
Not checked in the free run.
- Interpretationreasoning
Reelin and ApoE receptor signaling play an important role in protecting the synapse from Aβ-induced suppression.
“These findings highlight the important role for Reelin and ApoE receptor signaling in protecting the synapse from Aβ-induced suppression.”
Quote in the paperSubstantial claim - Interpretationcitation
A healthy CNS can homeostatically compensate for Reelin loss.
“suggesting an ability of a healthy CNS to homeostatically compensate for Reelin loss”
Quote in the paperSubstantial claim - Premisecitation
A common consequence of these interactions is the activation of calcineurin (PP2B).
“A common consequence of these interactions is the activation of calcineurin (PP2B) [28].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Snyder EM 2005 Regulation of NMDA receptor trafficking by amyloid-beta Nat Neurosci 8 8 1051 8 16025111 source
Not checked in the free run.
- Premisecitation
The ApoE receptors Apoer2 and Vldlr are expressed at the presynaptic membrane.
“recent studies have shown that the ApoE receptors Apoer2 and Vldlr are also expressed at the presynaptic membrane.”
Quote in the paperSubstantial claim - Interpretationcitation
When ApoE4 is present, Reelin is compromised in its ability to effectively balance the inhibitory effect of Aβ on LTP.
“As a result, Reelin is compromised in its ability to effectively balance the inhibitory effect of Aβ on LTP (see above) when ApoE4 is present [72].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [72] Chen Y 2010 ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling Proc Natl Acad Sci U S A 107 26 12011 6 20547867 PMC2900641 source
Not checked in the free run.
- Premisecitation
Overexpression of Aβ in Reelin-deficient mice leaves them heavily impaired in the Morris Water maze task of learning and memory.
“overexpression of Aβ in Reelin-deficient mice leaves them heavily impaired in the Morris Water maze task of learning and memory [42].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Lane-Donovan C 2015 Reelin protects against amyloid beta toxicity in vivo Sci Signal 8 384 ra67 26152694 PMC4652952 source
Not checked in the free run.
- Premisecitation
In AD, Ca2+ homeostasis inclines toward a higher level of resting Ca2+.
“In AD, Ca2+ homeostasis inclines toward a higher level of resting Ca2+ [51].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [51] Berridge MJ 2011 Calcium signalling and Alzheimer’s disease Neurochem Res 36 7 1149 56 21184278 source
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- Premisecitation
PP2B regulates levels and activity of striatal-enriched protein tyrosine phosphatase (STEP).
“PP2B regulates levels and activity of striatal-enriched protein tyrosine phosphatase (STEP) [34].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Valjent E 2005 Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum Proc Natl Acad Sci U S A 102 2 491 6 15608059 PMC544317 source
Not checked in the free run.
- Interpretationreasoning
Reelin protects the synapse against the deleterious effects of Aβ through a complex signaling cascade that maintains the balance of kinase and phosphatase activity.
“these findings provide a rational concept of Reelin and ApoE receptor signaling whereby Reelin protects the synapse against the deleterious effects of Aβ through a complex signaling cascade to maintain the balance of kinase and phosphatase activity”
Quote in the paperSubstantial claim - Interpretationreasoning
Aβ oligomers reduce LTP as a result of activated GSK3β and increased calcineurin and STEP activation.
“As a result of these two mechanisms, activated GSK3β and increased calcineurin and STEP activation, Aβ oligomers reduce LTP [40].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Walsh DM 2002 Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo Nature 416 6880 535 9 11932745 source
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- Premisecitation
Adult loss of Reelin and ApoE receptor signaling in mice is well-tolerated in the absence of amyloid pathology, likely due to homeostatic regulation and compensation by other neuromodulatory mechanisms.
“adult loss of Reelin and ApoE receptor signaling in mice is well-tolerated in the absence of amyloid pathology, likely due to homeostatic regulation and compensation by other neuromodulatory mechanisms [42].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Lane-Donovan C 2015 Reelin protects against amyloid beta toxicity in vivo Sci Signal 8 384 ra67 26152694 PMC4652952 source
Not checked in the free run.
- Premisecitation
Emerging data indicate that ApoE receptors have a similarly important role in regulating presynaptic vesicle release.
“emerging data indicate that ApoE receptors have a similarly important role in regulating presynaptic vesicle release [73].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [73] Bal M 2013 Reelin Mobilizes a VAMP7-Dependent Synaptic Vesicle Pool and Selectively Augments Spontaneous Neurotransmission Neuron 80 4 934 46 24210904 PMC3840105 source
Not checked in the free run.
- Premisecitation
This Ca2+ elevation specifically increases the fusion of vesicles containing vesicle-associated membrane protein 7 (VAMP7), an alternative SNARE protein that participates in spontaneous vesicle release.
“This Ca2+ elevation specifically increases the fusion of vesicles containing vesicle-associated membrane protein 7 (VAMP7), an alternative ‘soluble N-ethylmaleimide sensitive factor attachment protein receptor’ (SNARE) protein that participates in spontaneous vesicle release [74].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [74] Hua Z 2011 v-SNARE composition distinguishes synaptic vesicle pools Neuron 71 3 474 87 21835344 PMC3155686 source
Not checked in the free run.
- Interpretationreasoning
ApoE receptors play an important role at the post-synaptic neuron, separate from modulation of synaptic plasticity, by regulating structural changes to the dendritic spine itself.
“it is clear that the ApoE receptors play an important role at the post-synaptic neuron separate from modulation of synaptic plasticity by regulating structural changes to the dendritic spine itself.”
Quote in the paperNot a substantial claim - Premisereasoning
Aβ-mediated activation of STEP leads to excessive internalization of NMDARs.
“Thus, Aβ-mediated activation of STEP leads to excessive internalization of NMDARs [28, 35].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [28] Snyder EM 2005 Regulation of NMDA receptor trafficking by amyloid-beta Nat Neurosci 8 8 1051 8 16025111 source
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- cites [35] Pelkey KA 2002 Tyrosine phosphatase STEP is a tonic brake on induction of long-term potentiation Neuron 34 1 127 38 11931747 source
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- Premisecitation
Patients who are completely ApoE-deficient have broadly normal cognition.
“patients who are completely ApoE-deficient have broadly normal cognition [3].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Mak AC 2014 Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function JAMA Neurol 71 10 1228 36 25111166 PMC4714860 source
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- Premisecitation
Reelin application to hippocampal slices prevents the reduction in LTP induced by Aβ.
“Importantly, Reelin application to hippocampal slices prevents the reduction in LTP induced by Aβ [41].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Durakoglugil MS 2009 Reelin signaling antagonizes beta-amyloid at the synapse Proc Natl Acad Sci U S A 106 37 15938 43 19805234 PMC2747222 source
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- Premisecitation
Adult loss of Reelin does not cause significant cognitive impairment.
“adult loss of Reelin does not cause significant cognitive impairment”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Lane-Donovan C 2015 Reelin protects against amyloid beta toxicity in vivo Sci Signal 8 384 ra67 26152694 PMC4652952 source
Not checked in the free run.
- Premisecitation
ApoE expression, in both mice and humans, begins relatively late in development.
“ApoE expression, in both mice and humans, begins relatively late in development [46, 47].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [46] Miller JA 2014 Transcriptional landscape of the prenatal human brain Nature 508 7495 199 206 24695229 PMC4105188 source
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- cites [47] Lein ES 2007 Genome-wide atlas of gene expression in the adult mouse brain Nature 445 7124 168 76 17151600 source
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- Premisecitation
Aβ activates GSK3β through a signaling cascade involving caspase-3 and Akt.
“Aβ activates GSK3β through a signaling cascade involving caspase-3 and Akt [37].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] Jo J 2011 Abeta(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3beta Nat Neurosci 14 5 545 7 21441921 source
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- Premisecitation
Intraventricular injection of Reelin in mice improves learning and memory.
“intraventricular injection of Reelin in mice improves learning and memory [30].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Rogers JT 2011 Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density Learn Mem 18 9 558 64 21852430 PMC3166788 source
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- Premisecitation
Application of Aβ to hippocampal slices elevates resting Ca2+ levels.
“application of Aβ to hippocampal slices elevates resting Ca2+ levels [52, 53].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [52] Lopez JR 2008 Increased intraneuronal resting [Ca2+] in adult Alzheimer’s disease mice J Neurochem 105 1 262 71 18021291 source
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- cites [53] Kuchibhotla KV 2008 Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks Neuron 59 2 214 25 18667150 PMC2578820 source
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- Premisecitation
Reelin signaling through Apoer2 and Vldlr receptors on the presynaptic membrane leads to transient elevations of intracellular Ca2+.
“Reelin signaling through Apoer2 and Vldlr receptors on the presynaptic membrane leads to transient elevations of intracellular Ca2+ [73].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [73] Bal M 2013 Reelin Mobilizes a VAMP7-Dependent Synaptic Vesicle Pool and Selectively Augments Spontaneous Neurotransmission Neuron 80 4 934 46 24210904 PMC3840105 source
Not checked in the free run.
- Premisenone given
Most ApoE in the brain is expressed by astrocytes.
“Most ApoE in the brain is expressed by astrocytes.”
Quote in the paperNot a substantial claim - Premisenone given
The effect of Aβ on NMDAR internalization is specific to oligomeric, not monomeric, Aβ.
“This effect is specific to oligomeric, not monomeric, Aβ.”
Quote in the paperSubstantial claim - Premisecitation
Expression of calbindin D-28k (CB) prevents some of the elevation in resting Ca2+ levels induced by Aβ.
“expression of CB prevents some of the elevation in resting Ca2+ levels induced by Aβ [59].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [59] Bezprozvanny I Mattson MP 2008 Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease Trends Neurosci 31 9 454 63 18675468 PMC2566585 source
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- Premisecitation
ApoE4 produces the strongest glial activation.
“with ApoE4 causing the greatest activation [97]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [97] Zhu Y 2012 APOE genotype alters glial activation and loss of synaptic markers in mice Glia 60 4 559 69 22228589 PMC3276698 source
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- Premisecitation
Glial activation is influenced by ApoE isoform.
“glial activation is affected by ApoE isoform”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [97] Zhu Y 2012 APOE genotype alters glial activation and loss of synaptic markers in mice Glia 60 4 559 69 22228589 PMC3276698 source
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- Interpretationnone given
ApoE4 most severely disrupts the neuromodulatory roles of ApoE receptors.
“with ApoE4 most severely disrupting the neuromodulatory roles of ApoE receptors”
Quote in the paperNot a substantial claim - Premisecitation
Mice expressing Lrp4 in muscle on an Lrp4 knockout background show reduced synaptic transmission and long-term potentiation.
“these mice have a reduction of synaptic transmission and long-term potentiation [93]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [93] Gomez AM 2014 Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4 Elife 3 e04287 25407677 PMC4270049 source
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- Premisecitation
The substances released by astrocytes can influence synaptic transmission.
“which can then affect synaptic transmission [81]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [81] Bezzi P Volterra A 2001 A neuron-glia signalling network in the active brain Curr Opin Neurobiol 11 3 387 94 11399439 source
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- Premisecitation
These calcium changes cause astrocytes to release glutamate, D-serine, and ATP.
“that trigger the release of various substances from the astrocyte, including glutamate, D-serine, and ATP”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [81] Bezzi P Volterra A 2001 A neuron-glia signalling network in the active brain Curr Opin Neurobiol 11 3 387 94 11399439 source
Not checked in the free run.
- Premisecitation
Lrp4 is absolutely required for neuromuscular junction development in mice.
“the absolute requirement of Lrp4 for NMJ development in mice”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [92] Weatherbee SD 2006 LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction Development 133 24 4993 5000 17119023 source
Not checked in the free run.
- Premisecitation
Ion flow through astrocytic glutamatergic receptors changes intracellular calcium stores.
“Ion flow through these receptors causes alterations in intracellular Ca2+ stores”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [81] Bezzi P Volterra A 2001 A neuron-glia signalling network in the active brain Curr Opin Neurobiol 11 3 387 94 11399439 source
Not checked in the free run.
- Premisecitation
Astrocytes can detect synaptic activity via glutamatergic receptors.
“Astrocytes are capable of detecting synaptic activity through glutamatergic receptors [80].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [80] Wang X 2006 Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo Nat Neurosci 9 6 816 23 16699507 source
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- Interpretationreasoning
ApoE4 promotes neuronal dysfunction by weakening the protective effect of Reelin and ApoE receptor signaling against Aβ's synaptic damage.
“weakening the ability of Reelin and ApoE receptor signaling to protect against the deleterious effects of Aβ on the synapse”
Quote in the paperSubstantial claim- Rests on an assumption: Mechanisms of ApoE and Lrp4 function observed in mouse models apply to human Alzheimer's disease.
- Premisecitation
ApoE isoforms differentially affect synaptic pruning, with ApoE4 limiting the ability of astrocytes to prune synapses.
“ApoE isoforms differentially affect this process, with ApoE4 limiting the ability of astrocytes to prune synapses [76, 77].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [76] Chung WS 2013 Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways Nature 504 7480 394 400 24270812 PMC3969024 source
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- cites [77] Chung WS 2016 Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes Proc Natl Acad Sci U S A 113 36 10186 91 27559087 PMC5018780 source
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- Premisereasoning
Mice completely lacking Lrp4 die around birth.
“mice that are completely deficient in Lrp4 die perinatally”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [92] Weatherbee SD 2006 LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction Development 133 24 4993 5000 17119023 source
Not checked in the free run.
- Premisecitation
The perinatal lethality of Lrp4-deficient mice prevented effective study of Lrp4 in the central nervous system until recently.
“which has precluded effective study of the role of Lrp4 in the CNS until recently [92]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [92] Weatherbee SD 2006 LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction Development 133 24 4993 5000 17119023 source
Not checked in the free run.
- Premisecitation
Adenosine signaling through presynaptic A1 receptors lowers the release probability of glutamate-containing vesicles.
“Adenosine signaling through adenosine A1 (A1A) receptors at the presynaptic membrane leads to a reduced release probability of glutamate-containing vesicles”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [96] Serrano A 2006 GABAergic network activation of glial cells underlies hippocampal heterosynaptic depression J Neurosci 26 20 5370 82 16707789 PMC6675310 source
Not checked in the free run.
- Interpretationnone given
ApoE isoforms differentially affect ApoE receptor functions.
“are differentially affected by ApoE isoforms”
Quote in the paperSubstantial claim - Interpretationnone given
ApoE receptors play a central role in regulating synapses at pre- and post-synaptic sites and at the peri-synaptic astrocyte.
“ApoE receptors have a central role as regulators of the synapse, both at pre- and post-synaptic sites, as well as at the peri-synaptic astrocyte.”
Quote in the paperNot a substantial claim - Interpretationreasoning
ApoE receptor functions are necessary for maintaining proper synaptic strength.
“These functions, which are essential for maintaining proper synaptic strength”
Quote in the paperNot a substantial claim - Premisecitation
Astrocytic Lrp4, rather than neuronal Lrp4, mediates this process.
“it is not neuronally expressed Lrp4, but rather astrocytic Lrp4 that mediates this process”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [95] Sun XD 2016 Lrp4 in astrocytes modulates glutamatergic transmission Nat Neurosci 19 8 1010 8 27294513 PMC4961622 source
Not checked in the free run.
- Premisecitation
This adenosine signaling reduces glutamatergic transmission.
“and thus reduced glutamatergic transmission [96]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [96] Serrano A 2006 GABAergic network activation of glial cells underlies hippocampal heterosynaptic depression J Neurosci 26 20 5370 82 16707789 PMC6675310 source
Not checked in the free run.
- Interpretationreasoning
ApoE4 drives neuronal dysfunction at the earliest stages of Alzheimer's disease pathology, before clinical manifestation.
“ApoE4 promotes neuronal dysfunction at the earliest stages of the pathology, leading up to the clinical manifestation of AD”
Quote in the paperSubstantial claim- Rests on an assumption: Mechanisms of ApoE and Lrp4 function observed in mouse models apply to human Alzheimer's disease.
- Premisecitation
The released ATP is broken down into adenosine in the extracellular space.
“which is subsequently broken down into adenosine in the extracellular milieu [95]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [95] Sun XD 2016 Lrp4 in astrocytes modulates glutamatergic transmission Nat Neurosci 19 8 1010 8 27294513 PMC4961622 source
Not checked in the free run.
- Premisecitation
Lrp4 is not absolutely required for neuromuscular junction development in humans and cattle.
“but intriguingly not in humans [86] and cattle [91]”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [86] Li Y 2010 LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome Am J Hum Genet 86 5 696 706 20381006 PMC2869043 source
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- cites [91] Drogemuller C 2007 Congenital syndactyly in cattle: four novel mutations in the low density lipoprotein receptor-related protein 4 gene (LRP4) BMC Genet 8 5 17319939 PMC1810560 source
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- Premisecitation
Mice with a hypomorphic Lrp4 allele show the same reduction in synaptic transmission and long-term potentiation.
“this finding is mimicked in mice carrying a hypomorphic allele for Lrp4 [94]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [94] Pohlkamp T 2015 Lrp4 domains differentially regulate limb/brain development and synaptic plasticity PLoS One 10 2 e0116701 25688974 PMC4331535 source
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- Premisecitation
In astrocytes, Agrin signaling through Lrp4 increases ATP release.
“In the astrocyte, Agrin signaling through Lrp4 leads to the increased release of ATP”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [95] Sun XD 2016 Lrp4 in astrocytes modulates glutamatergic transmission Nat Neurosci 19 8 1010 8 27294513 PMC4961622 source
Not checked in the free run.
- May combine two claims. 26
- Classified as probably not a substantial claim. 7
May combine two claims.
PremisecitationCarrying one copy of ApoE4 triples the risk of developing AD, and carrying two copies confers a 90% lifetime risk.
“Possession of one copy of ApoE4 triples the risk of developing AD, while individuals with two copies have a 90% lifetime risk of developing the disease.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Lutz MW 2016 A Genetics-based Biomarker Risk Algorithm for Predicting Risk of Alzheimer’s Disease Alzheimers Dement (N Y) 2 1 30 44 27047990 PMC4817110 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe allele frequency of ApoE4 is 15-20%, with some variation in incidence between populations.
“The allele frequency of ApoE4 is 15–20%, with some variation in incidence between populations [13].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Liu CC 2013 Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy Nat Rev Neurol 9 2 106 18 23296339 PMC3726719 source
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May combine two claims.
PremisecitationApoE2 is protective against AD, while ApoE3 is risk-neutral.
“Conversely, ApoE2 is considered to be protective against AD, while ApoE3 is considered risk-neutral”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Liu CC 2013 Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy Nat Rev Neurol 9 2 106 18 23296339 PMC3726719 source
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May combine two claims.
PremisecitationDab1-mediated activation of Src and Fyn leads to tyrosine phosphorylation of the NR2 subunits of NMDARs, which causes increased Ca2+ influx and reduces NMDAR endocytosis.
“Dab1-mediated activation of Src and Fyn leads to the tyrosine phosphorylation of the NR2 subunits of NMDARs, which causes increased Ca2+ influx when the receptors are activated and also reduces NMDAR endocytosis [27, 28]”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [27] Chen Y 2005 Reelin modulates NMDA receptor activity in cortical neurons J Neurosci 25 36 8209 16 16148228 PMC6725528 source
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- cites [28] Snyder EM 2005 Regulation of NMDA receptor trafficking by amyloid-beta Nat Neurosci 8 8 1051 8 16025111 source
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May combine two claims.
PremisecitationSTEP dephosphorylates and deactivates Fyn, enhancing the overall effect of STEP on NMDAR endocytosis.
“STEP additionally dephosphorylates and deactivates Fyn, enhancing the overall effect of STEP on NMDAR endocytosis [36].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Nguyen TH 2002 Striatal enriched phosphatase 61 dephosphorylates Fyn at phosphotyrosine 420 J Biol Chem 277 27 24274 9 11983687 source
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May combine two claims.
InterpretationreasoningApoE receptors activated by Reelin are essential in maintaining signal strength over the noise of rising Ca2+ levels induced by AD-promoting mechanisms, thereby protecting the synapse during early AD until Aβ and tau accumulate to levels that cause synaptic loss.
“the ApoE receptors activated by Reelin are essential in maintaining the signal strength over the noise of rising Ca2+ levels induced by AD-promoting mechanisms. This mechanism affords protection to the synapse by maintaining synaptic strength during the early stages of AD until Aβ and τ accumulate to such levels that the system breaks down and synaptic loss ensues.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDab1 activates phosphoinositol-3 (PI3) kinase and subsequently Akt, which phosphorylates glycogen synthase kinase 3β (GSK3β) at its inhibitory Ser-9 phosphorylation site, reducing phosphorylation of numerous targets including tau.
“Dab1 activates phosphoinositol-3 (PI3) kinase and subsequently Akt, which phosphorylates glycogen synthase kinase 3β (GSK3β) at its inhibitory Ser-9 phosphorylation site. This reduces the phosphorylation of numerous targets of GSK3β, the most relevant of which in the context of AD is the microtubule-associated protein τ [25].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Herz J Chen Y 2006 Reelin, lipoprotein receptors and synaptic plasticity Nat Rev Neurosci 7 11 850 9 17053810 source
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May combine two claims.
PremisecitationGSK3β activation reduces synaptic long-term potentiation (LTP) and provides a potential biochemical mechanism by which Aβ can induce tau hyperphosphorylation.
“GSK3β activation reduces synaptic long-term potentiation (LTP) and provides a potential biochemical mechanism by which Aβ can induce τ hyperphosphorylation [39].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Zhu LQ 2007 Activation of glycogen synthase kinase-3 inhibits long-term potentiation with synapse-associated impairments J Neurosci 27 45 12211 20 17989287 PMC6673262 source
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May combine two claims.
InterpretationreasoningHigher resting Ca2+ levels tip the balance of synaptic plasticity towards long-term depression (LTD), leading to memory trace erasure and loss of synapses.
“The main effect of higher resting levels of Ca2+ appears to be to tip the balance of synaptic plasticity towards LTD. The net result of this would be memory trace erasure and loss of synapses.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAβ oligomers reduce activity of LIMK, which leads to dephosphorylated active cofilin, depolymerization of actin filaments, and the generation of actin rods.
“Aβ oligomers reduce activity of LIMK, which in turns leads to dephosphorylated, active cofilin, depolymerization of actin filaments and the generation of actin rods [66].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [66] Zhao L 2006 Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease Nat Neurosci 9 2 234 42 16415866 source
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May combine two claims.
PremisecitationActin polymerization and dendritic spine growth exhibit a net increase in the presence of Reelin, and mice that overexpress Reelin have higher spine density and increased spine complexity.
“actin polymerization and dendritic spine growth exhibit a net increase in the presence of Reelin, and mice that overexpress Reelin have higher spine density and increased spine complexity [64, 65].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [64] Chai X 2009 Reelin stabilizes the actin cytoskeleton of neuronal processes by inducing n-cofilin phosphorylation at serine3 J Neurosci 29 1 288 99 19129405 PMC6664910 source
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- cites [65] Bosch C 2016 Reelin Regulates the Maturation of Dendritic Spines, Synaptogenesis and Glial Ensheathment of Newborn Granule Cells Cereb Cortex PMC5066826 27624722 source
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PremisecitationApoE has two structural domains: an N-terminal domain responsible for interaction with ApoE receptors, and a C-terminal domain responsible for lipoprotein binding.
“ApoE has two structural domains, an N-terminal domain, which is responsible for interaction with ApoE receptors, and a C-terminal domain, which is responsible for lipoprotein binding [68].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [68] Zhong N Weisgraber KH 2009 Understanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure J Biol Chem 284 10 6027 31 18948255 PMC2649104 source
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May combine two claims.
PremisecitationWhen ApoE4 is present, the final recycling step of ApoE receptors is delayed and the process is stalled in the endosome, presumably due to the propensity of ApoE4 to form molten globules at the lower pH of the endosome.
“when ApoE4 is present, the final recycling step is delayed and the process is stalled in the endosome, presumably due to the propensity of ApoE4 to form molten globules at the lower pH of the endosome [69, 71].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [69] Morrow JA 2002 Apolipoprotein E4 forms a molten globule. A potential basis for its association with disease J Biol Chem 277 52 50380 5 12393895 source
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- cites [71] Heeren J 2004 Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation J Biol Chem 279 53 55483 92 15485881 source
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May combine two claims.
PremisecitationThe presence of an arginine at position 112 promotes the formation of a salt bridge between Arg-61 and Glu-255, leading to a domain interaction between the N- and C-terminals. As a result, ApoE4 has a greater tendency to form molten globules over the other ApoE isoforms, as well as a greater propensity to aggregate at 37°C.
“The presence of an arginine at position 112 promotes the formation of a salt bridge between Arg-61 and Glu-255, leading to a “domain interaction” between the N- and C-terminals. As a result, ApoE4 has a greater tendency to form molten globules over the other ApoE isoforms, as well as a greater propensity to aggregate at 37°C [69, 70].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [69] Morrow JA 2002 Apolipoprotein E4 forms a molten globule. A potential basis for its association with disease J Biol Chem 277 52 50380 5 12393895 source
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- cites [70] Hatters DM 2006 Amino-terminal domain stability mediates apolipoprotein E aggregation into neurotoxic fibrils J Mol Biol 361 5 932 44 16890957 source
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May combine two claims.
Premisenone givenApoE binds the receptors at a different site from Reelin, and thus does not directly affect receptor signaling by hindering Reelin engagement; however, the ApoE isoforms do affect receptor trafficking.
“ApoE binds the receptors at a different site from Reelin, and thus does not directly affect receptor signaling by hindering Reelin engagement; however, the ApoE isoforms do affect receptor trafficking.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationThese findings suggest a reduced ability of presynaptic ApoE4 neurons to convert glutamine to glutamate and a compensatory increase in vesicular glutamate loading.
“suggesting a reduced ability of presynaptic ApoE4 neurons to convert glutamine to glutamate and a compensatory increase in vesicular glutamate loading [75].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [75] Dumanis SB 2013 APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals J Neurochem 124 1 4 14 22862561 PMC3509249 source
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PremisecitationApoE4 targeted replacement mice have a reduction in dendritic spine complexity, a finding that is mirrored in human ApoE4 carriers.
“ApoE4 targeted replacement mice have a reduction in dendritic spine complexity, a finding that is mirrored in human ApoE4 carriers [67].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [67] Ji Y 2003 Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer’s disease patients Neuroscience 122 2 305 15 14614898 source
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PremisecitationWith age, Reelin levels are reduced in the brain, and in AD, Reelin levels are particularly reduced in the entorhinal cortex.
“With age, Reelin levels are reduced in the brain and in AD, Reelin levels are particularly reduced in the entorhinal cortex [44].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [44] Chin J 2007 Reelin depletion in the entorhinal cortex of human amyloid precursor protein transgenic mice and humans with Alzheimer’s disease J Neurosci 27 11 2727 33 17360894 PMC6672562 source
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PremisecitationAstrocyte-derived ApoE is important for cholesterol transport through ApoE-containing 'HDL-like' particles, which play an important role in synaptic development and maintenance.
“Astrocyte-derived ApoE is important for cholesterol transport through ApoE-containing “HDL-like” particles, which play an important role in synaptic development and maintenance [1, 4, 5].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [1] Lane-Donovan C 2014 More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration Neuron 83 4 771 87 25144875 PMC4240629 source
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- cites [4] Pfrieger FW 2010 Role of glial cells in the formation and maintenance of synapses Brain Res Rev 63 1–2 39 46 19931561 source
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- cites [5] Mahley RW 2016 Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism Arterioscler Thromb Vasc Biol 36 7 1305 15 27174096 PMC4942259 source
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PremisecitationReelin signaling activates PI3kinase, which initiates a pathway that induces phosphorylation of LIM kinase-1 (LIMK-1), which in turn phosphorylates cofilin at an inhibitory site, blocking the actin-depolymerizing activity of cofilin.
“Reelin signaling activates PI3kinase, as described above [61]. In turn, PI3kinase initiates a signaling pathway that induces phosphorylation of LIM kinase-1 (LIMK-1), which in turn phosphorylates cofilin at an inhibitory site, blocking the actin-depolymerizing activity of cofilin [62, 63].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [61] Bock HH 2003 Phosphatidylinositol 3-kinase interacts with the adaptor protein Dab1 in response to Reelin signaling and is required for normal cortical lamination J Biol Chem 278 40 38772 9 12882964 source
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- cites [62] Caroni P 2014 Synapse rearrangements upon learning: from divergent-sparse connectivity to dedicated sub-circuits Trends Neurosci 37 10 604 14 25257207 source
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- cites [63] Mizuno K 2013 Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation Cell Signal 25 2 457 69 23153585 source
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PremisecitationAβ oligomers bind to α7 nicotinic acetylcholine receptors (α7 nAChRs) and to metabotropic glutamate receptors, in particular mGluR5.
“Aβ binds to α7 nicotinic acetylcholine receptors (α7 nAChRs) and to metabotropic glutamate receptors, in particular mGluR5 [31–33].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [31] Dineley KT 2001 Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer’s disease J Neurosci 21 12 4125 33 11404397 PMC6762764 source
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- cites [32] Renner M 2010 Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5 Neuron 66 5 739 54 20547131 PMC3111138 source
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- cites [33] Lauren J 2009 Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers Nature 457 7233 1128 32 19242475 PMC2748841 source
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PremisecitationApoE exists in three isoforms that differ at residues 112 and 158: ApoE2 has cysteine at both positions, ApoE3 has cysteine at position 112 and arginine at position 158, and ApoE4 has arginines at both positions.
“ApoE exists in the human population in three isoforms, which differ at only two residues, 112 and 158. ApoE2 has a cysteine at both positions, ApoE3 has a cysteine at position 112 and an arginine at position 158, and ApoE4 has arginines at both positions [68].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [68] Zhong N Weisgraber KH 2009 Understanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure J Biol Chem 284 10 6027 31 18948255 PMC2649104 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningApoE4 induces a state of 'Reelin resistance' that likely affects more than synaptic plasticity, including Ca2+ homeostasis, spine remodeling, and pre-synaptic and astrocytic roles.
“In this way, ApoE4 induces a state of “Reelin resistance” that likely affects more than synaptic plasticity (e.g., Ca2+ homeostasis, spine remodeling, and the pre-synaptic and astrocytic roles described below).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLrp4 functions in neuromuscular junction development and in maintaining the adult neuromuscular junction.
“for its role in neuromuscular junction (NMJ) development and in the maintenance of the adult NMJ”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [87] Selcen D 2015 Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia JAMA Neurol 72 8 889 96 26052878 PMC4532561 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGlial activation indicates pro-inflammatory changes commonly seen in Alzheimer's disease brains.
“glial activation is an indication of pro-inflammatory changes that is commonly found in AD brains”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [98] Heppner FL 2015 Immune attack: the role of inflammation in Alzheimer disease Nat Rev Neurosci 16 6 358 72 25991443 source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAnti-Lrp4 and anti-MuSK antibodies contribute to myasthenia gravis.
“the role of anti-Lrp4 and anti-MuSK antibodies in myasthenia gravis [87]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [87] Selcen D 2015 Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia JAMA Neurol 72 8 889 96 26052878 PMC4532561 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAt the neuromuscular junction, Lrp4, APP, and MuSK form a complex that prepatterns the muscle.
“at the NMJ, Lrp4, APP and muscle-specific kinase (MuSK) form a complex to prepattern the muscle [88–90]”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [88] Choi HY 2013 APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice Elife 2 e00220 23986861 PMC3748711 source
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- cites [89] Kim N 2008 Lrp4 is a receptor for Agrin and forms a complex with MuSK Cell 135 2 334 42 18848351 PMC2933840 source
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- cites [90] Zhang B 2008 LRP4 serves as a coreceptor of agrin Neuron 60 2 285 97 18957220 PMC2743173 source
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PremisecitationLrp1 is highly expressed in astrocytes, where it is responsible for phagocytosis of degraded myelin.
“Lrp1 is highly expressed in astrocytes, where it is responsible for phagocytosis of degraded myelin [78, 79].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [78] Cahoy JD 2008 A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function J Neurosci 28 1 264 78 18171944 PMC6671143 source
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- cites [79] Gaultier A 2009 Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis J Cell Sci 122 Pt 8 1155 62 19299462 PMC2714439 source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLrp4 is the gene mutated in Cenani-Lenz syndrome.
“Lrp4 is more commonly known as the gene defective in Cenani-Lenz syndrome [83–86]”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [83] Karner CM 2010 Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome PLoS One 5 4 e10418 20454682 PMC2861670 source
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- cites [84] Johnson EB 2005 Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice Hum Mol Genet 14 22 3523 38 16207730 source
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- cites [85] Johnson EB 2006 Defective splicing of Megf7/Lrp4, a regulator of distal limb development, in autosomal recessive mulefoot disease Genomics 88 5 600 9 16963222 source
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- cites [86] Li Y 2010 LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome Am J Hum Genet 86 5 696 706 20381006 PMC2869043 source
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InterpretationreasoningApoE4 promotes neuronal dysfunction by impairing Aβ turnover and accelerating amyloid deposition.
“by two distinct mechanisms: impairing the turnover of Aβ, thereby accelerating amyloid deposition”
Quote in the paperSubstantial claim- Rests on an assumption: Mechanisms of ApoE and Lrp4 function observed in mouse models apply to human Alzheimer's disease.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAgrin released from motor neurons signals through APP, MuSK, and Lrp4 to recruit nicotinic acetylcholine receptors.
“Agrin is released from the motor neuron and signals through APP, MuSK and Lrp4 to recruit nicotinic acetylcholine receptors (AChRs).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [88] Choi HY 2013 APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice Elife 2 e00220 23986861 PMC3748711 source
Not checked in the free run.
- cites [89] Kim N 2008 Lrp4 is a receptor for Agrin and forms a complex with MuSK Cell 135 2 334 42 18848351 PMC2933840 source
Not checked in the free run.
- cites [90] Zhang B 2008 LRP4 serves as a coreceptor of agrin Neuron 60 2 285 97 18957220 PMC2743173 source
Not checked in the free run.
The paper relies on this without support.
Mechanisms of ApoE/ApoE receptor signaling and ApoE4 effects observed in mouse models and cell studies are relevant to human Alzheimer's disease.
“ApoE4 targeted replacement mice have a reduction in dendritic spine complexity, a finding that is mirrored in human ApoE4 carriers [67].”
The paper relies on this without support.
The tripartite synapse framework captures the relevant sites of ApoE/ApoE receptor action in Alzheimer's disease.
“We divide our discussion based on the three components of the tripartite synapse – the post-synaptic spine, the axon terminal, and the astrocyte – and delineate the newly discovered roles of ApoE receptor signaling at each of these compartments (Figure 1).”
The paper relies on this without support.
Mechanisms of ApoE and Lrp4 function observed in mouse models apply to human Alzheimer's disease.
“ApoE4 promotes neuronal dysfunction at the earliest stages of the pathology, leading up to the clinical manifestation of AD”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The binding of RELN results in clustering and activation of VLDLr and APOEr2, initiating a signaling pathway that leads to activation of Dab1.
“The binding of RELN results in the clustering and activation of VLDLr and APOEr2, initiating a signaling pathway that leads to the activation of Dab1 (refs. 4,7–9).”
From Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man (2023) · cites this paper as [8]
APOE binds to cell surface receptors including LDLR, LRP1, VLDLR, and APOER2.
“APOE binds to cell surface receptors, such as low‐density lipoprotein receptor (LDLR), LDLR‐related protein 1 (LRP1), very low‐density lipoprotein receptor (VLDLR), and apolipoprotein E receptor 2 (APOER2 or LRP8). 2 , 14 , 15”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [14]
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“The allele frequency of ApoE4 is 15–20%, with some variation in incidence between populations [13].”
BackgroundCahoy, J. D., Emery, B., Kaushal, A., Foo, L. C., Zamanian, J. L., Christopherson, K. S., Xing, Y., Lubischer, J. L., Krieg, P. A., Krupenko, S. A., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4178-07.2008 · Cited by 3,129 · cited 1× · see citing works
“Lrp1 is highly expressed in astrocytes, where it is responsible for phagocytosis of degraded myelin [78, 79].”
BackgroundImmune attack: the role of inflammation in Alzheimer disease
Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3880 · Cited by 2,134 · see citing works
Regulation of NMDA receptor trafficking by amyloid-β
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“PP2B regulates levels and activity of striatal-enriched protein tyrosine phosphatase (STEP) [34].”
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Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
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“Briefly, large Ca2+ influx through NMDARs stimulates Ca2+/ calmodulin dependent protein kinase II (CaMKII) activity and G proteins, ultimately resulting in the insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and growth of the spine [48, 49].”
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“Conversely, expression of CB prevents some of the elevation in resting Ca2+ levels induced by Aβ [59].”
BackgroundApolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782 · cited 1× · see citing works
“There is an enormous amount of literature that explores the interaction between ApoE4 and Aβ, which has been reviewed in depth recently in [1, 17, 18]; therefore, this review will focus on the roles of ApoE and its receptors at the synapse.”
BackgroundSelf-citationAl-Atrache, Z., Cader, A., & Appelt, D. M. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.06.894 · Cited by 765 · see citing works
Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo
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“Astrocytes are capable of detecting synaptic activity through glutamatergic receptors [80].”
BackgroundLrp4 is a receptor for Agrin and forms a complex with MuSK
Kim, N., Stiegler, A. L., Cameron, T. O., Hallock, P. T., Gomez, A. M., Huang, J. H., Hubbard, S. R., Dustin, M. L., & Burden, S. J. (2008) · Cell · doi:10.1016/j.cell.2008.10.002 · Cited by 676 · see citing works
Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning
Weeber, E. J., Beffert, U., Jones, C., Christian, J. M., Förster, E., Sweatt, J. D., & Herz, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205147200 · Cited by 623 · cited 1× · see citing works
“Accordingly, when Reelin is applied to hippocampal slices, greater Ca2+ influx through opened NMDARs leads to increased long-term potentiation [29].”
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“Conversely, lower levels of Ca2+ influx preferentially activate the phosphatase calcineurin, which in turn activates protein phosphatase 1 (PP1) and STEP, resulting in the dephosphorylation of AMPARs and their removal from and long-term depression of the synapse (referred to as LTD) [50].”
InfluentialApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
Kanekiyo, T., Xu, H., & Bu, G. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.045 · Cited by 608 · see citing works
Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss
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Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders
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“Overt clinical symptoms typically do not appear until the underlying pathology is welldeveloped [8]; however, functional imaging studies suggest that changes in synaptic function occur several years before outward signs of the disease are apparent [9].”
BackgroundLRP4 serves as a coreceptor of Agrin
Zhang, B., Luo, S., Wang, Q., Suzuki, T., Xiong, W. C., & Mei, L. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.006 · Cited by 525 · see citing works
Reelin, lipoprotein receptors and synaptic plasticity
Herz, J., & Chen, Y. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn2009 · Cited by 524 · cited 2× · see citing works
“This reduces the phosphorylation of numerous targets of GSK3β, the most relevant of which in the context of AD is the microtubule-associated protein τ [25].”
BackgroundSelf-citationCentral Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism
Mahley, R. W. (2016) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.116.307023 · Cited by 516 · see citing works
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“Similar to Lrp1, the ApoE receptors Apoer2/Lrp8 and Vldlr form a complex with scaffolding proteins, such as PSD-95, and the glutamate receptors [21].”
BackgroundSelf-citationDeleterious Effects of Amyloid β Oligomers Acting as an Extracellular Scaffold for mGluR5
Renner, M., Lacor, P. N., Velasco, P. T., Xu, J., Contractor, A., Klein, W. L., & Triller, A. (2010) · Neuron · doi:10.1016/j.neuron.2010.04.029 · Cited by 468 · see citing works
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A neuron–glia signalling network in the active brain
Bezzi, P., & Volterra, A. (2001) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(00)00223-3 · Cited by 446 · cited 1× · see citing works
“Ion flow through these receptors causes alterations in intracellular Ca2+ stores that trigger the release of various substances from the astrocyte, including glutamate, D-serine, and ATP, which can then affect synaptic transmission [81].”
BackgroundLong-Term Potentiation: From CaMKII to AMPA Receptor Trafficking
Herring, B. E., & Nicoll, R. A. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021014-071753 · Cited by 425 · cited 1× · see citing works
“Briefly, large Ca2+ influx through NMDARs stimulates Ca2+/ calmodulin dependent protein kinase II (CaMKII) activity and G proteins, ultimately resulting in the insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and growth of the spine [48, 49].”
BackgroundKim, T., Vidal, G. S., Djurisic, M., William, C. M., Birnbaum, M. E., Garcia, K. C., Hyman, B. T., & Shatz, C. J. (2013) · Science · doi:10.1126/science.1242077 · Cited by 410 · see citing works
GABAergic network activation of glial cells underlies hippocampal heterosynaptic depression
Serrano, A., Haddjeri, N., Lacaille, J.-C., & Robitaille, R. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.5255-05.2006 · Cited by 398 · cited 1× · see citing works
“Adenosine signaling through adenosine A1 (A1A) receptors at the presynaptic membrane leads to a reduced release probability of glutamate-containing vesicles and thus reduced glutamatergic transmission [96] (Figure 5).”
BackgroundSignaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation
Mizuno, K. (2013) · Cellular Signalling · doi:10.1016/j.cellsig.2012.11.001 · Cited by 396 · cited 1× · see citing works
“In turn, PI3kinase initiates a signaling pathway that induces phosphorylation of LIM kinase-1 (LIMK-1), which in turn phosphorylates cofilin at an inhibitory site, blocking the actindepolymerizing activity of cofilin [62, 63].”
BackgroundChen, Y., Durakoglugil, M. S., Xian, X., & Herz, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914984107 · Cited by 368 · cited 2× · see citing works
“Thus, in the presence of ApoE4, the recycling of the Reelin receptors and the glutamate receptors trapped in the same vesicle back to the synapse is stalled, Reelin signaling is blunted and glutamate receptor homeostasis is impaired [72] (Figure 3).”
BackgroundSelf-citationMolecular mechanisms of dendrite stability
Koleske, A. J. (2013) · Nature reviews. Neuroscience · doi:10.1038/nrn3486 · Cited by 351 · cited 1× · see citing works
“Dendritic spines are the central sites of post-synaptic transmission, and the formation and elimination of spines is a dynamic process that continues throughout life and that is dependent on many extraneuronal and intraneuronal signals [60].”
BackgroundLDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction
Weatherbee, S. D., Anderson, K. V., & Niswander, L. A. (2006) · Development · doi:10.1242/dev.02696 · Cited by 351 · cited 1× · see citing works
“Importantly, the absolute requirement of Lrp4 for NMJ development in mice, but intriguingly not in humans [86] and cattle [91], means that mice that are completely deficient in Lrp4 die perinatally, which has precluded effective study of the role of Lrp4 in the CNS until recently [92].”
BackgroundRole of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease
Zhao, L., Ma, Q.-L., Calon, F., Harris-White, M. E., Yang, F., Lim, G. P., Morihara, T., Ubeda, O. J., Ambegaokar, S., Hansen, J. E., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1630 · Cited by 317 · cited 1× · see citing works
“Aβ oligomers reduce activity of LIMK, which in turns leads to dephosphorylated, active cofilin, depolymerization of actin filaments and the generation of actin rods [66].”
BackgroundAβ1-42 inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β
Jo, J., Whitcomb, D. J., Olsen, K. M., Kerrigan, T. L., Lo, S.-C., Bru-Mercier, G., Dickinson, B., Scullion, S., Sheng, M., Collingridge, G., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2785 · Cited by 305 · see citing works
Reelin modulates NMDA receptor activity in cortical neurons
Chen, Y., Beffert, U., Ertunc, M., Tang, T.-S., Kavalali, E. T., Bezprozvanny, I., & Herz, J. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1951-05.2005 · Cited by 299 · cited 1× · see citing works
“the NR2 subunits of NMDARs, which causes increased Ca2+ influx when the receptors are activated and also reduces NMDAR endocytosis [27, 28], thereby producing a large net influx of Ca2+ into the dendrite.”
BackgroundSelf-citationThe involvement of Reelin in neurodevelopmental disorders
Folsom, T. D., & Fatemi, S. H. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.08.015 · Cited by 275 · cited 1× · see citing works
“Alterations in Reelin signaling in the adult brain have been implicated in numerous neurodevelopmental disorders including schizophrenia, autism, and mood disorders [43].”
BackgroundDean, D. C., Jerskey, B. A., Chen, K., Protas, H., Thiyyagura, P., Roontiva, A., O'Muircheartaigh, J., Dirks, H., Waskiewicz, N., Lehman, K., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2013.4544 · Cited by 263 · see citing works
Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes
Chung, W.-S., Verghese, P. B., Chakraborty, C., Joung, J., Hyman, B. T., Ulrich, J. D., Holtzman, D. M., & Barres, B. A. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1609896113 · Cited by 242 · cited 1× · see citing works
“Astrocytes actively partake in synaptic pruning by phagocytosing synaptosomes, and ApoE isoforms differentially affect this process, with ApoE4 limiting the ability of astrocytes to prune synapses [76, 77].”
BackgroundZhu, L.-Q., Wang, S.-H., Liu, D., Yin, Y.-Y., Tian, Q., Wang, X.-C., Wang, Q., Chen, J.-G., & Wang, J.-Z. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3321-07.2007 · Cited by 234 · cited 1× · see citing works
“GSK3β activation reduces synaptic long-term potentiation (LTP) and provides a potential biochemical mechanism by which Aβ can induce τ hyperphosphorylation [39].”
BackgroundAPOE genotype alters glial activation and loss of synaptic markers in mice
Zhu, Y., Nwabuisi‐Heath, E., Dumanis, S. B., Tai, L. M., Yu, C., Rebeck, G. W., & Ladu, M. J. (2012) · Glia · doi:10.1002/glia.22289 · Cited by 224 · cited 1× · see citing works
“When discussing effects of ApoE receptor signaling on the astrocyte, it is important to point out that glial activation is affected by ApoE isoform, with ApoE4 causing the greatest activation [97].”
BackgroundBock, H. H., Jossin, Y., Liu, P., Förster, E., May, P., Goffinet, A. M., & Herz, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306416200 · Cited by 213 · cited 1× · see citing works
“Briefly, Reelin signaling activates PI3kinase, as described above [61].”
MethodSelf-citationTyrosine phosphatase STEP is a tonic brake on induction of long-term potentiation
Pelkey, K. A., Askalan, R., Paul, S., Kalia, L. V., Nguyen, T.-H., Pitcher, G. M., Salter, M. W., & Lombroso, P. J. (2002) · Neuron · doi:10.1016/s0896-6273(02)00633-5 · Cited by 208 · cited 6× · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript the NR2 subunits of NMDARs, which causes increased Ca2+ influx when the receptors are activated and also reduces NMDAR endocytosis [27, 28], thereby producing a large net influx of Ca2+ into the dendrite.”
BackgroundInfluentialApolipoprotein E4 Forms a Molten Globule
Morrow, J. A., Hatters, D. M., Lu, B., Höchtl, P., Oberg, K. A., Rupp, B., & Weisgraber, K. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204898200 · Cited by 204 · see citing works
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“As a result, actin polymerization and dendritic spine growth exhibit a net increase in the presence of Reelin, and mice that overexpress Reelin have higher spine density and increased spine complexity [64, 65].”
BackgroundReceptor Clustering Is Involved in Reelin Signaling
Strasser, V., Fasching, D., Hauser, C., Mayer, H., Bock, H. H., Hiesberger, T., Herz, J., Weeber, E. J., Sweatt, J. D., Pramatarova, A., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.3.1378-1386.2004 · Cited by 193 · cited 1× · see citing works
“When Apoer2/Lrp8 and Vldlr are bound by Reelin, they cluster and induce phosphorylation of the adaptor protein Disabled-1 (Dab1), which has several important consequences [25, 26].”
BackgroundSelf-citationJi, Y., Gong, Y., Gan, W., Beach, T., Holtzman, D. M., & Wisniewski, T. (2003) · Neuroscience · doi:10.1016/j.neuroscience.2003.08.007 · Cited by 189 · cited 1× · see citing works
“While direct opposition of Reelin and Aβ at the level of actin polymerization, or an effect of ApoE on this process, has yet to be definitively shown, it is important to point out that ApoE4 targeted replacement mice have a reduction in dendritic spine complexity, a finding that is mirrored in human ApoE4 carriers [67…”
ResultChin, J., Massaro, C. M., Palop, J. J., Thwin, M. T., Yu, G.-Q., Bien-Ly, N., Bender, A., & Mucke, L. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3758-06.2007 · Cited by 188 · cited 1× · see citing works
“With age, Reelin levels are reduced in the brain and in AD, Reelin levels are particularly reduced in the entorhinal cortex [44].”
BackgroundFerreira, I. L., Bajouco, M., Mota, S. I., Auberson, Y. P., Oliveira, C. R., & Rego, A. C. (2011) · Cell Calcium · doi:10.1016/j.ceca.2011.11.008 · Cited by 185 · see citing works
Striatal enriched phosphatase 61 dephosphorylates Fyn at phosphotyrosine 420
Nguyen, T.-H., Liu, J., & Lombroso, P. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111683200 · Cited by 185 · cited 1× · see citing works
“STEP additionally dephosphorylates and deactivates Fyn, enhancing the overall effect of STEP on NMDAR endocytosis [36].”
BackgroundReelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density
Rogers, J. T., Rusiana, I., Trotter, J., Zhao, L., Donaldson, E., Pak, D. T. S., Babus, L. W., Peters, M., Banko, J. L., Chavis, P., et al. (2011) · Learning & Memory · doi:10.1101/lm.2153511 · Cited by 181 · cited 1× · see citing works
“This effect is mirrored in vivo by the finding that intraventricular injection of Reelin in mice improves learning and memory [30].”
ResultLi, Y., Pawlik, B., Elcioglu, N., Aglan, M., Kayserili, H., Yigit, G., Percin, F., Goodman, F., Nürnberg, G., Cenani, A., et al. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.03.004 · Cited by 171 · see citing works
Self-citationv-SNARE composition distinguishes synaptic vesicle pools
Hua, Z., Leal-Ortiz, S., Foss, S. M., Waites, C. L., Garner, C. C., Voglmaier, S. M., & Edwards, R. H. (2011) · Neuron · doi:10.1016/j.neuron.2011.06.010 · Cited by 168 · cited 1× · see citing works
“This Ca2+ elevation specifically increases the fusion of vesicles containing vesicle-associated membrane protein 7 (VAMP7), an alternative ‘soluble N-ethylmaleimide sensitive factor attachment protein receptor’ (SNARE) protein that participates in spontaneous vesicle release [74].”
BackgroundCalcium signalling and Alzheimer's disease
Berridge, M. J. (2011) · Neurochemical Research · doi:10.1007/s11064-010-0371-4 · Cited by 167 · cited 2× · see citing works
“Additionally, there are other Ca2+ sensing molecules, like calmodulin, which regulates the activity of both Ca2+ sensitive kinases (CaMKII) as well as phosphatases (calcineurin), and whose levels are also disrupted in AD [51].”
BackgroundIncreased intraneuronal resting [Ca<sup>2+</sup>] in adult Alzheimer’s disease mice
Lopez, J. R., Lyckman, A., Oddo, S., LaFerla, F. M., Querfurth, H. W., & Shtifman, A. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05135.x · Cited by 162 · cited 1× · see citing works
“This has been shown in AD mouse models, particularly in the area surrounding amyloid plaques, and application of Aβ to hippocampal slices elevates resting Ca2+ levels [52, 53].”
BackgroundUnderstanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure
Zhong, N., & Weisgraber, K. H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.r800009200 · Cited by 159 · cited 2× · see citing works
“ApoE2 has a cysteine at both positions, ApoE3 has a cysteine at position 112 and an arginine at position 158, and ApoE4 has arginines at both positions [68].”
BackgroundMore than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration
Lane-Donovan, C., Philips, G. T., & Herz, J. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.005 · Cited by 158 · cited 6× · see citing works
“A uthor M anuscript A uthor M anuscript (LDLR), LDLR-related receptor 1 (LRP1), very-low-density lipoprotein receptor (VLDLR), megalin (LRP2), apolipoprotein E receptor 2 (Apoer2 or LRP8), LRP4, and LRP1b [1].”
BackgroundInfluentialSelf-citationReelin signaling antagonizes β-amyloid at the synapse
Durakoglugil, M. S., Chen, Y., White, C. L., Kavalali, E. T., & Herz, J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908176106 · Cited by 153 · see citing works
Self-citationNew insights into Reelin-mediated signaling pathways
Lee, G. H., & D’Arcangelo, G. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00122 · Cited by 144 · cited 1× · see citing works
“The primary ligand for these receptors in the CNS is not ApoE, but rather the glycoprotein Reelin [22].”
BackgroundAbnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice
Johnson, E. B., Hammer, R. E., & Herz, J. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi381 · Cited by 141 · see citing works
Self-citationImpaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation
Heeren, J., Grewal, T., Laatsch, A., Becker, N., Rinninger, F., Rye, K.-A., & Beisiegel, U. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409324200 · Cited by 139 · cited 1× · see citing works
“However, when ApoE4 is present, the final recycling step is delayed and the process is stalled in the endosome, presumably due to the propensity of ApoE4 to form molten globules at the lower pH of the endosome [69, 71].”
BackgroundBal, M., Leitz, J., Reese, A. L., Ramirez, D. M. O., Durakoglugil, M., Herz, J., Monteggia, L. M., & Kavalali, E. T. (2013) · Neuron · doi:10.1016/j.neuron.2013.08.024 · Cited by 131 · cited 3× · see citing works
“Reelin does not affect other SNARE protein-mediated signaling [73] (Figure 4).”
BackgroundInfluentialSelf-citationRole of glial cells in the formation and maintenance of synapses
Pfrieger, F. W. (2010) · Brain Research Reviews · doi:10.1016/j.brainresrev.2009.11.002 · Cited by 124 · cited 2× · see citing works
“In the central nervous system (CNS), cholesterol and phospholipids produced by glia are vital for the formation and maintenance of healthy synapses [4].”
BackgroundLow-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis
Gaultier, A., Wu, X., Le Moan, N., Takimoto, S., Mukandala, G., Akassoglou, K., Campana, W. M., & Gonias, S. L. (2009) · Journal of Cell Science · doi:10.1242/jcs.040717 · Cited by 118 · cited 1× · see citing works
“Lrp1 is highly expressed in astrocytes, where it is responsible for phagocytosis of degraded myelin [78, 79].”
BackgroundLane-Donovan, C., Wong, W. M., Durakoglugil, M. S., Wasser, C. R., Jiang, S., Xian, X., & Herz, J. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1054-16.2016 · Cited by 115 · cited 1× · see citing works
“Complete genetic deficiency of ApoE, or deficiency limited to the CNS, results in a reduction of synapse number that is at least partially due to loss of astrocyte-derived particles [6].”
BackgroundSelf-citationReelin mouse mutants as models of cortical development disorders
D’Arcangelo, G. (2005) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2005.09.005 · Cited by 110 · cited 2× · see citing works
“In the adult brain, Reelin secretion by Cajal-Retzius neurons declines, as they are replaced by a subset of GABAergic interneurons that populate the cortex by tangential migration emanating from the medial ganglionic eminence, and by glutamatergic neurons within layer II of the entorhinal cortex, a region that is affe…”
BackgroundAlzheimer disease pathology in cognitively healthy elderly: A genome-wide study
Kramer, P. L., Xu, H., Woltjer, R. L., Westaway, S. K., Clark, D., Erten-Lyons, D., Kaye, J. A., Welsh-Bohmer, K. A., Troncoso, J. C., Markesbery, W. R., et al. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.01.010 · Cited by 108 · cited 1× · see citing works
“Some SNPs in the Reelin gene have been identified as being protective against AD and are hypothesized to increase Reelin levels in the presence of AD pathology [45]; however, definitive studies showing a protective effect of Reelin in humans are largely lacking.”
BackgroundAmino-terminal domain stability mediates apolipoprotein E aggregation into neurotoxic fibrils
Hatters, D. M., Zhong, N., Rutenber, E., & Weisgraber, K. H. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.06.080 · Cited by 105 · cited 1× · see citing works
“As a result, ApoE4 has a greater tendency to form molten globules over the other ApoE isoforms, as well as a greater propensity to aggregate at 37°C [69, 70].”
BackgroundLrp4 in astrocytes modulates glutamatergic transmission
Sun, X.-D., Li, L., Liu, F., Huang, Z.-H., Bean, J. C., Jiao, H.-F., Barik, A., Kim, S.-M., Wu, H., Shen, C., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4326 · Cited by 102 · cited 1× · see citing works
“In the astrocyte, Agrin signaling through Lrp4 leads to the increased release of ATP, which is subsequently broken down into adenosine in the extracellular milieu [95].”
BackgroundReelin protects against amyloid β toxicity in vivo
Lane-Donovan, C., Philips, G. T., Wasser, C. R., Durakoglugil, M. S., Masiulis, I., Upadhaya, A., Pohlkamp, T., Coskun, C., Kotti, T., Steller, L., et al. (2015) · Science Signaling · doi:10.1126/scisignal.aaa6674 · Cited by 96 · see citing works
Self-citationMak, A. C. Y., Pullinger, C. R., Tang, L. F., Wong, J. S., Deo, R. C., Schwarz, J.-M., Gugliucci, A., Movsesyan, I., Ishida, B. Y., Chu, C., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.2011 · Cited by 96 · cited 2× · see citing works
“As key components of cholesterol homeostasis, deficiency of either ApoE or LDLR in humans leads to severe hypercholesterolemia and premature atherosclerosis [3].”
BackgroundPresenilins function in ER calcium leak and Alzheimer's disease pathogenesis
Supnet, C. B., & Борисович, Б. И. (2011) · Cell Calcium · doi:10.1016/j.ceca.2011.05.013 · Cited by 95 · cited 1× · see citing works
“In general terms, there is an important role for presenilins in intracellular Ca2+ stores, which have been discussed in depth in other reviews [58].”
BackgroundSynapse rearrangements upon learning: from divergent–sparse connectivity to dedicated sub-circuits
Caroni, P., Chowdhury, A., & Lahr, M. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.08.011 · Cited by 85 · cited 1× · see citing works
“In turn, PI3kinase initiates a signaling pathway that induces phosphorylation of LIM kinase-1 (LIMK-1), which in turn phosphorylates cofilin at an inhibitory site, blocking the actindepolymerizing activity of cofilin [62, 63].”
BackgroundNakajima, C., Kulik, A., Frotscher, M., Herz, J., Schäfer, M., Bock, H. H., & May, P. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.444364 · Cited by 85 · see citing works
Self-citationThe amyloid beta ion channel hypothesis of Alzheimer’s disease
Shirwany, N. A., Payette, D. J., Xie, J., et al. (2007) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.a934 · Cited by 77 · cited 1× · see citing works
“Alternatively, Aβ oligomers have been proposed to themselves act as calcium leak channels [57].”
BackgroundKobro‐Flatmoen, A., Nagelhus, A., & Witter, M. P. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.05.012 · Cited by 74 · cited 1× · see citing works
“In the adult brain, Reelin secretion by Cajal-Retzius neurons declines, as they are replaced by a subset of GABAergic interneurons that populate the cortex by tangential migration emanating from the medial ganglionic eminence, and by glutamatergic neurons within layer II of the entorhinal cortex, a region that is affe…”
BackgroundChoi, H. Y., Liu, Y., Tennert, C., Sugiura, Y., Karakatsani, A., Kröger, S., Johnson, E. B., Hammer, R. E., Lin, W., & Herz, J. (2013) · eLife · doi:10.7554/elife.00220 · Cited by 71 · see citing works
Self-citationBosch, C., Masachs, N., Exposito-Alonso, D., Martínez, A., Teixeira, C. M., Fernaud, I., Pujadas, L., Ulloa, F., Comella, J. X., DeFelipe, J., et al. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhw216 · Cited by 70 · cited 1× · see citing works
“As a result, actin polymerization and dendritic spine growth exhibit a net increase in the presence of Reelin, and mice that overexpress Reelin have higher spine density and increased spine complexity [64, 65].”
BackgroundChen, Y., Chen, K., Zhang, J., Li, X., Shu, N., Wang, J., Zhang, Z., & Reiman, E. M. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2014.302 · Cited by 67 · see citing works
Johnson, E. B., Steffen, D. J., Lynch, K. W., & Herz, J. (2006) · Genomics · doi:10.1016/j.ygeno.2006.08.005 · Cited by 62 · see citing works
Self-citationDrögemüller, C., Leeb, T., Harlizius, B., Tammen, I., Distl, O., Höltershinken, M., Gentile, A., Duchesne, A., & Eggen, A. (2007) · BMC Genetics · doi:10.1186/1471-2156-8-5 · Cited by 60 · cited 1× · see citing works
“Importantly, the absolute requirement of Lrp4 for NMJ development in mice, but intriguingly not in humans [86] and cattle [91], means that mice that are completely deficient in Lrp4 die perinatally, which has precluded effective study of the role of Lrp4 in the CNS until recently [92].”
BackgroundKarner, C. M., Dietrich, M. F., Johnson, E. B., Kappesser, N., Tennert, C., Percin, F., Wollnik, B., Carroll, T. J., & Herz, J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010418 · Cited by 57 · see citing works
Self-citation<scp>APOE</scp> genotype affects the pre‐synaptic compartment of glutamatergic nerve terminals
Dumanis, S. B., DiBattista, A. M., Miessau, M., Moussa, C. E. H., & Rebeck, G. W. (2013) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07908.x · Cited by 55 · cited 1× · see citing works
“Studies in ApoE4 targeted replacement (TR) mice have shown decreased levels of glutamate, increased levels of glutamine (the precursor of glutamate), and a late increase in vesicular glutamate transporter 1 (vglut1), suggesting a reduced ability of presynaptic ApoE4 neurons to convert glutamine to glutamate and a comp…”
BackgroundSubjective Memory Complaints in APOE ɛ 4 Carriers are Associated with High Amyloid-β Burden
Zwan, M. D., Villemagne, V. L., Doré, V., Buckley, R. F., Bourgeat, P., Veljanoski, R., Salvado, O., Williams, R., Margison, L., Rembach, A., et al. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150446 · Cited by 53 · see citing works
Selcen, D., Ohkawara, B., Shen, X.-M., McEvoy, K., Ohno, K., & Engel, A. G. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2015.0853 · Cited by 53 · cited 1× · see citing works
“Lrp4 is more commonly known as the gene defective in Cenani-Lenz syndrome [83–86], and for its role in neuromuscular junction (NMJ) development and in the maintenance of the adult NMJ, which is highlighted clinically by the role of anti-Lrp4 and anti-MuSK antibodies in myasthenia gravis [87].”
BackgroundLista, S., Molinuevo, J. L., Cavedo, E., Rami, L., Amouyel, P., Teipel, S. J., Garaci, F., Toschi, N., Habert, M.-O., Blennow, K., et al. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-150202 · Cited by 53 · cited 1× · see citing works
“, patients who perform normally on standardized memory tests, but nevertheless report subjective memory impairment) have generally higher levels of Aβ deposition on positron emission tomography (PET) scanning [10, 11].”
BackgroundLRP1 is critical for the surface distribution and internalization of the NR2B NMDA receptor subtype
Maier, W., Bednorz, M., Meister, S., Roebroek, A., Weggen, S., Schmitt, U., & Pietrzik, C. U. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-25 · Cited by 50 · cited 1× · see citing works
“For example, Lrp1 interacts with the N-methyl-D-aspartate receptor (NMDAR), promoting the endocytosis of NMDAR from the cell surface [19].”
BackgroundSynaptic plasticity and cognitive function are disrupted in the absence of Lrp4
Gomez, A. M., Froemke, R. C., & Burden, S. J. (2014) · eLife · doi:10.7554/elife.04287 · Cited by 47 · cited 1× · see citing works
“Importantly, these mice have a reduction of synaptic transmission and long-term potentiation [93], and this finding is mimicked in mice carrying a hypomorphic allele for Lrp4 [94].”
BackgroundA genetics-based biomarker risk algorithm for predicting risk of Alzheimer's disease
Lutz, M. W., Sundseth, S. S., Burns, D. K., Saunders, A. M., Hayden, K. M., Burke, J. R., Welsh‐Bohmer, K. A., Roses, A. D., & Initiative, A. D. N. (2016) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2015.12.002 · Cited by 30 · see citing works
Lrp4 domains differentially regulate limb/brain development and synaptic plasticity
Pohlkamp, T., Durakoglugil, M., Lane-Donovan, C., Xian, X., Johnson, E. B., Hammer, R. E., & Herz, J. (2015) · PLOS ONE · doi:10.1371/journal.pone.0116701 · Cited by 28 · cited 1× · see citing works
“Importantly, these mice have a reduction of synaptic transmission and long-term potentiation [93], and this finding is mimicked in mice carrying a hypomorphic allele for Lrp4 [94].”
BackgroundSelf-citation
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Liver X receptors in lipid signalling and membrane homeostasis
Wang, B., & Tontonoz, P. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0037-x · Cited by 722 · see citing works
Microglia-Mediated Synapse Loss in Alzheimer's Disease
Rajendran, L., & Paolicelli, R. C. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.1136-17.2017 · Cited by 355 · see citing works
“ApoE is a major regulator of lipid homeostasis present in three allelic variants 2, 3, or 4; and although its function is varied (for review, see Lane-Donovan and Herz, 2017), it primarily transports cholesterol to neurons via specific ApoE receptors.”
BackgroundBeyond the neuron–cellular interactions early in Alzheimer disease pathogenesis
Henstridge, C. M., Hyman, B. T., & Spires-Jones, T. L. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0113-1 · Cited by 348 · see citing works
The integration of inflammaging in age-related diseases
Fülöp, T., Witkowski, J. M., Olivieri, F., & Larbi, A. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2018.09.003 · Cited by 356 · see citing works
APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease
Li, Z., Shue, F., Zhao, N., Shinohara, M., & Bu, G. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00413-4 · Cited by 306 · see citing works
Challenges and hopes for Alzheimer’s disease
Tatulian, S. A. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.01.016 · Cited by 291 · see citing works
Apolipoprotein E in lipid metabolism and neurodegenerative disease
Yang, L. G., March, Z. M., Stephenson, R. A., & Narayan, P. S. (2023) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2023.05.002 · Cited by 286 · see citing works
“The best understoodmechanism of transport is via the low-density lipoprotein receptor (LDLR) [14], and novel APOE receptors are emerging [15,16].”
Rab GTPases and Membrane Trafficking in Neurodegeneration
Kiral, F. R., Kohrs, F. E., Jin, E. J., & Hiesinger, P. R. (2018) · Current Biology · doi:10.1016/j.cub.2018.02.010 · Cited by 239 · see citing works
Kemp, S. B., Carpenter, E. S., Steele, N. G., Donahue, K. L., Nwosu, Z. C., Pacheco, A., Velez-Delgado, A., Menjivar, R. E., Lima, F., The, S., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3929 · Cited by 197 · see citing works
“…our scRNA-seq data that KPC tumor cells express 4 of the major ApoE receptors: low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), low-density lipoprotein receptor related protein 1 (LRP1), and low-density lipoprotein receptor-related protein 8 (LRP8) (34) (Fig.”
BackgroundInfluentialNoncoding RNAs in Alzheimer's disease
Idda, M. L., Munk, R. B., Abdelmohsen, K., & Gorospe, M. (2018) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1463 · Cited by 206 · see citing works
“Apolipoprotein E (APOE) is a lipid carrier present in the peripheral and central nervous systems (CNS) that supports membrane homeostasis and injury repair in the brain (Lane-Donovan & Herz, 2017; Mahley, 2016; Zhao, Liu, Qiao, & Bu, 2017).”
BackgroundAPOE4 derived from astrocytes leads to blood–brain barrier impairment
Jackson, R. J., Meltzer, J. C., Nguyen, H., Commins, C., Bennett, R. E., Hudry, E., & Hyman, B. T. (2022) · Brain · doi:10.1093/brain/awab478 · Cited by 205 · see citing works
Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man
Lopera, F., Marino, C., Chandrahas, A. S., O’Hare, M., Villalba-Moreno, N. D., Aguillon, D., Baena, A., Sanchez, J. S., Vila-Castelar, C., Ramirez Gomez, L., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02318-3 · Cited by 192 · see citing works
Updates in Alzheimer's disease: from basic research to diagnosis and therapies
Liu, E., Zhang, Y., & Wang, J. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00432-x · Cited by 220 · see citing works
“VLDL-R and LDL-R are predominantly located on the astrocyte membrane, while LRP is mainly distributed in neurons and activated astrocytes [45].”
BackgroundPark, J., Jang, S., Lee, D., Lee, J.-H., Kang, U., Chang, H., Kim, H. J., Han, S.-H., Seo, J., Choi, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20440-5 · Cited by 224 · see citing works
Moulton, M. J., Barish, S., Ralhan, I., Chang, J., Goodman, L. D., Harland, J. G., Marcogliese, P. C., Johansson, J. O., Ioannou, M. S., & Bellen, H. J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2112095118 · Cited by 180 · see citing works
Role of the peripheral innate immune system in the development of Alzheimer's disease
Page, A. Y. L., Dupuis, G., Frost, E. H., Larbi, A., Pawelec, G., Witkowski, J. M., & Fülöp, T. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.12.019 · Cited by 159 · see citing works
“The proinflammatory effect of these microbial products may be enhanced by the well-known ApoE4 genotype (Lane-Donovan and Herz, 2017) as it was shown in mice (Vitek et al.”
Beyond the CNS: The many peripheral roles of APOE
Martínez-Martínez, A. B., Torres-Perez, E., Devanney, N., Del Moral, R., Johnson, L. A., & Arbones-Mainar, J. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104809 · Cited by 149 · see citing works
Huang, Y.-W. A., Zhou, B., Nabet, A. M., Wernig, M., & Südhof, T. C. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.2994-18.2019 · Cited by 152 · see citing works
Tzioras, M., Davies, C., Newman, A., Jackson, R., & Spires‐Jones, T. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12529 · Cited by 147 · see citing works
Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease
Wadhwani, A. R., Affaneh, A., Van Gulden, S., & Kessler, J. A. (2019) · Annals of Neurology · doi:10.1002/ana.25455 · Cited by 142 · see citing works
“Effects of APOE isoform on calcium homeostasis have heretofore been attributed to differential binding of glial APOE on neuronal APOE receptors.(53) Our observations indicate that endogenous expression of E4 in neurons sensitizes them to calcium dysregulation, independently of glial APOE.”
BackgroundThe Epigenetics of Alzheimer’s Disease: Factors and Therapeutic Implications
Liu, X., Jiao, B., & Shen, L. H. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00579 · Cited by 147 · see citing works
“Among them, the ε4 isoform of apolipoprotein E (ApoE4) is well-known as the strongest genetic risk factor for LOAD (Lane-Donovan and Herz, 2017).”
BackgroundInfluentialMillan, M. J. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.004 · Cited by 146 · see citing works
Machine learning and digital biomarkers can detect early stages of neurodegenerative diseases
Chudzik, A., Śledzianowski, A., & Przybyszewski, A. W. (2024) · Sensors · doi:10.3390/s24051572 · Cited by 122 · see citing works
“Processes correlated with AD begin over 30 years, whereas cognitive changes begin over about 15–11 years, before the first AD symptoms [6,7].”
BackgroundRobert, J., Button, E. B., Yuen, B., Gilmour, M., Kang, K., Bahrabadi, A., Stukas, S. K., Zhao, W., Kulić, I., & Wellington, C. L. (2017) · eLife · doi:10.7554/elife.29595 · Cited by 113 · see citing works
“ApoE isoforms differentially reduce amyloid accumulation in bipartite vessels Genetic variation in APOE represents the most common genetic risk factor for AD, with APOE4 being detrimental and APOE2 protective (Zlokovic, 2013).”
Neuroinflammation in Alzheimer’s disease: insights from peripheral immune cells
Zhang, Q., Yang, G., Luo, Y., Jiang, L., Chi, H., & Tian, G. (2024) · Immunity & Ageing · doi:10.1186/s12979-024-00445-0 · Cited by 127 · see citing works
New therapeutics beyond amyloid-β and tau for the treatment of Alzheimer’s disease
Zhang, F., Zhong, R.-J., Cheng, C., Li, S., & Le, W.-D. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-00565-5 · Cited by 105 · see citing works
The cell biology of APOE in the brain
Windham, I. A., & Cohen, S. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.09.004 · Cited by 103 · see citing works
Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease
Xian, X., Pohlkamp, T., Durakoglugil, M. S., Wong, C. H., Beck, J. K., Lane-Donovan, C., Plattner, F., & Herz, J. (2018) · eLife · doi:10.7554/elife.40048 · Cited by 98 · see citing works
“It is present both pre- as well as postsynaptically where it primarily functions as a receptor for Reelin (Bal et al., 2013; Beffert et al., 2005; Lane-Donovan and Herz, 2017).”
BackgroundResultInfluentialSelf-citationThe ApoE receptors Vldlr and Apoer2 in central nervous system function and disease
Lane-Donovan, C., & Herz, J. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075507 · Cited by 94 · see citing works
Self-citationRoles of ApoE4 on the Pathogenesis in Alzheimer’s Disease and the Potential Therapeutic Approaches
Sun, Y.-Y., Wang, Z., & Huang, H. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01365-1 · Cited by 95 · see citing works
Consequences of Metabolic Disruption in Alzheimer's Disease Pathology
Ryu, J. C., Zimmer, E. R., Rosa‐Neto, P., & Yoon, S. O. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00755-y · Cited by 84 · see citing works
The Ubiquitin System in Alzheimer’s Disease
Harris, L. D., Jasem, S., & Licchesi, J. D. F. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-38266-7_8 · Cited by 76 · see citing works
Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation
Saroja, S. R., Gorbachev, K., Julia, T., Goate, A. M., & Pereira, A. C. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2108870119 · Cited by 75 · see citing works
Chiesa, P. A., Cavedo, E., Vergallo, A., Lista, S., Potier, M., Habert, M., Dubois, B., Thiebaut de Schotten, M., Hampel, H., and the INSIGHT‐preAD study group, et al. (2019) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2019.03.006 · Cited by 66 · see citing works
From degenerative disease to malignant tumors: Insight to the function of ApoE
Miao, G., Zhuo, D., Han, X. N., Yao, W., Liu, C., Liu, H., Cao, H., Sun, Y., Chen, Z., & Feng, T. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114127 · Cited by 71 · see citing works
Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics
Olivier, I. S., Cacabelos, R., & Naidoo, V. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113594 · Cited by 71 · see citing works
The Potential Role of Ferroptosis in Alzheimer’s Disease
Zhang, G., Zhang, Y.-R., Shen, Y., Wang, Y., Zhao, M. L., & Sun, L. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201369 · Cited by 69 · see citing works
Essayan-Perez, S., & Südhof, T. C. (2023) · Neuron · doi:10.1016/j.neuron.2023.07.005 · Cited by 65 · see citing works
A role of low-density lipoprotein receptor-related protein 4 (LRP4) in astrocytic Aβ clearance
Zhang, H., Chen, W., Tan, Z., Zhang, L., Dong, Z., Cui, W., Zhao, K., Wang, H., Jing, H., Cao, R., et al. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.0250-20.2020 · Cited by 58 · see citing works
“Third, Ab clearance is regulated by LDLR family members in particular LDLR and LRP1 (LDLR-related protein 1) (LaneDonovan et al., 2014; Lane-Donovan and Herz, 2017).”
BackgroundHishimoto, A., Pletnikova, O., Lang, D. L., Troncoso, J. C., Egan, J. M., & Liu, Q.-R. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0475-2 · Cited by 62 · see citing works
Pericytes Across the Lifetime in the Central Nervous System
Bennett, H. C., & Kim, Y. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.627291 · Cited by 47 · see citing works
Apolipoprotein E and Atherosclerosis
Marais, A. D. (2021) · Current Atherosclerosis Reports · doi:10.1007/s11883-021-00933-4 · Cited by 48 · see citing works
The translational potential of cholesterol-based therapies for neurological disease
Valenza, M., Birolini, G., & Cattaneo, E. F. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00864-5 · Cited by 48 · see citing works
László, Z. I., & Lele, Z. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.972059 · Cited by 49 · see citing works
“In addition, APOE4 also influences vesicular turnover and receptor recycling leading to altered Reelin and glutamate signaling (Lane-Donovan and Herz, 2017).”
BackgroundXun, C., Ge, L., Tang, F. R., Wang, L., Zhuo, Y., Long, L., Qi, J., Hu, L., Duan, D., Chen, P., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110584 · Cited by 44 · see citing works
NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
Pohlkamp, T., Xian, X., Wong, C. H. Y., Durakoglugil, M. S., Werthmann, G. C., Saido, T. C., Evers, B. M., White, C. L., Connor, J., Hammer, R. E., et al. (2021) · eLife · doi:10.7554/elife.72034 · Cited by 44 · see citing works
“We previously showed that ApoE4, in contrast to ApoE3 and ApoE2, prevents Reelin- mediated glutamate receptor insertion at the synapse, a state we refer to as ApoE4- mediated Reelin resistance (Chen et al., 2010; Durakoglugil et al., 2009; Lane- Donovan and Herz, 2017; Lane- Donovan et al., 2014; Xian et al., 2018).”
BackgroundInfluentialSelf-citationHan, J. S., Lu, C., Meng, Q., Halim, A., Yean, T. J., & Wu, G. (2019) · Nutrition & Metabolism · doi:10.1186/s12986-019-0409-9 · Cited by 39 · see citing works
A multi‐hit hypothesis for an <i>APOE4</i> ‐dependent pathophysiological state
Steele, O. G., Stuart, A. C., Minkley, L., Shaw, K., Bonnar, O., Anderle, S., Penn, A. C., Rusted, J., Serpell, L., Hall, C., et al. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15685 · Cited by 44 · see citing works
“Homeostatic control of cellular calcium levels is crucial for regulating neuronal activity and a myriad of processes including cell signalling cascades, organelle function and gene expression (Foster, 2007; Lane-Donovan et al., 2014; Lane-Donovan & Herz, 2017).”
BackgroundLong Non-coding RNA: Insight Into Mechanisms of Alzheimer's Disease
Lan, Z., Chen, Y., Jin, J., Xu, Y., & Zhu, X. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.821002 · Cited by 45 · see citing works
Neuronal ApoE4 in Alzheimer’s disease and potential therapeutic targets
Zhang, L., Xia, Y., & Gui, Y. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1199434 · Cited by 41 · see citing works
“Kounnas et al. demonstrated that LRP 1 binds to Kunitzcontaining eggs outside the cyto-soluble APP of the leukocyte inhibitor (KPI) domain (APP 751 and APP 770) and mediates their cellular catabolism (Kounnas et al., 1995; Trommsdorff et al., 1998; Pietrzik et al., 2004).”
BackgroundInfluentialWelcome, M. O. (2020) · PharmaNutrition · doi:10.1016/j.phanu.2020.100176 · Cited by 41 · see citing works
Revolution of Resting-State Functional Neuroimaging Genetics in Alzheimer’s Disease
Chiesa, P. A., Cavedo, E., Lista, S., Thompson, P. M., & Hampel, H. J. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.06.002 · Cited by 34 · see citing works
“Regulates amyloid-b (Ab) oligomerization, aggregation, and receptor-mediated clearance, brain lipid transport, glucose metabolism, neuronal signaling, and neuroinflammation [26,82,83].”
BackgroundLilrB3 is a putative cell surface receptor of APOE4
Zhou, J., Wang, Y., Huang, G., Yang, M., Zhu, Y., Jin, C., Jing, D., Ji, K., & Shi, Y. (2023) · Cell Research · doi:10.1038/s41422-022-00759-y · Cited by 44 · see citing works
“This is also true for a number of other cell surface receptors.(1,62,86,87) In contrast to TREM2, the LilrB/PirB family receptors contain the ITIMs on the intracellular side, binding of two APOE4 molecules to two LilrB3 receptors effectively brings their respective ITIMs to close proximity.”
BackgroundEmerging Role of microRNAs in Dementia
Ramakrishna, S., & Muddashetty, R. S. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.01.046 · Cited by 38 · see citing works
Evolving therapeutic interventions for the management and treatment of Alzheimer’s disease
Ahmad, F., Karan, A., Sharma, R., Sharma, N. S., Sundar, V., Jayaraj, R. L., Mukherjee, S., & DeCoster, M. A. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102229 · Cited by 38 · see citing works
SynBot is an open-source image analysis software for automated quantification of synapses
Savage, J. T., Ramirez, J. J., Risher, W. C., Wang, Y., Irala, D., & Eroğlu, Ç. (2024) · Cell Reports Methods · doi:10.1016/j.crmeth.2024.100861 · Cited by 51 · see citing works
“10 Therefore, studying synapse connectivity is crucial to understanding how neuronal circuits are established during development, remodeled throughout life, and impacted by diseases.”
Ramakrishna, S., Jhaveri, V., Konings, S. C., Nawalpuri, B., Chakraborty, S., Holst, B., Schmid, B., Gouras, G. K., Freude, K., & Muddashetty, R. S. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.0435-21.2021 · Cited by 33 · see citing works
Surala, M., Soso-Zdravkovic, L., Munro, D. A. D., Rifat, A., Ouk, K., Vida, I., Priller, J., & Madry, C. (2024) · EMBO Reports · doi:10.1038/s44319-024-00130-9 · Cited by 36 · see citing works
“While IL-10 plays a role in synapse formation (Lim et al, 2013), ApoE controls the rate of synaptic pruning by astrocytes (Chung et al, 2016) and can affect glutamatergic transmission in multiple ways via signaling through synaptic ApoE receptors (Lane-Donovan and Herz, 2017).”
BackgroundThe role of UNC5C in Alzheimer’s disease
Li, Q., Wang, B.-L., Sun, F.-R., Li, J., Cao, X., & Tan, L. (2018) · Annals of Translational Medicine · doi:10.21037/atm.2018.04.43 · Cited by 28 · see citing works
Mata‐Balaguer, T., Cuchillo‐Ibáñez, I., Calero, M., Ferrer, I., & Sáez‐Valero, J. (2018) · The FASEB Journal · doi:10.1096/fj.201700736rr · Cited by 28 · see citing works
“The possibility that reelin dysfunction and the alteration of ApoER2 processing ultimately influences synaptic function (67, 68) points to a role for these proteins in AD progression.”
BackgroundOpposing Roles of apolipoprotein E in aging and neurodegeneration
Hudry, E., Klickstein, J., Cannavo, C., Jackson, R., Muzikansky, A., Gandhi, S., Urick, D., Sargent, T., Wrobleski, L., Roe, A. D., et al. (2019) · Life Science Alliance · doi:10.26508/lsa.201900325 · Cited by 30 · see citing works
“…between A β and speci fi c cellular receptors (such as APP itself, as recently reported [Wang et al, 2017], TREM2 [Yeh et al, 2016], or any other APOE receptors [Holtzman et al, 2012; Lane-Donovan & Herz, 2017]) to initiate various deleterious molecular cascades in neurons or even in glial cells.”
BackgroundJiang, S., Li, X., Li, Y., Chang, Z., Yuan, M., Zhang, Y., Zhu, H., Xiu, Y., Cong, H., Yin, L., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adg5116 · Cited by 30 · see citing works
“In particular, APOE, one of the abundant apolipoprotein released by astrocytes in the brain ( 37 ), is further enriched in ADEVs isolated from AQP4-Ab–seropositive patients with NMOSD.”
BackgroundMolecular recognition of the interaction between ApoE and the TREM2 protein
Mai, Z., Wei, W., Yu, H., Chen, Y., Wang, Y., & Ding, Y. (2022) · Translational Neuroscience · doi:10.1515/tnsci-2022-0218 · Cited by 28 · see citing works
Therapeutic potential of ApoE-mimetic peptides in CNS disorders: Current perspective
Ahmed, S., Pande, A. H., & Sharma, S. S. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114051 · Cited by 27 · see citing works
Mhatre‐Winters, I., Eid, A., Han, Y., Tieu, K., & Richardson, J. R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179829 · Cited by 26 · see citing works
Conservation and Innovation: Versatile Roles for LRP4 in Nervous System Development
DePew, A. T., & Mosca, T. J. (2021) · Journal of Developmental Biology · doi:10.3390/jdb9010009 · Cited by 23 · see citing works
Plasma Apolipoprotein E Monomer and Dimer Profile and Relevance to Alzheimer’s Disease
Patra, K., Giannisis, A., Edlund, A. K., Sando, S. B., Lauridsen, C., Berge, G., Grøntvedt, G. R., Bråthen, G., White, L. R., & Nielsen, H. M. (2019) · Journal of Alzheimer's Disease · doi:10.3233/jad-190175 · Cited by 22 · see citing works
Günaydin, C., Sondhi, D., Kaminsky, S. M., Lephart, H. C., Leopold, P. L., Hackett, N. R., Khanna, R., & Crystal, R. G. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.11.003 · Cited by 26 · see citing works
Apolipoprotein E Recognizes Alzheimer's Disease Associated 3‐O Sulfation of Heparan Sulfate
Mah, D., Zhu, Y., Su, G., Zhao, J., Canning, A., Gibson, J. M., Song, X., Stancanelli, E., Xu, Y., Zhang, F., et al. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202212636 · Cited by 23 · see citing works
Molecular subtyping of Alzheimer’s disease with consensus non-negative matrix factorization
Zheng, C., & Xu, R. (2021) · PLoS ONE · doi:10.1371/journal.pone.0250278 · Cited by 22 · see citing works
Ramsden, C. E., Keyes, G. S., Calzada, E., Horowitz, M. S., Zamora, D., Jahanipour, J., Sedlock, A., Indig, F. E., Moaddel, R., Kapogiannis, D., et al. (2022) · Journal of Alzheimer's Disease · doi:10.3233/jad-220071 · Cited by 19 · see citing works
Zarini-Gakiye, E., Amini, J., Sanadgol, N., Vaezi, G., & Kazem, P. (2020) · Current Molecular Pharmacology · doi:10.2174/1874467213666200422090135 · Cited by 22 · see citing works
Evaluation of the Common Molecular Basis in Alzheimer’s and Parkinson’s Diseases
Rana, P., Franco, E. F., Rao, Y., Syed, K., Barh, D., Azevedo, V., Ramos, R. T. J., & Ghosh, P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20153730 · Cited by 20 · see citing works
Moos, P. J., Cheminant, J. R., Cowman, S. J., Noll, J., Wang, Q.-M., Musci, T. S., & Venosa, A. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1425466 · Cited by 19 · see citing works
The Role of MAPK's Signaling in Mediating ApoE4-Driven Pathology In Vivo
Salomon‐Zimri, S., Koren-Iton, A., Angel, A., Ben‐Zur, T., Offen, D., & Michaelson, D. M. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190228120254 · Cited by 16 · see citing works
Neuroglial Advances: New Roles for Established Players
Verkhratsky, A., Li, B., Niu, J., Lin, S.-S., Su, Y., Jin, W., Li, Y., Jiang, S., Yi, C., Shi, F., et al. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70080 · Cited by 19 · see citing works
“We found (through proteomic screening) a remarkable increase in apo-lipoprotein E (APOE, the lipoprotein released by astrocytes in the brain (Lane-Donovan and Herz 2017)) rich ADEVs in patients with AQP4- Abs-positive NMOSD as well as in a murine model of NMOSD (Figure 5).”
Hu, H., Wan, S., Hu, Y., Wang, Q., Li, H., & Zhang, N. (2025) · Annals of Medicine · doi:10.1080/07853890.2024.2445194 · Cited by 19 · see citing works
“Extensive experimental data suggest that APOE is primarily secreted by astrocytes in the brain [138,139] and serves as the main lipid carrier within the CNS [140].”
Aquino, R., de Concini, V., Dhénain, M., Lam, S., Gosset, D., Baquedano, L., Forero, M. G., Menuet, A., Baril, P., & Pichon, C. (2023) · Cells · doi:10.3390/cells12050694 · Cited by 19 · see citing works
Liu, S., Yang, S., Zhu, X., Li, X., Zhang, X., Zhou, X., Cheng, H., Huo, F.-Q., Mao, Q., & Liang, L. (2023) · Biology Direct · doi:10.1186/s13062-023-00444-z · Cited by 15 · see citing works
“APOE is primarily expressed in astrocytes in both the brain and the spinal cord, as well as in the glia surrounding the sensory neurons in DRGs, and the non-myelinating Schwann cells of peripheral nerves [9, 17, 26].”
BackgroundInfluentialApoE4 attenuates cortical neuronal activity in young behaving apoE4 rats
Har-Paz, I., Arieli, E., & Moran, A. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105373 · Cited by 14 · see citing works
“The prevalence of the E4 allele of the apolipoprotein E (apoE4) gene in late-onset Alzheimer’s disease (AD) patients is well established (Huang, 2011; Lane-Donovan and Herz, 2017).”
Zhu, P., Xiao, L., & Wang, Y. (2025) · Fluids and Barriers of the CNS · doi:10.1186/s12987-025-00721-1 · Cited by 15 · see citing works
Gene therapy: an alternative to treat Alzheimer’s disease
Doshi, V., Joshi, G., Sharma, S., & Choudhary, D. K. (2023) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-023-02873-z · Cited by 14 · see citing works
Gao, H., Zheng, W., Li, C., & Xu, H. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111582 · Cited by 14 · see citing works
Durakoglugil, M. S., Wasser, C. R., Wong, C. H. Y., Pohlkamp, T., Xian, X., Lane‐Donovan, C., Fritschle, K., Nästle, L., & Herz, J. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.0388-21.2021 · Cited by 13 · see citing works
“Considering the spectrum of neuromodulatory roles of Reelin (Wasser and Herz, 2016; Lane-Donovan and Herz, 2017), our findings suggest that Reelin is regulating pathways that are critical for mGluR-mediated LTD. Reelin cKOmice have elevated STEP61 levels LTD induction depends on both the…”
BackgroundSelf-citationKuang, L., Jia, J., Zhao, D., Xiong, F., Han, X., Wang, Y., & Initiative, A. D. N. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00188 · Cited by 13 · see citing works
“…al., 2009; Lambert et al., 2013; Yu et al., 2019) for the pathogenesis (Karch and Goate, 2015) of AD indicate the apolipoprotein E (APOE) e4 allele (Lane-Donovan and Herz, 2017) involves the accumulation of Amyloid-β (Caselli et al., 2010), leading to increasing Frontiers in Aging Neuroscience |…”
BackgroundHuang, Y. A., Zhou, B., Nabet, A. M., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/460899 · Cited by 14 · see citing works
SynBot: An open-source image analysis software for automated quantification of synapsesPreprint
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“Mutations or dysregulation of SAPs in the central nervous system causes synapse dysfunction, thereby promoting the progression of various neurodegenerative diseases (6-11).”
BackgroundMoulton, M. J., Barish, S., Ralhan, I., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.03.433580 · Cited by 13 · see citing works
An Update on the Role of Common Genetic Variation Underlying Substance Use Disorders
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Lipoprotein Metabolism, Protein Aggregation, and Alzheimer’s Disease: A Literature Review
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Dysregulation of neuroproteasomes by ApoE isoforms drives endogenous Tau aggregationPreprint
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“APOE ε4 is the strongest genetic risk factor for sporadic AD and has been implicated in synaptic dysfunction in cellular and animal models [76].”
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Extra-Hippocampal Learning Deficits in Young Apolipoprotein E4 Mice and Their Synaptic Underpinning
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“…of imaging and neuropathology studies tended to suggest some distinct aspects of pathophysiology in elderly people with different APOE genotypes 3,24 , it is still unclear whether different functional connectivity could result in distinct neuropsychological representations in elderly people…”
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- Authors
- Lane-Donovan, C., & Herz, J.
- Affiliations
- University of Freiburg (DE)
- Corresponding author
- Herz, Joachim
- ORCID
- Herz, Joachim
- Venue
- Trends in Endocrinology & Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 28
- Issue
- 4
- Pages
- 273-284
- ISSN
- 1043-2760 (ISSN-L)
- PMC
- PMC5366078
- OpenAlex
- W2568317134
- Cited by
- 157
- References
- 103
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 17 · 2023: 18 · 2022: 18 · 2021: 25 · 2020: 13 · 2019: 14 · 2018: 12 · 2017: 7
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (RF1AG053391, F30AG047799)
- National Heart, Lung, and Blood Institute (R37HL063762)
- National Institute of Neurological Disorders and Stroke (R01NS093382)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, apolipoprotein E, APOE ε4, apoE receptors, tripartite synapse, synapses, axon terminals, dendritic spines, astrocytes, neurodegeneration, late-onset Alzheimer's disease, genetic risk factors
- MeSH terms
- Reelin Protein, Alzheimer Disease, Animals, Apolipoproteins E, Disease Models, Animal, Female, Humans, Male, Synapses, Low Density Lipoprotein Receptor-Related Protein-1
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