The DOI matches its Crossref record; 100 of the 103 references it cites were found in a registry or an index; none of the 95 sources its claims cite is checked for support yet.
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.
Overview
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.
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Claims the paper makes
0 of 95 cited sources checked · 0 supported · 0 flagged
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating a role for ApoE in neuronal function prior to amyloid deposition”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE, ApoE Receptors, and Alzheimer’s Disease
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“some of these changes are present much earlier in life [16]”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE, ApoE Receptors, and Alzheimer’s Disease
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Lrp1 interacts with the N-methyl-D-aspartate receptor (NMDAR), promoting the endocytosis of NMDAR from the cell surface [19].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Reelin, ApoE receptors, and Glutamate Signaling
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“The primary ligand for these receptors in the CNS is not ApoE, but rather the glycoprotein Reelin [22].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Reelin, ApoE receptors, and Glutamate Signaling
What the sources say
- Not checked yetcites [22] Lee GH D’Arcangelo G 2016 New Insights into Reelin-Mediated Signaling Pathways Front Cell Neurosci 10 122 27242434 PMC4860420 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“ApoE4 hindering Aβ clearance significantly over ApoE3 and ApoE2 [14]”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE, ApoE Receptors, and Alzheimer’s Disease
What the sources say
- Not checked yetcites [14] Castellano JM 2011 Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance Sci Transl Med 3 89 89ra57 PMC3192364 21715678 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“the ApoE receptors Apoer2/Lrp8 and Vldlr form a complex with scaffolding proteins, such as PSD-95, and the glutamate receptors [21].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Reelin, ApoE receptors, and Glutamate Signaling
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“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].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Abstract
What the sources say
- Not checked yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § ApoE, ApoE Receptors, and Alzheimer’s Disease · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and thus directly increasing amyloid pathology”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE, ApoE Receptors, and Alzheimer’s Disease
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“older individuals who are ApoE4 carriers have structural and functional alterations in AD affected areas in the absence of cognitive dysfunction [15]”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE, ApoE Receptors, and Alzheimer’s Disease
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“loss of Lrp1 hinders some elements of NMDAR signaling, such as internalization of GluA1 and degradation of PSD-95 [20].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Reelin, ApoE receptors, and Glutamate Signaling
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- It may state two separate claims as one. 26
- Probably not a substantial claim. 7
In the paper
“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.”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE, ApoE Receptors, and Alzheimer’s Disease
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“The allele frequency of ApoE4 is 15–20%, with some variation in incidence between populations [13].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE, ApoE Receptors, and Alzheimer’s Disease
What the sources say
- Not checked yetcites [13] Liu CC 2013 Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy Nat Rev Neurol 9 2 106 18 23296339 PMC3726719 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Conversely, ApoE2 is considered to be protective against AD, while ApoE3 is considered risk-neutral”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE, ApoE Receptors, and Alzheimer’s Disease
What the sources say
- Not checked yetcites [13] Liu CC 2013 Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy Nat Rev Neurol 9 2 106 18 23296339 PMC3726719 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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]”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Reelin, ApoE receptors, and Glutamate Signaling
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“STEP additionally dephosphorylates and deactivates Fyn, enhancing the overall effect of STEP on NMDAR endocytosis [36].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Reelin, ApoE receptors, and Glutamate Signaling
What the sources say
- Not checked yetcites [36] Nguyen TH 2002 Striatal enriched phosphatase 61 dephosphorylates Fyn at phosphotyrosine 420 J Biol Chem 277 27 24274 9 11983687 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Calcium Dysregulation and ApoE receptors
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Reelin, ApoE receptors, and Glutamate Signaling
What the sources say
- Not checked yetcites [25] Herz J Chen Y 2006 Reelin, lipoprotein receptors and synaptic plasticity Nat Rev Neurosci 7 11 850 9 17053810 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“GSK3β activation reduces synaptic long-term potentiation (LTP) and provides a potential biochemical mechanism by which Aβ can induce τ hyperphosphorylation [39].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Reelin, ApoE receptors, and Glutamate Signaling
What the sources say
- Not checked yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Calcium Dysregulation and ApoE receptors
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Post-synaptic actin polymerization
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Post-synaptic actin polymerization
What the sources say
- Not checked yetcites [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
- Not checked yetcites [65] Bosch C 2016 Reelin Regulates the Maturation of Dendritic Spines, Synaptogenesis and Glial Ensheathment of Newborn Granule Cells Cereb Cortex PMC5066826 27624722 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE and Endocytic Trafficking
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE and Endocytic Trafficking
What the sources say
- Not checked yetcites [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
- Not checked yetcites [71] Heeren J 2004 Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation J Biol Chem 279 53 55483 92 15485881 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE and Endocytic Trafficking
What the sources say
- Not checked yetcites [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
- Not checked yetcites [70] Hatters DM 2006 Amino-terminal domain stability mediates apolipoprotein E aggregation into neurotoxic fibrils J Mol Biol 361 5 932 44 16890957 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE and Endocytic Trafficking
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
In the paper
“suggesting a reduced ability of presynaptic ApoE4 neurons to convert glutamine to glutamate and a compensatory increase in vesicular glutamate loading [75].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Presynaptic Roles of ApoE Receptors
What the sources say
- Not checked yetcites [75] Dumanis SB 2013 APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals J Neurochem 124 1 4 14 22862561 PMC3509249 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“ApoE4 targeted replacement mice have a reduction in dendritic spine complexity, a finding that is mirrored in human ApoE4 carriers [67].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Post-synaptic actin polymerization
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“With age, Reelin levels are reduced in the brain and in AD, Reelin levels are particularly reduced in the entorhinal cortex [44].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Reelin, ApoE receptors, and Glutamate Signaling
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Astrocytes
What the sources say
- Not checked yetcites [1] Lane-Donovan C 2014 More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration Neuron 83 4 771 87 25144875 PMC4240629 source
- Not checked yetcites [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
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Post-synaptic actin polymerization
What the sources say
- Not checked yetcites [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
- Not checked yetcites [62] Caroni P 2014 Synapse rearrangements upon learning: from divergent-sparse connectivity to dedicated sub-circuits Trends Neurosci 37 10 604 14 25257207 source
- Not checked yetcites [63] Mizuno K 2013 Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation Cell Signal 25 2 457 69 23153585 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Aβ binds to α7 nicotinic acetylcholine receptors (α7 nAChRs) and to metabotropic glutamate receptors, in particular mGluR5 [31–33].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Reelin, ApoE receptors, and Glutamate Signaling
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [33] Lauren J 2009 Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers Nature 457 7233 1128 32 19242475 PMC2748841 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE and Endocytic Trafficking
What the sources say
- Not checked yetcites [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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > ApoE and Endocytic Trafficking
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear? Based: unclearIt may state two separate claims as one.
In the paper
“for its role in neuromuscular junction (NMJ) development and in the maintenance of the adult NMJ”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Astrocytes
What the sources say
- Not checked yetcites [87] Selcen D 2015 Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia JAMA Neurol 72 8 889 96 26052878 PMC4532561 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“glial activation is an indication of pro-inflammatory changes that is commonly found in AD brains”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Astrocytes
What the sources say
- Not checked yetcites [98] Heppner FL 2015 Immune attack: the role of inflammation in Alzheimer disease Nat Rev Neurosci 16 6 358 72 25991443 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the role of anti-Lrp4 and anti-MuSK antibodies in myasthenia gravis [87]”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Astrocytes
What the sources say
- Not checked yetcites [87] Selcen D 2015 Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia JAMA Neurol 72 8 889 96 26052878 PMC4532561 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“at the NMJ, Lrp4, APP and muscle-specific kinase (MuSK) form a complex to prepattern the muscle [88–90]”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Astrocytes
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [90] Zhang B 2008 LRP4 serves as a coreceptor of agrin Neuron 60 2 285 97 18957220 PMC2743173 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Lrp1 is highly expressed in astrocytes, where it is responsible for phagocytosis of degraded myelin [78, 79].”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Astrocytes
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Lrp4 is more commonly known as the gene defective in Cenani-Lenz syndrome [83–86]”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Astrocytes
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“by two distinct mechanisms: impairing the turnover of Aβ, thereby accelerating amyloid deposition”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Concluding Remarks and future perspectives
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Mechanisms of ApoE and Lrp4 function observed in mouse models apply to human Alzheimer's disease.
None of the sources cited for this claim have been checked yet.
In the paper
“Agrin is released from the motor neuron and signals through APP, MuSK and Lrp4 to recruit nicotinic acetylcholine receptors (AChRs).”
§ ApoE, ApoE receptors, and the Synapse in Alzheimer’s Disease > Astrocytes
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [90] Zhang B 2008 LRP4 serves as a coreceptor of agrin Neuron 60 2 285 97 18957220 PMC2743173 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Of these, ApoE receptor-2 (Apoer2, a.k.a. LRP8) is the best characterized. 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).”
From Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease (2018) · cites this paper as Lane-Donovan and Herz, 2017
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“these data add nevertheless further support to our model which postulates impaired neuronal endosomal vesicle trafficking as the root cause for the increased AD risk imposed by ApoE4 (Chen et al., 2005; Chen et al., 2010; Lane-Donovan and Herz, 2017; Lane-Donovan et al., 2014).”
From Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease (2018) · cites this paper as Lane-Donovan and Herz, 2017
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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 Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [14]
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Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo
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BackgroundLrp4 is a receptor for Agrin and forms a complex with MuSK
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Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning
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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?
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BackgroundLRP4 serves as a coreceptor of Agrin
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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
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“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).”
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“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].”
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“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
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“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×
“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
Chai, X., Förster, E., Zhao, S., Bock, H. H., & Frotscher, M. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2934-08.2009 · Cited by 202 · cited 1×
“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].”
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 196
Receptor 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×
“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×
“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×
“With age, Reelin levels are reduced in the brain and in AD, Reelin levels are particularly reduced in the entorhinal cortex [44].”
BackgroundStriatal 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×
“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×
“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
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×
“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×
“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 [Ca2+] 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×
“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×
“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×
“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
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×
“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
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×
“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×
“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×
“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×
“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×
“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 113 · cited 2×
“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×
“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×
“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×
“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
Self-citationPresenilins 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×
“In general terms, there is an important role for presenilins in intracellular Ca2+ stores, which have been discussed in depth in other reviews [58].”
BackgroundMak, 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 94 · cited 2×
“As key components of cholesterol homeostasis, deficiency of either ApoE or LDLR in humans leads to severe hypercholesterolemia and premature atherosclerosis [3].”
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×
“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
Self-citationKobro‐Flatmoen, A., Nagelhus, A., & Witter, M. P. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.05.012 · Cited by 78 · cited 1×
“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…”
BackgroundThe 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×
“Alternatively, Aβ oligomers have been proposed to themselves act as calcium leak channels [57].”
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
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×
“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
Johnson, E. B., Steffen, D. J., Lynch, K. W., & Herz, J. (2006) · Genomics · doi:10.1016/j.ygeno.2006.08.005 · Cited by 62
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×
“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
Self-citationAPOE 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×
“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 55
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×
“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×
“, 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×
“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×
“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
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×
“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
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
“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
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 368
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
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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