ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease

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.”

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

In the paper

“The allele frequency of ApoE4 is 15–20%, with some variation in incidence between populations [13].”

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

In the paper

“Conversely, ApoE2 is considered to be protective against AD, while ApoE3 is considered risk-neutral”

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

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]”

What the sources say

• Not checked yetcites [27] Chen Y 2005 Reelin modulates NMDA receptor activity in cortical neurons J Neurosci 25 36 8209 16 16148228 PMC6725528 source
• Not checked yetcites [28] Snyder EM 2005 Regulation of NMDA receptor trafficking by amyloid-beta Nat Neurosci 8 8 1051 8 16025111 source

In the paper

“STEP additionally dephosphorylates and deactivates Fyn, enhancing the overall effect of STEP on NMDAR endocytosis [36].”

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

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.”

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].”

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

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].”

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

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.”

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].”

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

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].”

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

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].”

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

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].”

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

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].”

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

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.”

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].”

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

In the paper

“ApoE4 targeted replacement mice have a reduction in dendritic spine complexity, a finding that is mirrored in human ApoE4 carriers [67].”

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

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].”

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

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].”

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

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].”

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

In the paper

“Aβ binds to α7 nicotinic acetylcholine receptors (α7 nAChRs) and to metabotropic glutamate receptors, in particular mGluR5 [31–33].”

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

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].”

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

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).”

In the paper

“for its role in neuromuscular junction (NMJ) development and in the maintenance of the adult NMJ”

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

In the paper

“glial activation is an indication of pro-inflammatory changes that is commonly found in AD brains”

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

In the paper

“the role of anti-Lrp4 and anti-MuSK antibodies in myasthenia gravis [87]”

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

In the paper

“at the NMJ, Lrp4, APP and muscle-specific kinase (MuSK) form a complex to prepattern the muscle [88–90]”

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

In the paper

“Lrp1 is highly expressed in astrocytes, where it is responsible for phagocytosis of degraded myelin [78, 79].”

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

In the paper

“Lrp4 is more commonly known as the gene defective in Cenani-Lenz syndrome [83–86]”

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

In the paper

“by two distinct mechanisms: impairing the turnover of Aβ, thereby accelerating amyloid deposition”

In the paper

“Agrin is released from the motor neuron and signals through APP, MuSK and Lrp4 to recruit nicotinic acetylcholine receptors (AChRs).”

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