Cellular Source of Apolipoprotein E4 Determines Neuronal Susceptibility to Excitotoxic Injury in Transgenic Mice

Buttini, Manuel; Masliah, Eliezer; Yu, Gui-Qiu; Palop, Jorge J.; Chang, Shengjun; Bernardo, Aubrey; Lin, Charlene; Wyss‐Coray, Tony; Huang, Yadong; Mucke, Lennart

doi:10.2353/ajpath.2010.090973

Cited by 71 publications

(69 citation statements)

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“…ApoE4(Δ272-299)/mEKO mice, which had no Aβ accumulation in the hippocampus, showed a trend toward lower MAP2 immunoreactivity (IR) in the hilus and molecular layer of the dentate gyrus compared with mEKO mice (Fig. 3 A, B, E, and F), which had similar MAP2 IR to apoE3 transgenic mice, as we reported (33). hAPP FAD /mEKO mice, which had high levels of Aβ in the hippocampus (Fig.…”

Section: Apoe4 Fragment Acts In Concert With Aβ To Elicit Neuronal Desupporting

confidence: 56%

C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-β (Aβ) and acts in concert with Aβ to elicit neuronal and behavioral deficits in mice

Bien-Ly

Andrews-Zwilling²,

Xu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Apolipoprotein (apo) E4 is the major known genetic risk factor for Alzheimer's disease (AD). We have shown in vitro and in vivo that apoE4 preferentially undergoes aberrant cleavage in neurons, yielding neurotoxic C-terminal-truncated fragments. To study the effect of these fragments on amyloid-β (Aβ) clearance/deposition and their potential synergy with Aβ in eliciting neuronal and behavioral deficits, we cross-bred transgenic mice expressing apoE3, apoE4, or apoE4(Δ272-299) with mice expressing human amyloid protein precursor (APP) harboring familial AD mutations (hAPP FAD ). At 6-8 mo of age, hAPP FAD mice expressing apoE3 or apoE4 had lower levels of hippocampal Aβ (94% and 89%, respectively) and less Aβ deposition (89% and 87%) than hAPP FAD mice without apoE, whereas hAPP FAD mice expressing mouse apoE had higher Aβ levels. Thus, human apoE stimulates Aβ clearance, but mouse apoE does not. Expression of apoE4(Δ272-299) reduced total Aβ levels by only 63% and Aβ deposition by 46% compared with hAPP FAD mice without apoE. Unlike apoE3 and apoE4, the C-terminaltruncated apoE4 bound poorly with Aβ peptides, leading to decreased Aβ clearance and increased Aβ deposition. Despite their lower levels of Aβ and Aβ deposition, hAPP FAD /apoE4(Δ272-299) mice accumulated pathogenic Aβ oligomers and displayed neuronal and behavioral deficits similar to or more severe than those in hAPP FAD mice. Thus, the C-terminal-truncated apoE4 fragment inefficiently clears Aβ peptides and acts in concert with low levels of Aβ to elicit neuronal and behavioral deficits in mice.animal model | neurodegeneration A lzheimer's disease (AD) is a complex neurodegenerative disorder likely caused by interactions among multiple genetic and environmental factors. Mutations in amyloid protein precursor (APP), presenilin-1 (PS1), and PS2 have been linked to early-onset familial AD (1-3), which accounts for <5% of AD cases. All mutations affect APP processing and alter the production of amyloid-β(Aβ) peptides (1, 2). Several transgenic mouse models have been developed to study the effects of Aβ on neuronal and behavioral deficits (4). The J20 line of transgenic mice expressing human APP harboring familial AD mutations (hAPP FAD ) accumulates neurotoxic Aβ peptides and display synaptic and cognitive deficits at 5-6 mo of age (5-7).Apolipoprotein (apo) E4, one of three isoforms of apoE (apoE2, apoE3, and apoE4), is the major genetic risk factor for late-onset AD, which accounts for >95% of AD cases (8-10). ApoE4 carriers account for 65-80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis (11). Emerging data suggest that apoE4 contributes to AD by interacting with different pathogenic factors through various pathways (12)(13)(14)(15).Several mouse models have been established to study the roles of apoE4 in AD pathogenesis. Neuron-specific apoE4 transgenic mice (NSE-apoE4) develop neuronal and spatial learning and memory deficits (16-18). Astrocyte-specific apoE4 transgenic mice (GFAP-apoE4) display working memory deficits wit...

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Section: Apoe4 Fragment Acts In Concert With Aβ To Elicit Neuronal Desupporting

confidence: 56%

C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-β (Aβ) and acts in concert with Aβ to elicit neuronal and behavioral deficits in mice

Bien-Ly

Andrews-Zwilling²,

Xu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…These findings suggest that neurons and astrocytes respond differently to apoE4. Alternatively, neuronal apoE4 and astrocytic apoE4 act differently in their pathogenic roles, as suggested recently (16,47). For example, neuronal apoE4 is less lipidated than neuronal apoE3 (13), whereas astrocytic apoE4 and apoE3 have no difference in lipidation (48).…”

Section: Discussionmentioning

confidence: 60%

Structure-dependent Impairment of Intracellular Apolipoprotein E4 Trafficking and Its Detrimental Effects Are Rescued by Small-molecule Structure Correctors

Brodbeck

McGuire

Liu

et al. 2011

Journal of Biological Chemistry

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Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer disease (AD) and likely contributes to neuropathology through various pathways. Here we report that the intracellular trafficking of apoE4 is impaired in Neuro-2a cells and primary neurons, as shown by measuring fluorescence recovery after photobleaching. In Neuro-2a cells, more apoE4 than apoE3 molecules remained immobilized in the endoplasmic reticulum (ER) and the Golgi apparatus, and the lateral motility of apoE4 was significantly lower in the Golgi apparatus (but not in the ER) than that of apoE3. Likewise, the immobile fraction was larger, and the lateral motility was lower for apoE4 than apoE3 in mouse primary hippocampal neurons. ApoE4 with the R61T mutation, which abolishes apoE4 domain interaction, was less immobilized, and its lateral motility was comparable with that of apoE3. The trafficking impairment of apoE4 was also rescued by disrupting domain interaction with the small-molecule structure correctors GIND25 and PH002. PH002 also rescued apoE4-induced impairments of neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons. ApoE4 did not affect trafficking of amyloid precursor protein, another AD-related protein, through the secretory pathway. Thus, domain interaction renders more newly synthesized apoE4 molecules immobile and slows their trafficking along the secretory pathway. Correcting the pathological structure of apoE4 by disrupting domain interaction is a potential therapeutic approach to treat or prevent AD related to apoE4.The three isoforms of human apoE (apoE2, apoE3, and apoE4) differ at amino acid positions 112 or 158 or both (1, 2). ApoE4 is the major genetic risk factor for Alzheimer disease (AD) 2 (3-5), and apoE4 carriers account for 65-80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis (6). Two biophysical properties that distinguish apoE4 from the other isoforms likely hold the key to a mechanistic understanding of its association with AD. First, apoE4 is more unstable and tends to form a molten globule state (7,8). Second, the amino-terminal domain (amino acids 1-191) of apoE4 interacts with its carboxyl-terminal domain (amino acids 223-299) (9, 10). This domain interaction occurs predominantly in apoE4, in which positively charged Arg-112 repels the side chain of Arg-61 in the amino-terminal domain, allowing the formation of a salt bridge between Arg-61 and the negatively charged Glu-255 in the carboxyl-terminal domain (9, 10). Domain interaction occurs to a significantly lesser extent in apoE2 and apoE3 because both have Cys-112, resulting in a different conformation of Arg-61 (11). Importantly, only human apoE has Arg-61; the 17 other species in which the apoE gene has been sequenced have 11). Mutation of Arg-61 to Thr in apoE4 prevents domain interaction, converting apoE4 to an apoE3-like molecule (9 -12). ApoE4 domain interaction occurs on lipoprotein particles in vitro in human plasma, in cultured Neuro-2a cells, and in Arg-61 knock-in mice, in wh...

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“…3 However, of the apoE isoforms, ε4 appears to possess a diminished reparative capacity, interferes with the beneficial function of the other isoforms, 47 and promotes cell death after excitotoxic injury when neuronally expressed. 48 By impairing neuronal repair mechanisms, the ε4 isoform can synergistically enhance damage due to neurological insults. 49 Therefore, persons with the ε4 allele may be more vulnerable to deleterious effects of non-specific risk factors.…”

Section: Discussionmentioning

confidence: 99%

Neighborhood Psychosocial Environment, Apolipoprotein E Genotype, and Cognitive Function in Older Adults

Lee

Glass

James

et al. 2011

Arch Gen Psychiatry

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Context The social environment may influence cognitive function in aging. However, to our knowledge, no studies have investigated whether specific genes modify this association. Objective To examine whether the apolipoprotein E (APOE) epsilon-4 allele modified the associations of neighborhood psychosocial hazards and cognitive function. Design A cross-sectional analysis. Setting The Baltimore Memory Study, a population-based sample of older urban residents. The 65 study neighborhoods in Baltimore city were characterized using the Neighborhood Psychosocial Hazards scale, designed to assess social disorganization, physical disorder, public safety, and economic deprivation. Participants One thousand one hundred forty urban residents aged 50 to 70 years at baseline. Main Outcome Measures Cognitive performance on 20 standard tests was measured and combined to form 7 summary domain scores (language, processing speed, eye-hand coordination, executive functioning, verbal memory and learning, visual memory, and visuoconstruction). Results In analyses fully adjusted for individual covariates, we found that high (i.e., worse) neighborhood psychosocial hazards were not consistently associated with worse cognitive performance. However, the interaction of high neighborhood psychosocial hazards and APOE ε4 genotype was found to be associated with worse cognitive domain scores, with evidence of associations in the domains of processing speed (p = 0.02) and executive functioning (p < 0.001). Suggestive evidence was also found for eye-hand coordination (p = 0.05). Conclusion Living in a psychosocially hazardous neighborhood was associated with worse cognitive function in persons with the APOE ε4 allele, evidence of a novel gene x environment interaction.

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Cellular Source of Apolipoprotein E4 Determines Neuronal Susceptibility to Excitotoxic Injury in Transgenic Mice

Cited by 71 publications

References 58 publications

C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-β (Aβ) and acts in concert with Aβ to elicit neuronal and behavioral deficits in mice

C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-β (Aβ) and acts in concert with Aβ to elicit neuronal and behavioral deficits in mice

Structure-dependent Impairment of Intracellular Apolipoprotein E4 Trafficking and Its Detrimental Effects Are Rescued by Small-molecule Structure Correctors

Neighborhood Psychosocial Environment, Apolipoprotein E Genotype, and Cognitive Function in Older Adults

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