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

Lane-Donovan, Courtney; Herz, Joachim

doi:10.1016/j.tem.2016.12.001

Cited by 120 publications

(95 citation statements)

References 98 publications

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“…53 Our observations indicate that endogenous expression of E4 in neurons sensitizes them to calcium dysregulation, independently of glial APOE. Effects of APOE isoform on calcium homeostasis have heretofore been attributed to differential binding of glial APOE on neuronal APOE receptors.…”

Section: Discussionmentioning

confidence: 64%

“…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. This finding offers an interesting human correlate to murine models that suggest a toxic gain-offunction role of E4 in neuronal injury and aging.…”

Section: Discussionmentioning

confidence: 64%

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Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease

Wadhwani

Affaneh

Gulden

et al. 2019

Annals of Neurology

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Objective:The apolipoprotein E (APOE) E4 isoform is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Although APOE is predominantly expressed by astrocytes in the central nervous system, neuronal expression of APOE is of increasing interest in age-related cognitive impairment, neurological injury, and neurodegeneration. Here, we show that endogenous expression of E4 in stem-cell-derived neurons predisposes them to injury and promotes the release of phosphorylated tau. Methods: Induced pluripotent stem cells from 2 unrelated AD patients carrying the E4 allele were corrected to the E3/E3 genotype with the CRISPR/Cas9 system and differentiated into pure cultures of forebrain excitatory neurons without contamination from other cells types. Results: Compared to unedited E4 neurons, E3 neurons were less susceptible to ionomycin-induced cytotoxicity. Biochemically, E4 cells exhibited increased tau phosphorylation and ERK1/2 phosphoactivation. Moreover, E4 neurons released increased amounts of phosphorylated tau extracellularly in an isoform-dependent manner by a heparin sulfate proteoglycan-dependent mechanism. Interpretation: Our results demonstrate that endogenous expression of E4 by stem-cell-derived forebrain excitatory neurons predisposes neurons to calcium dysregulation and ultimately cell death. This change is associated with increased cellular tau phosphorylation and markedly enhanced release of phosphorylated tau. Importantly, these effects are independent of glial APOE. These findings suggest that E4 accelerates spreading of tau pathology and neuron death in part by neuron-specific, glia-independent mechanisms. ANN NEUROL 2019;85:726-739 T he apolipoprotein E (APOE) E4 allele, the strongest genetic risk factor for sporadic Alzheimer disease (AD), differs from the risk-neutral E3 allele by a single nucleotide polymorphism (SNP). 1,2 E4 patients exhibit greater brain atrophy, accumulation of hyperphosphorylated tau protein, and deposition of amyloid, albeit by unclear mechanisms. 3-6 Although most APOE is expressed by astrocytes in the brain, 7-9 neuronal APOE is of increasing interest in age-related cognitive impairment, neurological injury, and neurodegeneration. 10-12 Disease modeling using isogenic stem cells has demonstrated that, compared to E3, expression of E4 leads to distinct transcriptomic differences in multiple neural cell types and increases tau phosphorylation in neurons. 13,14 However, the effects of APOE genotype on neuronal viability and tau release are unknown. Using genome editing and a reductionist human stem cell culture approach, we show that endogenous expression of E4 predisposes pure cultures of forebrain excitatory neurons to injury and promotes release of phosphorylated tau (p-tau). These findings suggest that neuronal APOE can accelerate brain atrophy and the spreading of tau pathology in E4-carrying AD patients independently of glia. Subjects and Methods Reprogramming and Culture of Stem CellsFibroblast lines from patients diagnosed with AD (AD1, AG11414; AD...

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 64%

Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease

Wadhwani

Affaneh

Gulden

et al. 2019

Annals of Neurology

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“…Because ApoER2-ICD exerts transcriptional control on reelin expression, decreased production of ApoER2-ICD may be responsible for increased reelin expression. 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.…”

Section: Discussionmentioning

confidence: 99%

Decreased generation of C‐terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease

et al. 2018

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Increasing evidence indicates that altered reelin signaling could contribute to synaptic dysfunction in Alzheimer's disease (AD). We found that reelin protein and mRNA levels were increased in the AD brain (particularly at advanced Braak stages in apolipoprotein E4 noncarriers), compared with that of control subjects. The β-amyloid (Aβ) protein impairs reelin activity and increases reelin expression through a mechanism that is not yet understood. To explore that mechanism, we examined the effect of Aβ aa 1-42 (Aβ) on DNA methylation of the RELN promoter and the processing of reelin receptor apolipoprotein E receptor 2 (ApoER2) in differentiated SH-SY5Y cells because ApoER2 C-terminal fragments (CTFs), generated after reelin binding, regulate reelin expression. We found that Aβ decreased nuclear levels of DNA-methyltransferase 1. However, RELN promoter methylation did not change in Aβ-treated cells or in AD brain extracts. Instead, the levels of ApoER2-CTF appeared significantly lower in Aβ-treated cells and in AD extracts from advanced Braak stages of apolipoprotein E4 noncarriers. Our data show that ApoER2-CTF levels are decreased, whereas reelin expression is increased in AD brain at advanced Braak stages and after Aβ treatment, supporting the view that ApoER2-CTF exerts a modulatory role on reelin expression.-Mata-Balaguer, T., Cuchillo-Ibañez, I., Calero, M., Ferrer, I., Sáez-Valero, J. Decreased generation of C-terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease.

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“…Regulates amyloid-β (Aβ) oligomerization, aggregation, and receptor-mediated clearance, brain lipid transport, glucose metabolism, neuronal signaling, and neuroinflammation [26,82,83]. …”

Section: Pathophysiology Genetics and Functional Brain Processing Umentioning

confidence: 99%

Revolution of Resting-State Functional Neuroimaging Genetics in Alzheimer’s Disease

Chiesa

Cavedo

Lista

et al. 2017

Trends in Neurosciences

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The quest to comprehend genetic, biological, and symptomatic heterogeneity underlying Alzheimer’s disease (AD) requires a deep understanding of mechanisms affecting complex brain systems. Neuroimaging genetics is an emerging field that provides a powerful way to analyze and characterize intermediate biological phenotypes of AD. Here, we describe recent studies showing the differential effect of genetic risk factors for AD on brain functional connectivity in cognitively normal, preclinical, prodromal, and AD dementia individuals. Functional neuroimaging genetics holds particular promise for the characterization of preclinical populations; target populations for disease prevention and modification trials. To this end, we emphasize the need for a paradigm shift towards integrative disease modeling and neuroimaging biomarker-guided precision medicine for AD and other neurodegenerative diseases.

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

Cited by 120 publications

References 98 publications

Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease

Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease

Decreased generation of C‐terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease

Revolution of Resting-State Functional Neuroimaging Genetics in Alzheimer’s Disease

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