ApoE4 Accelerates Early Seeding of Amyloid Pathology

Liu, Chia-Chen; Zhao, Na; Fu, Yuan; Wang, Na; Linares, Cynthia; Tsai, Chih Wei; Bu, Guojun

doi:10.1016/j.neuron.2017.11.013

Cited by 298 publications

(275 citation statements)

References 42 publications

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“…Recombinant E4 has been reported to increase Aß production by receptor-mediated effects, 63 and in transgenic mouse models, E4 promotes the seeding of amyloid plaques. 4,5,63 Aß can in turn induce tau phosphorylation via GSK3ß activation. 64 In our neuronal cultures, genetic correction of E4 did not increase APP expression, Aß42/Aß40 ratio, or GSK3ß phosphoactivation.…”

Section: Discussionmentioning

confidence: 99%

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

Wadhwani

Affaneh

Gulden

et al. 2019

Annals of Neurology

107

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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: 99%

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

Wadhwani

Affaneh

Gulden

et al. 2019

Annals of Neurology

107

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“…Multiple lines of evidence suggest that ApoE4 risk in AD principally relates to enhanced and accelerated cerebral Aβ pathology [4]. More precisely, ApoE4 appears to accelerate the early seeding of amyloid pathology, most likely by decreasing Aβ clearance and enhancing Aβ aggregation [5]. Shi et al .…”

Section: Characteristics Of Patients With Frontotemporal Dementia (Ftmentioning

confidence: 99%

“…Multiple lines of evidence suggest that ApoE4 risk in AD principally relates to enhanced and accelerated cerebral Ab pathology [4]. More precisely, ApoE4 appears to accelerate the early seeding of amyloid pathology, most likely by decreasing Ab clearance and enhancing Ab aggregation [5]. Shi et al recently described how ApoE4 increases the burden of cerebral tau pathology, neuroinflammation, and brain atrophy in a P301S mouse model of frontotemporal dementia (FTD) and in vitro; they also demonstrated that in patients with a primary tauopathy, ApoE4 was associated with more severe regional neurodegeneration and that ApoE41 AD patients with amyloid-b (Ab) pathology showed faster disease progression [6].…”

mentioning

confidence: 99%

ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid‐β copathology

Koriath

Lashley

Taylor

et al. 2019

Alz & Dem Diag Ass & Dis Mo

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Introduction Apolipoprotein E (ApoE) is the most important genetic risk factor for Alzheimer's disease (AD), with ApoE4 thought to enhance and accelerate amyloid‐β (Aβ) pathology. ApoE4 has recently been described to increase neurodegeneration in a mouse model of frontotemporal dementia (FTD), in vitro, and in patients, demonstrating that ApoE4 modifies tauopathy independently of Aβ. This raises the question whether ApoE genotype also modifies the clinical phenotype in patients with FTD with tau pathology. Methods We analyzed 704 patients with FTD, including a genetically and neuropathologically confirmed subset, and 452 healthy elderly controls. We compared ApoE4 genotype frequency and age at onset in tau+ or TDP43+ FTD patients with or without Aβ copathology. Results The ApoE4 genotype lowered age at onset in patients with FTD and tau pathology, particularly once accounting for confounding effects of Aβ pathology. Discussion We conclude that ApoE4 accelerates neurodegeneration in FTD patients with MAPT mutations or FTLD‐tau pathology, independent of Aβ.

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“…ApoE functions as the main cholesterol carrier in the brain (Mahley, 1988), and the variant E4 increases the risk of developing AD (Corder et al, 1993). Aside from its role in fat metabolism, ApoE4 has been shown to speed up Aβ seeding (Bales et al, 1997;Liu et al, 2017) and mediate the clearance of Aβ peptide less efficiently than other ApoE variants (Castellano et al, 2011;Robert et al, 2017). Interestingly, mice carrying the ApoE4 variant show impaired endosomal-lysosomal pathways (Nuriel et al, 2017) and EV biogenesis (Peng et al, 2019).…”

Section: Genetic and Biological Evidence For A Role Of Degradativementioning

confidence: 99%

“…It is tempting to hypothesize that ILVs/exosomes may enhance the formation of Aβ fibers to trap undegraded cellular material accumulated in MVBs due to lysosomal dysfunction. Indeed, ApoE (ApoE4 isoform is the second highest risk factor for AD after aging) was shown to be required for amyloid plaque formation (Bales et al, 1997;Liu et al, 2017). Then amyloid fibers entangled with cellular waste would be secreted to the cellular space after the fusion of MVBs to the plasma membrane and cleared by microglia.…”

Section: Enhanced Secretion Of Exosomes May Trigger Increased Aβ Gementioning

confidence: 99%

The interplay between aging‐associated loss of protein homeostasis and extracellular vesicles in neurodegeneration

Guix

2019

J of Neuroscience Research

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The finding of an effective cure or treatment for neurodegenerative diseases is one of the biggest challenges for this century. Although these diseases show different clinical manifestations, the presence of toxic protein aggregates in the brain of patients is a common feature to all of them, suggesting a loss of protein homeostasis.Aging, the primary risk factor for the majority of neurodegenerative disorders, is linked to the impairment of degradative compartments such as lysosomes and autophagosomes. Besides, many genetic factors for Alzheimer's disease, Parkinson's disease, or frontotemporal dementia, as examples of frequent neurodegenerative diseases, are causative of endo-lysosomal and autophagosomal dysfunctions. There is scientific evidence suggesting that neurons can counteract the accumulation of undegraded cellular material by the secretion of extracellular vesicles (EVs), which are vesicles with a size ranging from 50 to 100 nm generated in a type of endosomal compartment named multivesicular body. EVs play a crucial role in removing cellular waste, promoting protein aggregation, and spreading toxic protein aggregates in the brain of patients. In this review, the interplay between the impairment of degradative compartments, the secretion of EVs, and their pathological/beneficial role in neurodegeneration is described.

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ApoE4 Accelerates Early Seeding of Amyloid Pathology

Cited by 298 publications

References 42 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

ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid‐β copathology

The interplay between aging‐associated loss of protein homeostasis and extracellular vesicles in neurodegeneration

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