APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types

Lin, Yong; Seo, Jinsoo; Gao, Fan; Feldman, Heather; Wen, Hsin-Lan; Penney, Jay; Cam, Hugh P.; Gjoneska, Elizabeta; Raja, Waseem; Cheng, Jemmie; Rueda, Richard; Kritskiy, Oleg; Abdurrob, Fatema; Peng, Zhuyu; Milo, Blerta; Yu, Chung Jong; Elmsaouri, Sara; Dey, Dilip; Ko, Tak; Yankner, Bruce A.; Tsai, Li‐Huei

doi:10.1016/j.neuron.2018.05.008

Cited by 744 publications

(823 citation statements)

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“…64 In our neuronal cultures, genetic correction of E4 did not increase APP expression, Aß42/Aß40 ratio, or GSK3ß phosphoactivation. 13,14 Taken together, these findings suggest that E4 increases tau phosphorylation by a cell-intrinsic mechanism. The vast majority of Aß and APOE in the central nervous system is released into the extracellular milieu by neurons and astrocytes, respectively, where they interact in an isoform-dependent manner.…”

Section: Discussionmentioning

confidence: 69%

“…Therefore, these findings suggest that neuronal APOE genotype does not influence amyloid processing or secretion, and furthermore, that the observed effect of APOE on tau in our cultures is likely to be amyloid-independent. 13 This suggests that an effect of E4 on Aß release may be activity-dependent. 65 The effect of APOE on amyloid processing, clearance, and plaque formation is therefore more likely to be a distinct function of glial APOE.…”

Section: Discussionmentioning

confidence: 99%

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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: 69%

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

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“…More recent studies have further built upon these initial proof‐of‐concept experiments to begin to unravel the genetic underpinnings of this disease. In one elegant example, Lin et al, examined the effects of the APOE ε4 allele, the most significant AD risk gene (Farrer et al, ; Harold et al, ; Lambert et al, ), on the transcriptome and function of human microglia (Lin et al, ). Using CRISPR/Cas9 genome editing, an APOE3/3 iPSC line was modified to generate an isogenic APOE4/4 line.…”

Section: Disease Applicationsmentioning

confidence: 99%

Human iPSC‐derived microglia: A growing toolset to study the brain's innate immune cells

Hasselmann

Blurton‐Jones

2020

Glia

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Recent advances in the generation of microglia from human induced pluripotent stem cells (iPSCs) have provided exciting new approaches to examine and decipher the biology of microglia. As these techniques continue to evolve to encompass more complex in situ and in vivo paradigms, so too have they begun to yield novel scientific insight into the genetics and function of human microglia. As such, researchers now have access to a toolset comprised of three unique “flavors” of iPSC‐derived microglia: in vitro microglia (iMGs), organoid microglia (oMGs), and xenotransplanted microglia (xMGs). The goal of this review is to discuss the variety of research applications that each of these techniques enables and to highlight recent discoveries that these methods have begun to uncover. By presenting the research paradigms in which each model has been successful, as well as the key benefits and limitations of each approach, it is our hope that this review will help interested researchers to incorporate these techniques into their studies, collectively advancing our understanding of human microglia biology.

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“…Although a recent technique, these cells are indeed microglial‐like and have been validated as a viable research tool (Abud et al, ; Pocock and Piers, ). The generation of microglial‐like iPSCS from APOE4 carriers shows transcriptomic changes alongside impaired phagocytosis of Aβ (Lin et al, ). Microglial IPSCs have recently been used to investigate specific missense mutations in TREM2, a newly identified AD risk factor (Garcia‐Reitboeck et al, ).…”

Section: Microglia Transcriptomic Changes In Admentioning

confidence: 99%

“…Utilizing CRISPR/Cas9 editing, Lin et al . () recently generated isogenic IPSC lines containing either APOE3 or APOE4, which were then differentiated to microglial‐like cells. APOE4‐containing cells were shown to have enhanced inflammatory transcriptomes and an impaired uptake of Aβ 1–42 .…”

Section: Gwas Microgliamentioning

confidence: 99%

The involvement of microglia in Alzheimer's disease: a new dog in the fight

Moore

Crack

2018

British J Pharmacology

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First described clinically in 1906, Alzheimer's disease (AD) is the most common neurodegenerative disease and form of dementia worldwide. Despite its prevalence, only five therapies are currently approved for AD, all dealing with the symptoms rather than the underlying causes of the disease. A multitude of experimental evidence has suggested that the once thought inconsequential process of neuroinflammation does, in fact, contribute to the AD pathogenesis. One such CNS cell type critical to this process are microglia. Plastic in nature with varied roles, microglia are emerging as key contributors to AD pathology. This review will focus on the role of microglia in the neuroinflammatory response in AD, highlighting recent studies implicating aberrant changes in microglial function in disease progression. Of critical note is that with these advances, a reconceptualization of the framework in which we view microglia is required. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types

Cited by 744 publications

References 71 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

Human iPSC‐derived microglia: A growing toolset to study the brain's innate immune cells

The involvement of microglia in Alzheimer's disease: a new dog in the fight

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