APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer’s disease

Abstract

Genome-wide association studies (GWAS) have identified polymorphism in the Apolipoprotein E gene (APOE) to be the most prominent risk factor for Alzheimer’s disease (AD). Compared to individuals homozygous for the APOE3 variant, individuals with the APOE4 variant have a significantly elevated risk of AD. On the other hand, longitudinal studies have shown that the presence of the APOE2 variant reduces the lifetime risk of developing AD by 40 percent. While there has been significant research that has identified the risk-inducing effects of APOE4, the underlying mechanisms by which APOE2 influences AD onset and progression have not been extensively explored. In this study, we utilize an isogenic human induced pluripotent stem cell (hiPSC)-based system to demonstrate that conversion of APOE3 to APOE2 greatly reduced the production of amyloid-beta (Aβ) peptides in hiPSC-derived neural cultures. Mechanistically, analysis of pure populations of neurons and astrocytes derived from these neural cultures revealed that mitigating effects of APOE2 are mediated by cell autonomous and non-autonomous effects. In particular, we demonstrated the reduction in Aβ is potentially driven by a mechanism related to non-amyloidogenic processing of amyloid precursor protein (APP), suggesting a gain of the protective function of the APOE2 variant. Together, this study provides insights into the risk-modifying effects associated with the APOE2 allele and establishes a platform to probe the mechanisms by which APOE2 enhances neuroprotection against AD.

The Emergence of Model Systems to Investigate the Link Between Traumatic Brain Injury and Alzheimer’s Disease

“…As it relates to the use of in vitro models, recent studies have demonstrated the utility of hiPSC-based platforms combined with powerful gene editing techniques such as CRISPR/Cas9 in investigating the contribution of genetic risk factors to disease onset and progression. With respect to APOE, isogenic hiPSCs to investigate the mechanisms by which APOE4 increases and APOE2 decreases AD risk ( Lin et al, 2018 ; Wang et al, 2018 ; Brookhouser et al, 2021 ; Martens et al, 2021 ; Sienski et al, 2021 ) can be used in conjunction with in vitro injury models to determine the combinatorial effect of APOE isoforms and cell injury on the manifestation of AD-related phenotypes. In addition, numerous genome-wide association studies (GWAS) studies have identified several risk factors associated with altered probability of AD onset ( Bettens et al, 2010 ).…”

Calcium Ions Aggravate Alzheimer’s Disease Through the Aberrant Activation of Neuronal Networks, Leading to Synaptic and Cognitive Deficits

“…In N2a-APP 695 cells, APOE4 exacerbates the effects of ethanol on inducing neurotoxicity by increasing oxidative stress and apoptosis (Ji et al, 2019 ). In contrast, APOE1–3 has been shown to protect primary cultures of rat cortical neurons from the neurotoxic effects of the nonfibrillar C-terminal domain of Aβ (Drouet et al, 2001 ; Brookhouser et al, 2021 ). APOE isoforms play different roles in neurotoxicity by modulating Aβ deposition in the mouse brain (Drouet et al, 2001 ).…”

APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids

“…Indeed, astrocytic apoE has been associated with multiple neuronal functions, including axon guidance, survival, amyloid-β (Aβ) metabolism, neurogenesis, and synaptic plasticity (5,6,11). Since apoE also plays a critical role in lipid efflux from brain cells (12), apoE is predicted to mediate diverse functions in both cell-autonomous and non-cellautonomous manners (5,9,(13)(14)(15). In humans, the APOE gene exists as three polymorphic alleles (APOE2, APOE3, and APOE4), where APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD) (16)(17)(18).…”