Building in vitro models of the brain to understand the role ofAPOEin Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a devastating, complex, and incurable disease that represents an increasingly problematic global health issue. The etiology of sporadic AD that accounts for a vast majority of cases remains poorly understood, with no effective therapeutic interventions. Genetic studies have identified AD risk genes including the most prominent, APOE, of which the ɛ4 allele increases risk in a dose-dependent manner. A breakthrough discovery enabled the creation of human induced pluripotent stem cells (hiPSCs) that can be differentiated into various brain cell types, facilitating AD research in genetically human models. Herein, we provide a brief background on AD in the context of APOE susceptibility and feature work employing hiPSC-derived brain cell and tissue models to interrogate the contribution of APOE in driving AD pathology. Such models have delivered crucial insights into cellular mechanisms and cell type–specific roles underlying the perturbed biological functions that trigger pathogenic cascades and propagate neurodegeneration. Collectively, hiPSC-based models are envisioned to be an impactful platform for uncovering fundamental AD understanding, with high translational value toward AD drug discovery and testing.

Aβ Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer’s Disease

“…There is extensive data that APOE and CLU interaction with AA amyloid deposits alters the local cellular response, and influence amyloid deposition itself [86][87][88]113,114 Because of their genetic association with AD, they are also considered therapeutic targets, though it has been challenging to develop therapeutic approaches that modulate APOE or CLU and show robust preclinical disease modifying impacts 115 . We have not yet explored studies in knockout mice, however, overexpression studies suggest that Mdk and PTN, like APOE and CLU, can increase amyloid deposition and both also increase CAA.…”

Loss of Lipid Carrier ApoE Exacerbates Brain Glial and Inflammatory Responses after Lysosomal GBA1 Inhibition

“…ApoE is the major brain apolipoprotein [23,24] that binds lipids and facilitates extracellular lipid transport between cells [25,26]. It is likely that ApoE-lipid transport is central to the lipid biological adaptations during cellular lipid elevations [4,7,9,18,27].…”