Modeling Alzheimer's disease with human iPS cells: advancements, lessons, and applications

Abstract

One in three people will develop Alzheimer's disease (AD) or another dementia and, despite intense research efforts, treatment options remain inadequate. Understanding the mechanisms of AD pathogenesis remains our principal hurdle to developing effective therapeutics to tackle this looming medical crisis. In light of recent discoveries from whole-genome sequencing and technical advances in humanized models, studying disease risk genes with induced human neural cells presents unprecedented advantages. Here, we first review the current knowledge of the proposed mechanisms underlying AD and focus on modern genetic insights to inform future studies. To highlight the utility of human pluripotent stem cell-based innovations, we then present an update on efforts in recapitulating the pathophysiology by induced neuronal, non-neuronal and a collection of brain cell types, departing from the neuron-centric convention. Lastly, we examine the translational potentials of such approaches, and provide our perspectives on the promise they offer to deepen our understanding of AD pathogenesis and to accelerate the development of intervention strategies for patients and risk carriers.

Keywords: Alzheimer’s disease (AD); Amyloid-β (Aβ); Apolipoprotein E (apoE); Astrocytes; Blood-brain barrier (BBB); Genetic risk; Induced pluripotent stem cell (iPSC); Microglia; Oligodendrocytes; Tau.

Figure 1.. Pathophysiology of Alzheimer’s disease (AD)

The pathological hallmarks of AD are extracellular amyloid plaques and intraneuronal neurofibrillary tangles, whose building blocks are amyloid-β (Aβ) peptides and phosphorylated tau, respectively. Aβ is a proteolytic fragment of transmembrane amyloid precursor protein (APP) after cleavages by β- and γ-secretases. Tau is a brain-specific, axon-enriched microtubule-associated proteins and phosphorylated by an array of kinases. The other major pathological features, such as neuroinflammation and vascular dysfunction, contribute to and are reciprocally affected by the formation of plaques and tangles in AD development. The major steps of Aβ biogenesis, including APP gene transcription, protein trafficking and processing on endosome membrane, have been heavily implicated in AD pathogenesis. The proposed mechanisms mediating Aβ clearance, including engulfment by brain immune cells microglia and uptake by receptors important for lipid metabolism, are found dysregulated in AD brains as well. Recently, several large-scale genome-wide searches for risk genes have substantially progressed our understanding about pathogenetic mechanisms for AD. The confirmed hits indeed support cellular functions tied to AD pathophysiology: 1) lipid metabolism, e.g. APOE, CLU and LRP1, 2) inflammation, e.g. TREM2, CD33 and CR1, and 3) endocytosis, e.g. PICALM, BIN1 and SORL1. The linkage of risk genes to pathophysiological features leads to a comprehensive view based on coordination among different brain cell types, going beyond the classic amyloid cascade hypothesis and a neuron-centric convention. Images are modified from Servier Medical Art by Servier under a Creative Commons Attribution 3.0 Unported License.