Abstract
Traditional approaches to studying Alzheimer’s disease (AD) using mouse models and cell lines have advanced our understanding of AD pathogenesis. However, with the growing divide between model systems and clinical therapeutic outcomes, the limitations of these approaches are increasingly apparent. Thus, to generate more clinically relevant systems that capture pathological cascades within human neurons, we generated human-induced neurons (HiNs) from AD and non-AD individuals to model cell autonomous disease properties. We selected an AD patient population expressing mutations in presenilin 1 (mPS1), which is linked to increased amyloid production, tau pathology, and calcium signaling abnormalities, among other features. While these AD components are detailed in model systems, they have yet to be collectively identified in human neurons. Thus, we conducted molecular, immune-based, electrophysiological, and calcium imaging studies to establish patterns of cellular pathology in this patient population. We found that mPS1 HiNs generate increased Aβ42 and hyperphosphorylated tau species relative to non-AD controls, and exaggerated ER calcium responses that are normalized with ryanodine receptor (RyR) negative allosteric modulators. The inflammasome product, interleukin-18 (IL-18), also increased PS1 expression. This work highlights the potential for HiNs to model AD pathology and validates their role in defining cellular pathogenesis and their utility for therapeutic screening.
Highlights
Animal models expressing PS1 mutations have significantly advanced our understanding of Alzheimer’s disease (AD) pathology but have yet to lead to an effective therapy
We identified that AD human-induced neurons (HiNs) (n = 16 wells) have elevated tau phosphorylation compared to non-AD HiNs (n = 16 wells) (two-tailed t-test, t (1,30) = 2.93; p < 0.01
We found that AD HiNs have a significantly larger somatic ryanodine receptor (RyR)-calcium response (24.4% ± 1.8% over baseline; n = 189) than non-AD HiNs (7.8% ± 1.4% over baseline; n = 125; F(2,318) = 24.38; p < 0.001), effects that were mitigated with dantrolene treatment in the AD neurons (2.5% ± 1.7% over baseline; n = 5; Figure 4A)
Summary
Despite significant resource investment in AD research, a disease-modifying treatment has yet to be found despite promising outcomes in AD animal models. This dichotomy, in large part, likely reflects a limitation in the available model systems which rely heavily on exogenous (over)expression of human AD mutations in rodents or in non-excitable cell lines. While much information has been obtained from these models, the clear disconnect between successful therapeutic indicators in model systems and failed human clinical trials indicates a significant gap in translation. The ability to generate human AD neuronal cells may provide much-needed insight into disease mechanisms and therapeutic targets that are currently unobtainable from animal models or cell lines
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