Investigating the Role of Inositol 1,4,5-Trisphosphate Receptors in the Pathogenesis of Alzheimer’s Disease Through Computational Modeling

Alzheimer’s disease (AD) is the most common form of dementia, characterized by the progressive accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles of tau protein in and around neurons. However, these markers appear relatively late in the disease, and their direct causality is incompatible with clinical observations. Extensive data suggest that dysregulation of Ca2+ signaling is an early event in the pathogenesis of AD. In familial AD (FAD), mutations in presenilin are shown to alter Ca2+ homeostasis by affecting the gating properties and/or the expression levels of inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) and ryanodine receptor (RyRs)—the main channels responsible for Ca2+ release from the endoplasmic reticulum (ER). Thus, understanding the mechanism through which these channels disrupt Ca2+ homeostasis at different spatiotemporal scales is crucial to determining their role in AD. Here, we use computational modeling to investigate how the gating kinetics of single IP3R in FAD-affected cells differ from those in wildtype (WT) cells and how these differences translate to impaired Ca2+ signaling at subcellular and whole-cell levels. Our detailed analysis reveals a significantly lower threshold for Ca2+ oscillations at the whole-cell level in terms of agonist concentration, with higher frequency and amplitudes in FAD-affected cells. These results shed new light on the observed Ca2+ hyperactivity in the pre-clinical stage of AD, reporting high-frequency Ca2+ oscillations in neurons.