The protective paradox: APOE3ch and disease-associated microglia regulating calcium signaling impact the niche in Alzheimer resilience
Year: 2025
Type: article
Abstract: Alzheimer’s disease (AD) resilience refers to the preservation of cognitive function despite substantial neuropathological burden. Among the most informative examples is the APOE3-Christchurch (APOE3ch; R136S) variant, which has been associated with delayed clinical expression of autosomal dominant AD despite extensive amyloid deposition. This review examines APOE3ch as a natural model for investigating protective biology in AD, with particular attention to ApoE–heparan sulfate proteoglycan (HSPG) interactions, tau handling, plaque microenvironment dynamics, disease-associated microglia (DAM), and microglial calcium (Ca²⁺) signaling. Current evidence supports a role for APOE3ch in weakening ApoE–HSPG interactions and modifying tau-related pathological processes. HSPG sulfation patterns also influence tau internalization and proteopathic spread, while TREM2-dependent DAM responses may exert stage-specific protective or harmful effects. Microglial Ca²⁺ signaling, including store-operated calcium entry through Orai/STIM pathways, is increasingly recognized as a key regulator of microglial motility, phagocytosis, cytokine release, and transcriptional programming. However, direct evidence linking APOE3ch-mediated HSPG disruption to altered microglial Ca²⁺ dynamics remains lacking. Therefore, this review proposes the APOE3ch–HSPG–Ca²⁺–DAM axis as a hypothesis-generating framework rather than an established mechanistic pathway. We highlight current evidence, identify inferential gaps, discuss alternative mechanisms of resilience, and outline experimental strategies needed to test whether APOE3ch-associated extracellular remodeling influences microglial Ca²⁺ signaling and protective DAM states. Therapeutic translation will require genotype-sensitive designs, human-relevant models, spatiotemporal resolution, validated biomarkers, and careful safety evaluation.
Source: DergiPark (Istanbul University)
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7217797969