ThermAPP · When neurons run hot: γ-Secretase thermal vulnerability as an Alzheimer's pathogenic mechanism

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Project objective

Alzheimer’s disease (AD) is the leading cause of dementia, yet current therapies provide only modest benefit. Mutations in presenilin (PSEN1/2), the catalytic subunit of γ-secretase (GSEC), cause familial AD by destabilizing the GSEC–APP/C99 complex and shifting processing toward longer, aggregation-prone Aβ42/43 peptides. Importantly, even wild-type GSEC produces small amounts of these species, suggesting that subtle complex destabilization also contributes to sporadic AD. This raise a critical unresolved question: what triggers this instability in the absence of mutations?I hypothesize that neuronal thermogenesis destabilizes GSEC–APP complexes, promoting pathogenic Aβ production. Synaptic mitochondria, acting as local bioenergetic hubs, can generate transient temperature rises of several degrees. Our preliminary data show that fever-range heating induces “FAD-like” Aβ profiles, supporting temperature as a direct pathogenic driver.Aim 1 will define thermal thresholds for GSEC dysfunction by quantifying Aβ peptide ratios across controlled temperature gradients in iPSC-derived neurons and synaptosomes.Aim 2 will establish the causal link between mitochondrial heat production and pathogenic Aβ using genetically encoded thermosensors in live neurons.Aim 3 will assess thermal susceptibility of GSEC in neurons transdifferentiated from aged and AD patient fibroblasts, integrating thermogenesis, aging, and APP processing.This project introduces thermodynamics as a novel mechanism in AD pathogenesis and paves the way for translational opportunities. Identifying temperature-sensitive molecular nodes may enable development of small-molecule GSEC stabilizers or mitochondrial modulators as disease-modifying therapies for both familial and sporadic AD.

Original text from CORDIS.

Participants

• VIB VZW · ZWIJNAARDE - GENTCoordinatorBelgium

Links

• View on CORDIS
• DOI: 10.3030/101283097