Project description
Mitochondrial heat production and Alzheimer’s disease
Alzheimer’s disease is a leading cause of dementia, affecting millions of people worldwide. However, we lack complete understanding of the underlying triggers. A key event in disease development is the abnormal processing of amyloid precursor protein (APP), a transmembrane protein concentrated in neuron synapses. APP is cleaved to produce amyloid-beta peptides that accumulate and cause synaptic dysfunction and cognitive decline. With the support of the Marie Skłodowska-Curie Actions programme, the ThermAPP project aims to investigate the hypothesis that heat generated by neuronal mitochondria can serve as a pathogenic driver, destabilising the molecular machinery responsible for APP processing. Project results could open new avenues for the design of novel therapies that target temperature-sensitive molecular pathways.
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules
- medical and health sciences basic medicine neurology neurodegenerative diseases dementia
- natural sciences biological sciences genetics mutation
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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(opens in new window) HORIZON-MSCA-2025-PF
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9052 ZWIJNAARDE - GENT
Belgium
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