BPS2026 – Mitochondrial hypermetabolism and dysregulation of ATP synthase leak channel in a humanized APP/PSEN1 Alzheimer’s disease mouse model

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and memory loss. Despite its increasing global burden, AD lacks effective disease-modifying therapies. There is growing evidence implicating mitochondrial dysfunction as a central driver of disease progression. However, the precise mechanisms linking mitochondrial impairment to AD progression remain poorly understood. Impaired ATP synthesis and activation of the mitochondrial permeability transition pore (mPTP) may contribute to synaptic damage, energy deficits, and neuronal death. This study aims to investigate the role of ATP synthase inhibitory factor 1 (IF1) in mitochondrial dysfunction in AD-related neurodegeneration by using a humanized AD mouse model (hAD) expressing human amyloid-beta (Aβ) precursor protein (APP) and presenilin-1 (PSEN1) genes, recapitulating key features of familial AD, including Aβ plaque deposition. We assessed the oligomeric state and subunit composition of ATP synthase and mitochondrial function in mice in an age-dependent manner. Changes in mitochondrial morphology and bioenergetic function were measured through a combination of electron microscopy imaging, high-resolution respirometry (Oroboros), and lipid-bilayer electrophysiology. Our preliminary findings reveal significant age-dependent bioenergetic impairments in hAD mice, characterized by a hypermetabolic phenotype with increased oxygen consumption compared to WT controls. In addition, the expression of IF1 decreased in an age-dependent manner that correlated with mitochondrial dysfunction. Electrophysiological recordings from inner mitochondrial vesicles further demonstrated channels with more frequent and prolonged openings in hAD mice relative to WT, consistent with enhanced mitochondrial permeability. These findings highlight ATP synthase’s role in mitochondrial dysfunction as a critical driver of neurodegeneration in AD. Future studies will focus on translating these findings into clinically relevant strategies, including the development of mitochondria-targeted therapies for AD patients.