Alzheimer’s disease (AD) is characterized by hallmark neuropathologies such as amyloid-beta (Aβ) plaques and tau neurofibrillary tangles, leading to progressive cognitive decline. However, the molecular mechanisms contributing to early AD pathogenesis, specifically axonal transport impairments and neuronal hyperexcitability, remain poorly understood. This proposal aims to dissect the roles of axonal transport and neuronal excitability in neurodegeneration, with a particular focus on the function of SORLA (SORL1), a sorting receptor implicated in AD, as a key regulator of amyloid precursor protein (APP) trafficking. Our unique preliminary data suggest that SORLA dysfunction disrupts not only APP processing but also the axonal transport machinery, which could eventually lead to neuronal dysfunction. Utilizing human induced pluripotent stem cell (iPSC)-derived cortical neurons, this project seeks to: 1) elucidate how axonal transport is influenced by SORL1 mutantion, especially the trafficking of endosomes and mitochondria; 2) uncover the relationship between axonal transport deficits and neuronal hyperexcitability; and 3) assess the broad impact of these abnormalities across different SORLA and PSEN1 genetic variants. An important part of this investigation is the modulation of non-muscle myosin II (NMII), which is hypothesized to restore normal axonal transport by correcting cytoskeletal and motor protein interactions disrupted in AD. Through the use of the state-of-the-art models of iPSCs, combined with advanced imaging techniques, electrophysiological profiling, molecular biology assays, and targeted modulation of NMII activity, this research will advance our understanding of the cellular and molecular bases of AD and could identify novel therapeutic targets to alleviate early neuronal dysfunction in AD.

Sustainable Development Goals

Masaryk University is committed to the UN Sustainable Development Goals, which aim to improve the conditions and quality of life on our planet by 2030.