Investigating neuronal hyperactivity as a link between amyloid-beta and tau spreading in Alzheimer's disease (NeurActAmy)

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In Alzheimer's disease (AD), the amyloid-beta-associated aggregation of tau triggers neurodegeneration and cognitive decline; hence, preventing tau aggregation is a key therapeutic target. Preclinical research found that i) amyloid-beta precipitates neuronal hyperactivity, ii) neuronal hyperactivity promotes synaptic release of soluble hyperphosphorylated tau (p-tau) seeds, and iii) p-tau seeds spread across synapses, ensuing tau aggregation. Similarly, our research in AD patients shows that amyloid-beta-related soluble p-tau increase mediates tau spreading across interconnected brain regions. Therefore, we hypothesize that amyloid-beta drives neuronal hyperactivity, triggering p-tau increase, followed by connectivity-mediated tau spreading in AD. Thus, attenuating amyloid-beta-related neuronal hyperactivity may limit p-tau release, tau aggregation and cognitive decline. To test this hypothesis, we will perform a translational research project combining clinical AD datasets with neuroimaging, fluid biomarkers, electrophysiology, and patient derived neuron cell models. With these translational data, we will assess mechanistic links between amyloid-beta, neuronal hyperactivity, p-tau increase and tau spreading across connected neurons/brain regions. Our findings will be essential to assess neuronal activity as a potential treatment target (e.g. by repurposing approved anti-epileptic drugs) to prevent tau spreading, neurodegeneration and cognitive decline. This work will be instrumental for informing future clinical trials targeting neuronal hyperexcitability for disease modification in AD.