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

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.

This translational study will systematically assess how amyloid-beta drives tau spreading in Alzheimer's disease (AD). Specifically, we will test whether amyloid-beta triggers neuronal hyperactivity, ensuing increased activity-dependent phosphorylated-tau (p-tau) secretion and faster p-tau dependent tau spreading across connected neurons. For clinical data, we will recruit 35 amyloid-beta-positive subjects in Munich who will undergo amyloid-beta/tau-PET, EEG, resting-state functional MRI and plasma p-tau assessments. For validation, we will add an ongoing cohort in Sheffield with amyloid-beta-PET, EEG/MEG and plasma tau data from 20 AD patients. In these samples, we will assess whether i) higher global amyloid-beta-PET is associated with neuronal hyperactivity (i.e. slope of aperiodic 1/f background in EEG/MEG), ii) whether neuronal hyperactivity drives p-tau increases, and iii) whether higher p-tau predicts higher tau-PET uptake in brain regions connected to temporal-lobe tau epicentres. For preclinical data, we will establish AD patient-derived iNPC neuron cultures on multi-electrode array systems to monitor neuronal activity. In these AD model systems, we will assess whether amyloid-beta production relates to neuronal activity, and whether neuronal hyperactivity drives neuronal p-tau secretion and trans-neuronal tau spreading using tau seeding assays. Lastly, we will determine whether tau spreading can be attenuated by applying neuronal activity lowering drugs (i.e. levetiracetam).