Unravelling the Role of Cerebral Amyloid-beta Angiopathy in Epilepsy: Inflammatory Pathways and Interneuron Dysfunction

Cel

Late-onset epilepsy is a growing yet underexplored medical condition/disease in the aging population. Clinical studies increasingly associate cerebral amyloid-β (Aβ) angiopathy (CAA) – the accumulation/aggregation of Aβ in cerebral vessels – with high seizure incidence, especially in the inflammation-driven CAA subtype. However, the mechanisms by which CAA contributes to epileptogenesis remain unclear.
I hypothesise that CAA creates an inflammatory microenvironment that selectively impairs cortical inhibitory interneurons, leading to disrupted network inhibition and heightened seizure susceptibility.
To test this, I will use well-characterized transgenic CAA mouse models together with post-mortem human CAA tissue to:
(1) map the spatiotemporal progression of interneuron degeneration;
(2) profile glial and vascular inflammatory responses using multiplex immunohistochemistry and single-nucleus multi-omics;
(3) assess seizure susceptibility and network hyperexcitability in vivo using electroencephalography (EEG) and seizure susceptibility assays, and test whether anti-inflammatory intervention can mitigate these phenotypes.
By integrating interneuron mapping, inflammatory profiling, and functional network assessment, EPICAA will provide mechanistic insight into how CAA contributes to late-onset epilepsy and nominate therapeutic targets for seizure prevention in cerebrovascular disease.
My expertise in EEG and network pathology, combined with know-how in aged CAA mouse models and vascular inflammation in my host lab, ensures feasibility. Through EPICAA, I will receive hands-on training in single-nucleus multi-omics and vascular amyloidosis while transferring my expertise in network hyperexcitability. Targeted career development (leadership, grant writing, mentoring), open science, and proactive dissemination will maximise impact and position me to transition to research independence, strengthening European capacity in brain ageing and epilepsy research.