Investigating the mechanisms of Alzheimer’s disease-related epileptic activity (360G-Wellcome-207219_Z_17_Z)

Inflammatory-related epilepsy and aberrant neuronal activity are primary consequences of conditions including infection and brain trauma. The consequences of brain trauma have gained significant attention in recent years, given the association between neurodegenerative conditions like Alzheimer’s (AD) and Parkinson’s disease, and repeated concussive injuries such as those related to contact sport and military activities. The AD brain is characterised by the accumulation of the toxic protein beta-amyloid (Abeta). This acts as a chronic inflammatory stimulus, leading to the excessive activation of microglia and subsequent deterioration in neuronal integrity. Abeta induces many of its inflammatory effects through activation of toll-like receptors (TLRs), similarly to some bacterial infections and trauma-induced inflammation; the adverse effects of which are widely recognised. Microglial TLR expression is increased under such conditions, rendering them more sensitive to infectious agents and Abeta. We have previously highlighted the importance of TLR2 in mediating the negative impact of Abeta on microglial activation and neuronal function. We now propose to examine the cellular mechanisms through which TLR2 stimulation conveys sensitivity to the neuronal dysfunction and excitotoxicity associated with Abeta exposure. Elucidating these mechanisms holds the key to identifying strategies for reducing vulnerability to AD in high-risk individuals.