09/09 : LE 13H DE ELSA SUBERBIELLE @ RESTORE

In Alzheimer’s disease (AD), cognitive decline largely precedes neuronal degeneration. Epigenetic processes have emerged as major mechanisms underlying memory. Alterations of the epigenome affect neuronal function, which may, in turn, progressively lead to neurodegeneration. DNA double-strand breaks (DSBs) – the most severe form of DNA damage – are complex epigenetic events, which have recently been shown as part of physiological neuronal activity. In mice overexpressing human amyloid precursor protein (hAPP, line J20), which simulate key aspects of AD, elevated DSBs levels are caused by Amyloid beta (Ab)-induced abnormal neuronal activity.

The mechanisms of generation or repair of activity-dependent DSBs that may be altered by Ab remain unknown, and the pathological contribution of persistent DSBs to cognitive decline, largely unexplored. We showed that AD patients and hAPPJ20 mice had decreased levels of repair factor BRCA1 in their brain. Experimental decrease of BRCA1 expression in the dentate gyrus by RNA interference showed that BRCA1 was essential for the repair of activity-induced DSBs, and that defective DNA repair and persistence of DSBs contribute to cognitive impairment. It did not promote neuronal apoptosis, confirming a new role for DSBs response in the regulation of neuronal function involved in cognitive processes.

Inflammaging, a low-grade inflammation increasing with age is a state that is associated with cognitive decline in normal and pathological aging. Yet, the mechanisms underlying this relationship are unclear, certainly because it is conditioned by multiple factors. Notably, chronic inflammation and persistent brain infections are thought to contribute to these processes. Our ongoing research efforts focus on understanding the interplay of inflammation, infection and the alteration of the DSB response and their contribution to cognitive decline.