BEYOND AMYLOID AND TAU: AAV DELIVERY OF CELLULAR RESILIENCE ENHANCER PREVENTS COGNITIVE DECLINE IN ALZHEIMER’S DISEASE MOUSE MODEL

Alzheimer’s disease (AD) is characterised by the accumulation of amyloid plaques and tau tangles. These protein aggregates induce proteotoxic stress, disrupt cellular homeostasis and contribute to neurodegeneration. However, therapeutics aimed at clearing amyloid plaques and tau tangles have demonstrated limited clinical benefit, and many individuals with substantial amyloid and tau pathology do not develop memory loss. These findings suggest that amyloid plaques and tau tangles alone are insufficient to explain disease onset and progression, highlighting a critical gap in understanding the contribution of cellular resilience in the diseased brain.
We aimed to develop and validate a novel adeno-associated viral (AAV) vector-based therapeutic strategy that enhances intrinsic cellular resilience to mitigate AD progression. Rather than focusing exclusively on eliminating protein aggregates, this approach builds on our discovery of a stress-resilience mechanism termed SITA (Stress Induced Transcriptional Attenuation). SITA enables cells to suppress non essential transcription during proteotoxic stress, thereby preserving resources required for maintaining proteostasis.
Our data demonstrate that SITA deficiency accelerates disease progression in mouse models of AD, whereas enhancing SITA through AAV delivery in diseased brains restored SITA function and prevented the onset of cognitive decline. Together, these findings shift the therapeutic paradigm from eliminating protein aggregates toward strengthening cellular resilience, establishing a new avenue for AAV therapeutics in neurodegeneration.