Publication
Tuberous sclerosis complex‐1 (TSC1) contributes to selective neuronal vulnerability in Alzheimer's disease
Publisher:
Wiley
Date:
11-05-2023
DOI:
10.1111/NAN.12904
Abstract: Selective neuronal vulnerability of hippoc al Cornu Ammonis (CA)‐1 neurons is a pathological hallmark of Alzheimer's disease (AD) with an unknown underlying mechanism. We interrogated the expression of tuberous sclerosis complex‐1 (TSC1 hamartin) and mTOR‐related proteins in hippoc al CA1 and CA3 subfields. A human post‐mortem cohort of mild ( n = 7) and severe ( n = 10) AD and non‐neurological controls ( n = 9) was used for quantitative and semi‐quantitative analyses. We also developed an in vitro TSC1 knockdown model in rat hippoc al neurons, and transcriptomic analyses of TSC1 knockdown neuronal cultures were performed. We found a selective increase of TSC1 cytoplasmic inclusions in human AD CA1 neurons with hyperactivation of one of TSC1's downstream targets, the mammalian target of rapamycin complex‐1 (mTORC1), suggesting that TSC1 is no longer active in AD. TSC1 knockdown experiments showed accelerated cell death independent of amyloid‐beta toxicity. Transcriptomic analyses of TSC1 knockdown neuronal cultures revealed signatures that were significantly enriched for AD‐related pathways. Our combined data point to TSC1 dysregulation as a key driver of selective neuronal vulnerability in the AD hippoc us. Future work aimed at identifying targets amenable to therapeutic manipulation is urgently needed to halt selective neurodegeneration, and by extension, debilitating cognitive impairment characteristic of AD.