Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: Mechanisms and Therapeutic Approaches

This research examines how Down syndrome (trisomy 21) causes accelerated aging and early-onset Alzheimer's disease through widespread failure of the cellular proteostasis network, including endoplasmic reticulum stress, mitochondrial dysfunction, and compromised protein degradation systems. The chronic proteotoxic and oxidative stress state, sustained from early development, establishes a feed-forward cycle of protein accumulation and cellular damage that progressively erodes resilience and explains the emergence of Alzheimer-like pathology in the DS brain.