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Beyond gene-dosage imbalance, trisomy 21 induces widespread transcriptional, metabolic, and proteomic remodeling that establishes a chronic state of proteotoxic and oxidative stress from early development. Increasing evidence identifies DS as a disorder of proteostasis network failure, in which sustained translational pressure, redox disequilibrium, and degradation pathway insufficiency progressively erode cellular resilience. In the DS brain, persistent endoplasmic reticulum stress with PERK-dominant signaling, mitochondrial dysfunction characterized by oxidative phosphorylation deficits and excessive reactive oxygen species production, and impaired antioxidant responses create a highly vulnerable intracellular environment. Concomitantly, degradation systems become compromised: proteasomal catalytic activity declines, ubiquitin-dependent signaling is remodeled, and chronic mTOR hyperactivation suppresses autophagic and mitophagic flux. The coordinated impairment of the ubiquitin\u2013proteasome system and autophagy establish a feed-forward cycle of proteotoxic accumulation and redox amplification. Within this framework, Alzheimer-like neuropathology in DS emerges not solely from amyloid precursor protein triplication but as the late manifestation of decades-long proteostasis exhaustion. Therapeutic strategies aimed at restoring global proteostasis and redox balance may therefore represent a more effective systems-level approach to mitigating neurodegeneration in DS.<\/jats:p>","DOI":"10.3390\/antiox15040520","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T09:01:24Z","timestamp":1776848484000},"page":"520","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: From Mechanisms to Interventions"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9564-2086","authenticated-orcid":false,"given":"Antonella","family":"Tramutola","sequence":"first","affiliation":[{"name":"Department of Biochemical Sciences \u201cA. Rossi-Fanelli\u201d, Sapienza University of Rome, Piazzale A. 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