Loss of Proteostasis and Abnormal Aging in Down Syndrome: From Mechanisms to Interventions

Topic: Brain proteins, microglia and lab models

Down syndrome (DS), caused by trisomy 21, is the most prevalent genetic condition associated with accelerated aging and near-universal development of early-onset Alzheimer’s disease (AD). 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 insuffi-ciency progressively erode cellular resilience.

Key findings

• 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 insuffi-ciency progressively erode cellular resilience.
• In the DS brain, persistent endoplasmic reticulum stress with PERK-dominant signaling, mitochondrial dysfunction characterized by oxidative phosphorylation deficits and exces-sive 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 mi-tophagic flux.

Why it matters

This review describes Down syndrome as a disorder of proteostasis network failure that contributes to accelerated aging and early-onset Alzheimer's disease. It discusses mechanisms only and reports no tested treatment, cure, or prevention.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.20944/preprints202603.1305.v1
• Original source →

Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.

@article{tramutola2026-08b5b6ac,
  author  = {Tramutola, A. and Lanzillotta, C. and Di Domenico, F. and Barone, E. and Perluigi, M.},
  title   = {{Loss of Proteostasis and Abnormal Aging in Down Syndrome: From Mechanisms to Interventions}},
  journal = {Antioxidants (Basel, Switzerland)},
  year    = {2026},
  doi     = {10.20944/preprints202603.1305.v1},
  url     = {https://doi.org/10.20944/preprints202603.1305.v1}
}

Related studies in Down syndrome and Alzheimer's

• Loss of Proteostasis and Early-Onset Neurodegeneration in Down Syndrome: From Mechanisms to Interventions Antioxidants (Basel, Switzerland) · 2026-04-21 · usefulness score 39/100
• The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates Frontiers in medicine · 2018-03-12 · usefulness score 52/100
• [Transgenic mice overexpressing copper-zinc superoxide dismutase: a model for the study of radical mechanisms and aging] Comptes rendus des seances de la Societe de biologie et de ses filiales · 1993-01-01 · usefulness score 32/100
• Cognitive enhancement by pharmacological and behavioral interventions: the murine Down syndrome model Biochemical pharmacology · 2012-08-08 · usefulness score 36/100
• Impairment of proteostasis network in Down syndrome prior to the development of Alzheimer's disease neuropathology: redox proteomics analysis of human brain Biochimica et biophysica acta · 2013-04-18 · usefulness score 36/100
• Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and Down syndrome Neurobiology of aging · 2004-11-01 · usefulness score 41/100

Also tagged “down”

527 studies in the library carry the topic tag “down”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 527 tagged studies.

• Exploring the relationship between epilepsy and neurodegenerative diseases Romanian Journal of Neurology · 2025-09-21 · usefulness score 38/100 · Down syndrome and Alzheimer's
• Motion perception deficit in Down Syndrome Neuropsychologia · 2015-06-06 · usefulness score 32/100 · Down syndrome and Alzheimer's
• Forensic issues in Down syndrome fatalities Journal of forensic and legal medicine · 2007-03-26 · usefulness score 30/100 · Down syndrome and Alzheimer's

Similar studies

• Aging in Down Syndrome and the Development of Alzheimer's Disease Neuropathology 2016 · Inflammation and the immune system
• The Genetics and Mechanisms of Alzheimer's Disease in Down Syndrome 2026 · Down syndrome and Alzheimer's
• [Biochemical alterations in patients with Down syndrome] 2008 · Down syndrome and Alzheimer's
• Clinical aspects of Down syndrome from infancy to adulthood 1990 · Down syndrome and Alzheimer's
• An investigation of the molecular mechanisms engaged before and after the development of Alzheimer disease neuropathology in Down syndrome: a proteomics approach 2014 · Down syndrome and Alzheimer's
• Glucose, memory, and aging 1998 · Down syndrome and Alzheimer's

More on Down syndrome and Alzheimer's

• A review that covers this ground Mitochondrial dysfunction in down syndrome: molecular mechanisms and therapeutic targets Molecular medicine (Cambridge, Mass.) · 2018-03-15 · usefulness score 41/100
• Newest in this subject Differential endothelial cell remodeling in Down syndrome and APP duplication drives distinct blood brain barrier dysfunction bioRxiv · 2026-10-30 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Memory and Plasma pTau217 Refine Prognosis in Down Syndrome Annals of neurology · 2026-10-02 · Peer-reviewed · usefulness score 47/100

See all studies in Down syndrome and Alzheimer's →