mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia

Fabio Di Domenico, Antonella Tramutola, Cesira Foppoli, Elizabeth Head, Marzia Perluigi, D. Allan Butterfield

Research output: Contribution to journalReview articlepeer-review

69 Scopus citations


The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studies linked the alterations of mTOR pathway to age-dependent cognitive decline, pathogenesis of Alzheimer disease (AD) and AD-like dementia in Down syndrome (DS). DS is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of AD in DS is complex and involves impaired mitochondrial function, defects in neurogenesis, increased oxidative stress, altered proteostasis and autophagy networks as a result of triplication of chromosome 21(chr 21). The chr21 gene products are considered a principal neuropathogenic moiety in DS. Several genes involved respectively in the formation of senile plaques and neurofibrillary tangles (NFT), two main pathological hallmarks of AD, are mapped on chr21. Further, in subjects with DS the activation of mTOR signaling contributes to Aβ generation and the formation of NFT. This review discusses recent research highlighting the complex role of mTOR associated with the presence of two hallmarks of AD pathology, senile plaques (composed mostly of fibrillar Aß peptides), and NFT (composed mostly of hyperphosphorylated tau protein). Oxidative stress, associated with chr21-related Aβ and mitochondrial alterations, may significantly contribute to this linkage of mTOR to AD-like neuropathology in DS.

Original languageEnglish
Pages (from-to)94-101
Number of pages8
JournalFree Radical Biology and Medicine
StatePublished - Jan 2018

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.


  • Amyloid β-peptide
  • Down syndrome
  • Neurofibrillary tangles
  • Oxidative stress
  • Senile plaques
  • mTOR

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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