Reducing ribosomal protein S6 kinase 1 expression improves spatial memory and synaptic plasticity in a mouse model of Alzheimer’s disease

Antonella Caccamo, Caterina Branca, Joshua S. Talboom, Darren M. Shaw, Dharshaun Turner, Luyao Ma, Angela Messina, Zebing Huang, Jie Wu, Salvatore Oddo

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Aging is the most important risk factor associated with Alzheimer’s disease (AD); however, the molecular mechanisms linking aging to ADremain unclear. Suppression of the ribosomal protein S6 kinase 1 (S6K1) increases healthspan and lifespan in several organisms, from nematodes to mammals. Here we show that S6K1 expression is upregulated in the brains of AD patients. Using a mouse model of AD, we found that genetic reduction of S6K1 improved synaptic plasticity and spatial memory deficits, and reduced the accumulation of amyloid-β and tau, the two neuropathological hallmarks of AD. Mechanistically, these changes were linked to reduced translation of tau and the β-site amyloid precursor protein cleaving enzyme 1, a key enzyme in the generation of amyloid-β. Our results implicate S6K1 dysregulation as a previously unidentified molecular mechanism underlying synaptic and memory deficits in AD. These findings further suggest that therapeutic manipulation of S6K1 could be a valid approach to mitigate AD pathology.

Original languageEnglish (US)
Pages (from-to)14042-14056
Number of pages15
JournalJournal of Neuroscience
Volume35
Issue number41
DOIs
StatePublished - Oct 14 2015

Fingerprint

Ribosomal Protein S6 Kinases
Neuronal Plasticity
Alzheimer Disease
Memory Disorders
Amyloid
Amyloid beta-Protein Precursor
Brain Diseases
Enzymes
Spatial Memory
Mammals
Pathology

Keywords

  • AD
  • Aging
  • mTOR
  • Plaques
  • Tangles

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Reducing ribosomal protein S6 kinase 1 expression improves spatial memory and synaptic plasticity in a mouse model of Alzheimer’s disease. / Caccamo, Antonella; Branca, Caterina; Talboom, Joshua S.; Shaw, Darren M.; Turner, Dharshaun; Ma, Luyao; Messina, Angela; Huang, Zebing; Wu, Jie; Oddo, Salvatore.

In: Journal of Neuroscience, Vol. 35, No. 41, 14.10.2015, p. 14042-14056.

Research output: Contribution to journalArticle

Caccamo, Antonella ; Branca, Caterina ; Talboom, Joshua S. ; Shaw, Darren M. ; Turner, Dharshaun ; Ma, Luyao ; Messina, Angela ; Huang, Zebing ; Wu, Jie ; Oddo, Salvatore. / Reducing ribosomal protein S6 kinase 1 expression improves spatial memory and synaptic plasticity in a mouse model of Alzheimer’s disease. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 41. pp. 14042-14056.
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