Genetically reducing mTOR signaling rescues central insulin dysregulation in a mouse model of Alzheimer's disease

Antonella Caccamo, Ramona Belfiore, Salvatore - Oddo

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease. The causes of sporadic AD, which represents more than 95% of AD cases, are unknown. Several AD risk factors have been identified and among these, type 2 diabetes increases the risk of developing AD by 2-fold. However, the mechanisms by which diabetes contributes to AD pathogenesis remain elusive. The mammalian target of rapamycin (mTOR) is a protein kinase that plays a crucial role in the insulin signaling pathway and has been linked to AD. We used a crossbreeding strategy to remove 1 copy of the mTOR gene from the forebrain of Tg2576 mice, a mouse model of AD. We used 20-month-old mice to assess changes in central insulin signaling and found that Tg2576 mice had impaired insulin signaling. These impairments were mTOR dependent as we found an improvement in central insulin signaling in mice with lower brain mTOR activity. Furthermore, removing 1 copy of mTOR from Tg2576 mice improved cognition and reduced levels of Aβ tau, and cytokines. Our findings indicate that mTOR signaling is a key mediator of central insulin dysfunction in Tg2576. These data further highlight a possible role for mTOR signaling in AD pathogenesis and add to the body of evidence indicating that reducing mTOR activity could be a valid therapeutic approach for AD.

Original languageEnglish (US)
Pages (from-to)59-67
Number of pages9
JournalNeurobiology of Aging
Volume68
DOIs
StatePublished - Aug 1 2018

Fingerprint

Sirolimus
Alzheimer Disease
Insulin
Genetic Hybridization
Prosencephalon
Neurodegenerative Diseases
Protein Kinases
Type 2 Diabetes Mellitus
Cognition
Cytokines
Brain

Keywords

  • AD
  • Amyloid beta
  • Diabetes
  • Glucose
  • Tangles
  • Tau

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Genetically reducing mTOR signaling rescues central insulin dysregulation in a mouse model of Alzheimer's disease. / Caccamo, Antonella; Belfiore, Ramona; Oddo, Salvatore -.

In: Neurobiology of Aging, Vol. 68, 01.08.2018, p. 59-67.

Research output: Contribution to journalArticle

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