Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Panminerva Med. 2012 Sep;54(3):171-8.

Metabolic derangements mediate cognitive impairment and Alzheimer's disease: role of peripheral insulin-resistance diseases.

Author information

  • Department of Neuropathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA. Suzanne_DeLaMonte_MD@Brown.edu

Abstract

Herein, we review evidence that systemic insulin-resistance diseases linked to obesity, type 2 diabetes, and non-alcoholic steatohepatitis promote neurodegeneration. Insulin-resistance dysregulates lipid metabolism, which promotes ceramide accumulation with attendant inflammation and endoplasmic reticulum (ER) stress. Mechanistically, we propose that toxic ceramides generated in extra-CNS tissues, e.g. liver, get released into peripheral blood, and subsequently transit across the blood-brain barrier into the brain where they induce brain insulin-resistance, inflammation, and cell death (extrinsic pathway). These abnormalities establish or help propagate a cascade of neurodegeneration associated with increased ER stress and ceramide generation, which exacerbate brain insulin-resistance, cell death, myelin degeneration, and neuro-inflammation. The data suggest that a mal-signaling network mediated by toxic ceramides, ER stress, and insulin-resistance should be targeted to disrupt positive feedback loops that drive the AD neurodegeneration cascade.

PMID:
22801434
[PubMed - indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Loading ...
    Write to the Help Desk