Editors' ChoiceAlzheimer’s Disease

Diseases of Resistance

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Science Translational Medicine  04 Apr 2012:
Vol. 4, Issue 128, pp. 128ec60
DOI: 10.1126/scitranslmed.3004067

Reduced cellular responsiveness to insulin gradually erodes our health. It is well known that type 2 diabetes results from such insulin resistance in peripheral tissues. Recent findings also indicate that insulin resistance in the brain might be a causal factor for Alzheimer’s disease (AD)—and two new studies provide insight into this connection.

Talbot et al. found that levels of insulin and its associated signaling molecules were normal in postmortem brain samples from AD patients and that insulin signaling could be activated in these samples. However, signaling was strongly reduced in the hippocampal formation (which shows signs of disease early in AD) and moderately reduced in the cerebellar cortex (which shows signs of disease late in AD). Such reduced responses correlated with serine phosphorylation of insulin receptor substrate (IRS), a critical component of insulin signaling. Levels of phosphorylated IRS (pS-IRS) were increased in the hippocampal formation in AD brains as compared with the brains of non–cognitively impaired subjects—regardless of diabetes status.

Bomfim et al. likewise found that pS-IRS is increased in the AD brain, as it is in peripheral tissues in diabetes. Furthermore, they found that amyloid-β (Aβ) peptide oligomers, which form neuritic plaques in the AD brain, induce pS-IRS in cultured rat hippocampal neurons and in the hippocampi of monkeys after injection into the brain, where Aβ oligomers also elicit an inflammatory response.

Inflammatory kinases such as c-Jun N-terminal kinases (JNKs) are mediators of metabolic stress–induced pS-IRS in type 2 diabetes. Bomfim et al. demonstrate that these stress kinases are involved in the induction of pS-IRS in AD. In hippocampal neurons, Aβ-mediated pS-IRS levels are diminished by inhibition of JNK. Administration of an approved antidiabetic medicine that stimulates the insulin signaling pathway decreases JNK activation and pS-IRS levels in the brain and improves cognition in a mouse model of AD.

These studies shed light on a curious relationship between AD and type 2 diabetes: Insulin resistance haunts both diseases. Unraveling their common features may pave the way for their prevention and eventual cure. Indeed, the impact of antidiabetic medicine on AD is of great importance to the development of therapeutic strategies to combat AD.

K. Talbot et al., Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Invest. 22 March 2012 (10.1172/JCI59903). [Full Text]

T. R. Bomfim et al., An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers. J. Clin. Invest. 22 March 2012 (10.1172/JCI57256). [Full Text]

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