In this issue of the JCI
, two studies make great strides in revealing a molecular pathway in AD that can be modified by drugs already approved by the FDA for other indications (4
). Previous studies have suggested that the molecular pathophysiology of AD significantly overlaps with that of type 2 diabetes and the metabolic syndrome, most notably in insulin resistance. Talbot et al. now demonstrate that insulin resistance in AD occurs not only in peripheral tissues, but also in the brain (4
). The authors show that hippocampal brain slices in AD were less responsive to insulin than controls because of increased phosphorylation of IRS-1 that attenuated downstream Akt and ERK signaling. Brain insulin resistance in AD was not dependent on diabetes, or on the APOE4
genotype, which also affects the Akt pathway (6
) and is a major determinant of risk for non-Mendelian AD.
Demonstrating insulin resistance in the AD brain has therapeutic implications, since this pathway can be modified by FDA-approved insulin-sensitizing drugs: metformin, the glucagon-like peptide–1 (GLP-1) mimetics exenatide and liraglutide, and PPARγ agonists. Also in this issue, Bomfim et al. demonstrate a critical role of the soluble Aβ oligomer in producing brain insulin resistance in AD and successfully demonstrate pharmacologic manipulation of this pathway by a GLP-1 agonist (5
). Using multiple model systems, the authors show that soluble Aβ oligomers increased the production of the inflammatory cytokine TNF-α, leading to phosphorylation of IRS-1 by JNK. Moreover, a small-molecule activator of the GLP-1 receptor, developed to treat type 2 diabetes, reduced the phosphorylation of IRS-1 in the brain and improved cognition in a mouse model of AD.
Additional support for the pharmacologic enhancement of insulin signaling to treat AD comes from other investigators who have shown that nasally inhaled insulin improved clinical outcomes in small trials (7