Glucagon-Like Peptide-1-Mediated Modulation of Inflammatory Pathways in the Diabetic Brain: Relevance to Alzheimer's Disease

Neuroinflammation has emerged as an important cause of cognitive decline during aging and in Alzheimer's disease (AD). Chronic low-grade inflammation is observed in obesity and diabetes, which are important risk factors for AD. Therefore, we examined the markers of inflammation in the brain hippocampal samples of Zucker diabetic fatty (ZDF) rats. Pathway-specific gene expression profiling revealed significant increases in the expression of oxidative stress and inflammatory genes. Western blot analysis further showed the activation of NF-kB, defective CREB phosphorylation, and decreases in the levels of neuroprotective CREB target proteins, including Bcl-2, BDNF, and BIRC3 in the diabetic rat brain samples, all of which are related to AD pathology. As therapies based on glucagon-like peptide-1 (GLP-1) are effective in controlling blood glucose levels in type 2 diabetic patients, we tested the in vivo actions of GLP-1 in the diabetic brain by a 10-wk treatment of ZDF rats with alogliptin, an inhibitor of dipeptidyl peptidase. Alogliptin increased the circulating levels of GLP-1 by 125% and decreased blood glucose in diabetic rats by 59%. Normalization of defective signaling to CREB in the hippocampal samples of treated diabetic rats resulted in the increased expression of CREB targets. Dual actions of GLP-1 in the pancreatic beta cells and in the brain suggest that incretin therapies may reduce cognitive decline in the aging diabetic patients and also have the potential to be used in treating Alzheimer's patients.