COMBINATION THERAPY OF TYPE 2 DIABETES MEDICATIONS AS A TREATMENT TARGET FOR ALZHEIMER DISEASE

Abstract

Changes in the insulin receptors (IR) signaling pathway are associated with the major neurobiological abnormalities of Alzheimer's disease (AD): Aβ, hyperphosphorylated and conformationally abnormal tau, and reduced synaptic proteins. IR's are particularly abundant in brain regions supporting cognition including the hippocampus and cerebral cortex. Enhanced brain insulin signaling was found to improve memory processes and possesses neuroprotective properties in both healthy and AD patients. Recent studies show that elderly persons with type 2 diabetes (T2D) treated with both insulin and other hypoglycemic medications (combination therapy) have dramatically less AD neuropathology than otherwise similar non-T2D subjects. The aim of this study was to evaluate the effects of combination therapy on AD-like neuropathology and behavior in an AD animal model and to identify molecular-biological pathways affected in AD and restored by combination therapy. Tg2576, an Alzheimer mouse model, and control mice (WT) were randomly divided into 4 groups of medications: Insulin, GLP-1 agonist, combination therapy (Insulin+GLP-1) and saline as a control. At the age of 4 month, Tg2576 and WT mice were randomly divided into 4 groups of nasal treatment administration. When mice reached 11 months of age, they were assessed for learning and memory. Brains were extracted and were assessed for neuropathological changes: amyloid pathology as well as gene expression of IR, neuronal and vascular pathways. No differences in serum insulin levels were found between the medication groups indicating that intranasal treatment did not have periphery systemic effect. Tg2756 mice who received combination therapy had a better learning curve in the Morris water maze than those who received saline or insulin only. No differences were found in insoluble amyloid beta levels in the hippocampus. The genes altered in AD animals and which were restored to normal levels or even improved by combination therapy of T2D medications, were primarily of vascular signaling (e.g. FTO, HILPDA) rather than from the insulin receptor signaling pathway. Combination therapy of insulin with a GLP1 agonist may have neuroprotective effects against AD-like behavior. These effects may be mediated via the vascular pathway.