Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models

Abstract

Type 2 diabetes is a risk factor for several chronic neurodegenerative disorders such as Alzheimer's or Parkinson's disease. The link appears to be insulin de-sensitisation in the brain. Insulin is an important neuroprotective growth factor. GLP-1 and GIP are growth factors that re-sensitise insulin and GLP-1 mimetics are used in the clinic to treat diabetes. GLP-1 and GIP mimetics initially designed to treat diabetes show good protective effects in animal models of Alzheimer's and Parkinson's disease. Based on these results, several clinical trials have shown first encouraging effects in patients with Alzheimer's or Parkinson' disease. Novel dual GLP-1/GIP receptor agonists have been developed to treat diabetes, and they also show good neuroprotective effects that are superior to single GLP-1 analogues. Several newer dual analogues have been tested that have been engineered to cross the blood -brain barrier. They show clear neuroprotective effects by reducing inflammation and oxidative stress and apoptotic signalling and protecting memory formation, synaptic numbers and synaptic activity, motor activity, dopaminergic neurons, cortical activity and energy utilisation in the brain. These results demonstrate the potential of developing disease-modifying treatments for Alzheimer's and Parkinson's disease that are superior to current single GLP-1 mimetics. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

Keywords: GIP; GLP-1; Growth factors; Inflammation; Insulin; Neurodegeneration.