Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent neurodegenerative disorders. Despite their pathophysiological and clinical differences, they share several mechanistic similarities at cellular and sub-cellular levels. The current treatments of AD and PD are only symptomatic, since many clinically -tested drugs failed to prevent or halt their progression. There is now evidence that type 2 diabetes mellitus is among the main risk factors for AD and PD and that the insulin resistance in the brain plays a crucial role in their neuropathological processes. Therefore, insulin nasal ad-ministration was suggested for the treatment of AD and PD, both in diabetic and non-diabetic patients. However, the adverse effects of chronic insulin prompted the research of alternative strategies, such as the novel antidia-betic drugs based on the incretin hormones glucagon-like protein-1 (GLP-1) and glucose-dependent insulinotro-pic Peptide (GIP). The rapid inactivation of these incretins by dipeptidyl-peptidase IV (DPP-IV) suggested the development of DPP-IV-resistant GLP-1 receptor agonists (GLP-1Ras), the recent dual GLP-1/GIP receptor ago-nists and the DPP-IV inhibitors (DPP-IVis).This review will first describe the experimental, pathophysiological and clinical approach for AD and PD treat-ment with insulin. Afterwards, the main pharmacologic properties of GLP-1Ras and of DPP-IVis will be discussed, detailing their ability to cross the BBB and get access to the brain for GLP-1Ras, and the novel strategies for BBB crossing as regards DPP-IVis. Emphasis will be placed on the main findings obtained from AD and PD experimen-tal models about the neuroprotective effects of these drugs. For AD, the improvement of learning and memory exerted by incretin-based drugs correlated with reduction of chronic inflammation, brain AI3 plaque, tau hyperphosphorylation, protection of mitochondria, enhancement of energy utilisation. For PD, both GLP-1Ras and of DPP-IVis reversed the nigrostriatal dopaminergic cell loss progression, restored dopamine synthesis, exerted anti-inflammatory activity and improved motor functions.Finally, the encouraging results of the first clinical trials on AD and PD patients and the adverse effects of GLP-1Ras and DPP-IVis will be discussed, highlighting how the above-mentioned neuroprotective effects have a great potential to be translated into clinical settings and that the incretin-based approach represents novel prom-ising strategy for the treatment of AD and PD, although more convincing clinical pieces of evidence are required. In perspective, the new approaches that are being developed to allow GLP-1Ras and DPP-IVis rapid entering into the Central Nervous System may substantially contribute to their repurposing for neurodegenerative disease.(c) 2022 Elsevier Inc. All rights reserved.
