Metabolic Mechanisms Connecting Alzheimer's and Parkinson's Diseases: Potential Avenues for Novel Therapeutic Approaches

Alzheimer's (AD) and Parkinson's Diseases (PD) are common neurodegenerative disorders growing in incidence and prevalence and for which there are no disease-modifying treatments. While there are considerable complexities in the presentations of these diseases, the histological pictures of these pathologies, as well as several rare genetic predispositions for each, point to the involvement of maladaptive protein processing and inflammation. Importantly, the common presentations of AD and PD are connected to aging and to dysmetabolism, including common co-diagnosis of metabolic syndrome or diabetes. Examination of anti-diabetic therapies in preclinical models and in some observational clinical studies have suggested effectiveness of the first generation insulin sensitizer pioglitazone in both AD and PD. Recently, the mitochondrial pyruvate carrier (MPC) was shown to be a previously unrecognized target of pioglitazone. New insulin sensitizers are in development that can be dosed to full engagement of this previously unappreciated mitochondrial target. Here we review molecular mechanisms that connect modification of pyruvate metabolism with known liabilities of AD and PD. The mechanisms involve modification of autophagy, inflammation, and cell differentiation in various cell types including neurons, glia, macrophages, and endothelium. These observations have implications for the understanding of the general pathology of neurodegeneration and suggest general therapeutic approaches to disease modification.

Automated summary

Alzheimer's and Parkinson's Diseases are neurodegenerative disorders with no disease-modifying treatments currently available. These diseases involve maladaptive protein processing and inflammation, and are connected to aging and dysmetabolism. The insulin sensitizer pioglitazone has shown effectiveness in both diseases, and its previously unrecognized target, the mitochondrial pyruvate carrier, has been discovered. Understanding the molecular mechanisms of pyruvate metabolism modification is important for understanding the general pathology of neurodegeneration and developing therapeutic approaches.