Metabolic dysfunction in Alzheimer's disease and related neurodegenerative disorders

Abstract

Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.

Fig. 1

An overview of some of the relationships between metabolic dysfunction, neurodegenerative disorders, and potential therapies. Metabolic dysfunction including impaired glucose metabolism, insulin resistance and abnormal appetite regulation are now known to be comorbid with AD and some other chronic neurodegenerative disorders, such as HD and PD. Treatments that target metabolic malfunctions may be effective for modifying neurodegenerative-disease pathology and symptoms. IGF-1 (insulin-like growth factor-1); PPARs (peroxisome proliferator-activated receptors); DPP-4 (dipeptidyl peptidase-4); APP (amyloid precursor protein); PS 1 (presenilin 1); PS 2 (presenilin 2); APOE (apolipoprotein E); α-SYN (α-synuclein); LRRK2 (leucine-rich repeat kinase 2); UCHL1 (ubiquitin carboxy-terminal hydrolase L1) [202, 203].