Metabolic Dysfunction in Alzheimers 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.

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

“…36 The reasons for the discrepancies among these studies are unclear, but the APN level may be affected by multiple factors. Given that many AD patients have concomitant metabolic disorders,1 it is possible that plasma APN may fluctuate during coprogression of the disease 37. Furthermore, hypoadiponectinemia has been observed in alexithymia and tension‐type headache, in addition to metabolic disorders 38, 39.…”

“…A growing body of evidence suggests that metabolic dysfunction may play a major role in the pathogenesis of Alzheimer's disease (AD) and related neurodegenerative disorders 1. In support of this idea, various lifestyle‐related disorders, such as type II diabetes (T2DM), dyslipidemia, and obesity, have been epidemiologically linked to AD 2.…”

Diabetes, Neurodegenerative Diseases, GLP-1 & Surgery: Evidence Calls for Exploration

“…The misbalance in glucose metabolism can be explained as the anomalous huntingtin favors the inhibition of the hypothalamic receptors for insulin by inhibitors of Phosphoinositide 3-kinase, resulting in hepatic insulin resistance and a rise in hepatic glucose production. Management with insulin does not correct such anomalies, while management with a GLP1 analogue, exendin 4, results in substantial improvements to glucose homeostasis and reduces the number of anomalous huntingtin deposits at the brain and pancreas leading to an increased lifespan in a murine model of HD [7].…”

Role and Function of Dehydrogenases in CNS and Blood-Brain Barrier Pathophysiology

“…However, the etiology of the disease is still questionable. Both vascular as well as metabolic dysfunction have been accredited as major factors prodromic to the pathogenesis and progression of Alzheimer's disease (84). Vascular dysfunction includes reduction in cerebral blood flow, reduced glucose uptake, and reduced amyloid beta clearance with cerebral amyloid angiopathy.…”

“…Defective glucose utilization has been observed earlier than reduced cerebral blood flow (CBF), indicating the role of glucose metabolism in AD development. What is of primary interest to us is that it is slowly becoming well accepted that metabolic dysfunction, related oxidative stress and mitochondrial deficits can precede AD development (84)(85)(86). In one such recent study, triple transgenic mice 3xTg-AD were developed (having mutations in human APPSWE, TauP301L, PS1M146V genes linked with AD) along with their respective controls.…”