Regulating NAD Metabolism to Inhibit Axon Degeneration in Neurodegenerative Diseases

Washington University, Saint Louis MO

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Abstract

Project Summary/Abstract: Alzheimer's disease is the most common cause of dementia. Axon degeneration is an important contributor to the functional deficits of Alzheimer's disease (AD) and is observed early in the disease process. Metabolic abnormalities also contribute to AD, a link made apparent by the increased risk of AD in patients with type II diabetes. Metabolism is also a critical regulator of axonal health. We have found that neuronal metabolism, particularly NAD metabolism, plays an important role in maintaining axon integrity and function. Injured axons degenerate via activation of a self-destructive program that is controlled, in part, by the TIR adaptor protein SARM1. Upon injury, the NAD biosynthetic enzyme NMNAT2 is rapidly lost from the axon. At the same time, SARM1 is activated and stimulates a pathway that leads to the rapid degradation of axonal NAD. This disruption in axonal NAD homeostasis, along with calcium and kinase signaling cascades, culminates in the degeneration of the damaged axon. Conversely, overexpression of enzymes in the NAD biosynthetic pathway counteract this program and prevent damaged axons from degenerating. To understand how NAD homeostasis is controlled, we have developed assays to measure a wide range of NAD metabolites and to follow the synthesis and consumption of these molecules in healthy and damaged axons. The hallmark of tauopathy-related neurodegenerative disease like AD is the hyperphosphorylation and aggregation of tau. Abnormal tau conformers act like prion-like seed molecules that can propagate from cell-to- cell. These prion-like tau oligomers are thought to represent the predominant axonal insult in Alzheimer's disease. Interestingly, tau is also post-translationally modified by acetylation and O-GlcNAcylation, and these additions contribute to tau solubility and pathological potential. These modifications are regulated by cellular metabolism, thus providing a direct linkage between metabolism and neurodegeneration. These results lead us to hypothesize that changes in NAD metabolism contribute to AD progression through impaired axon stability due to alterations in tau modification that lead to increased formation of tau prion-like oligomers. To pursue this hypothesis we propose three aims: 1) To determine how alterations in NAD homeostasis lead to axon degeneration; 2) To identify the enzymology responsible for rapid NAD degradation in degenerating axons; and, 3) To establish the molecular association between NAD homeostasis and AD-related tau pathophysiology. Through these studies, we hope to show that therapies targeting NAD metabolism will be useful in treating neurodegenerative diseases like Alzheimer's disease.