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.

Public Health Relevance

Our research is focused on understanding how NAD homeostasis regulates axon maintenance and the development of neurodegenerative disease. We will explore the molecular link between a nerve injury-induced NAD degradation pathway and progression of tau pathology in Alzheimer's disease. The identification of drugs to block this pathway could be helpful in treating these neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG013730-21A1
Application #
9310590
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wise, Bradley C
Project Start
1996-07-01
Project End
2022-03-31
Budget Start
2017-07-01
Budget End
2018-03-31
Support Year
21
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Genetics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Beirowski, Bogdan; Wong, Keit Men; Babetto, Elisabetta et al. (2017) mTORC1 promotes proliferation of immature Schwann cells and myelin growth of differentiated Schwann cells. Proc Natl Acad Sci U S A 114:E4261-E4270
Summers, Daniel W; Gibson, Daniel A; DiAntonio, Aaron et al. (2016) SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. Proc Natl Acad Sci U S A 113:E6271-E6280
Kim, Sungsu; Maynard, Jason C; Sasaki, Yo et al. (2016) Schwann Cell O-GlcNAc Glycosylation Is Required for Myelin Maintenance and Axon Integrity. J Neurosci 36:9633-46
Gerdts, Josiah; Summers, Daniel W; Milbrandt, Jeffrey et al. (2016) Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism. Neuron 89:449-60
Musiek, Erik S; Xiong, David D; Patel, Tirth et al. (2016) Nmnat1 protects neuronal function without altering phospho-tau pathology in a mouse model of tauopathy. Ann Clin Transl Neurol 3:434-42
Sasaki, Yo; Nakagawa, Takashi; Mao, Xianrong et al. (2016) NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion. Elife 5:
Goyal, Manu S; Venkatesh, Siddarth; Milbrandt, Jeffrey et al. (2015) Feeding the brain and nurturing the mind: Linking nutrition and the gut microbiota to brain development. Proc Natl Acad Sci U S A 112:14105-12
Gerdts, Josiah; Brace, E J; Sasaki, Yo et al. (2015) SARM1 activation triggers axon degeneration locally via NAD? destruction. Science 348:453-7
Sasaki, Yo; Margolin, Zachary; Borgo, Benjamin et al. (2015) Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants. J Biol Chem 290:17228-38
Summers, Daniel W; DiAntonio, Aaron; Milbrandt, Jeffrey (2014) Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons. J Neurosci 34:9338-50

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