Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell's response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer's disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD.
|Journal||Journal of Clinical Investigation|
|State||Published - Feb 15 2021|
Bibliographical noteFunding Information:
We would like to thank Jun Tan and Huayan Hou (Silver Child Development Center, Morsani College of Medicine, University of South Florida) for providing the use of instrumentation. Human brain samples from the NIH NeuroBioBank were obtained from the University of Maryland, University of Miami, and Mt. Sinai brain repositories. The graphical abstract and supplemental figure were created with BioRender.com. This work was supported by grants from the Alzheimer’s Association (MNIRGD-12-242665 to DCL), Brightfocus Foundation (A20155045 to DCL), CurePSP, Inc. (520-14 to DCL), Florida Department of Health (5AZ11 to DCL), and NIH R01AG054559 (to DCL).
© 2021, American Society for Clinical Investigation.
ASJC Scopus subject areas
- Medicine (all)