Spermidine/spermine-N1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response

Alzheimer's Research & Therapy

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[1] 0000 0001 2353 285X, grid.170693.a, Byrd Alzheimer’s Institute, Department of Molecular Medicine, University of South Florida, 33613, Tampa, FL, USA;0000 0001 2353 285X, grid.170693.a, Byrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South Florida, 33613, Tampa, FL, USA;0000 0001 2353 285X, grid.170693.a, Byrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South Florida, 33613, Tampa, FL, USA;0000 0001 2150 1785, grid.17088.36, Department of Translational Science & Molecular Medicine, Michigan State University, 400 Monroe Ave NW, 49503, Grand Rapids, MI, USA;0000 0001 2353 285X, grid.170693.a, Byrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South Florida, 4001 E. Fletcher Ave, 33613, Tampa, FL, USA;0000 0001 2353 285X, grid.170693.a, Byrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South Florida, 4001 E. Fletcher Ave, 33613, Tampa, FL, USA;0000 0004 1936 8753, grid.137628.9, Neuroscience Institute, Department of Neuroscience and Physiology, New York University School of Medicine, 1 Park Avenue, 10016, New York, NY, USA;

关键词: Tau;    Polyamine dysregulation;    Hippocampus;    Alzheimer’s disease;   

DOI  :  10.1186/s13195-019-0507-y

来源: publisher

【 摘 要 】

BackgroundTau stabilizes microtubules; however, in Alzheimer’s disease (AD) and tauopathies, tau becomes hyperphosphorylated, aggregates, and results in neuronal death. Our group recently uncovered a unique interaction between polyamine metabolism and tau fate. Polyamines exert an array of physiological effects that support neuronal function and cognitive processing. Specific stimuli can elicit a polyamine stress response (PSR), resulting in altered central polyamine homeostasis. Evidence suggests that elevations in polyamines following a short-term stressor are beneficial; however, persistent stress and subsequent PSR activation may lead to maladaptive polyamine dysregulation, which is observed in AD, and may contribute to neuropathology and disease progression.MethodsMale and female mice harboring tau P301L mutation (rTg4510) were examined for a tau-induced central polyamine stress response (tau-PSR). The direct effect of tau-PSR byproducts on tau fibrillization and oligomerization were measured using a thioflavin T assay and a N2a split superfolder GFP-Tau (N2a-ssGT) cell line, respectively. To therapeutically target the tau-PSR, we bilaterally injected caspase 3-cleaved tau truncated at aspartate 421 (AAV9 Tau ΔD421) into the hippocampus and cortex of spermidine/spermine-N1-acetyltransferase (SSAT), a key regulator of the tau-PSR, knock out (SSAT-/-), and wild type littermates, and the effects on tau neuropathology, polyamine dysregulation, and behavior were measured. Lastly, cellular models were employed to further examine how SSAT repression impacted tau biology.ResultsTau induced a unique tau-PSR signature in rTg4510 mice, notably in the accumulation of acetylated spermidine. In vitro, higher-order polyamines prevented tau fibrillization but acetylated spermidine failed to mimic this effect and even promoted fibrillization and oligomerization. AAV9 Tau ΔD421 also elicited a unique tau-PSR in vivo, and targeted disruption of SSAT prevented the accumulation of acetylated polyamines and impacted several tau phospho-epitopes. Interestingly, SSAT knockout mice presented with altered behavior in the rotarod task, the elevated plus maze, and marble burying task, thus highlighting the impact of polyamine homeostasis within the brain.ConclusionThese data represent a novel paradigm linking tau pathology and polyamine dysfunction and that targeting specific arms within the polyamine pathway may serve as new targets to mitigate certain components of the tau phenotype.

【 授权许可】

CC BY