Spermidine/spermine-N 1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response

Abstract Background Tau 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...

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Main Authors: Leslie A. Sandusky-Beltran, Andrii Kovalenko, Chao Ma, John Ivan T. Calahatian, Devon S. Placides, Mallory D. Watler, Jerry B. Hunt, April L. Darling, Jeremy D. Baker, Laura J. Blair, Mackenzie D. Martin, Sarah N. Fontaine, Chad A. Dickey, April L. Lussier, Edwin J. Weeber, Maj-Linda B. Selenica, Kevin R. Nash, Marcia N. Gordon, Dave Morgan, Daniel C. Lee
Format: Article
Language:English
Published: BMC 2019-06-01
Series:Alzheimer’s Research & Therapy
Subjects:
Online Access:http://link.springer.com/article/10.1186/s13195-019-0507-y
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author Leslie A. Sandusky-Beltran
Andrii Kovalenko
Chao Ma
John Ivan T. Calahatian
Devon S. Placides
Mallory D. Watler
Jerry B. Hunt
April L. Darling
Jeremy D. Baker
Laura J. Blair
Mackenzie D. Martin
Sarah N. Fontaine
Chad A. Dickey
April L. Lussier
Edwin J. Weeber
Maj-Linda B. Selenica
Kevin R. Nash
Marcia N. Gordon
Dave Morgan
Daniel C. Lee
author_facet Leslie A. Sandusky-Beltran
Andrii Kovalenko
Chao Ma
John Ivan T. Calahatian
Devon S. Placides
Mallory D. Watler
Jerry B. Hunt
April L. Darling
Jeremy D. Baker
Laura J. Blair
Mackenzie D. Martin
Sarah N. Fontaine
Chad A. Dickey
April L. Lussier
Edwin J. Weeber
Maj-Linda B. Selenica
Kevin R. Nash
Marcia N. Gordon
Dave Morgan
Daniel C. Lee
author_sort Leslie A. Sandusky-Beltran
collection DOAJ
description Abstract Background Tau 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. Methods Male 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-N 1-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. Results Tau 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. Conclusion These 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.
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spelling doaj.art-f6fdfce93d6549e184299e4d7d512e9b2022-12-21T23:19:25ZengBMCAlzheimer’s Research & Therapy1758-91932019-06-0111112410.1186/s13195-019-0507-ySpermidine/spermine-N 1-acetyltransferase ablation impacts tauopathy-induced polyamine stress responseLeslie A. Sandusky-Beltran0Andrii Kovalenko1Chao Ma2John Ivan T. Calahatian3Devon S. Placides4Mallory D. Watler5Jerry B. Hunt6April L. Darling7Jeremy D. Baker8Laura J. Blair9Mackenzie D. Martin10Sarah N. Fontaine11Chad A. Dickey12April L. Lussier13Edwin J. Weeber14Maj-Linda B. Selenica15Kevin R. Nash16Marcia N. Gordon17Dave Morgan18Daniel C. Lee19Byrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South FloridaByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South FloridaByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South FloridaByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South FloridaByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South FloridaByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Medicine, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South FloridaByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South FloridaByrd Alzheimer’s Institute, Department of Molecular Pharmacology and Physiology, University of South FloridaByrd Alzheimer’s Institute, Department of Pharmaceutical Sciences, University of South FloridaAbstract Background Tau 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. Methods Male 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-N 1-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. Results Tau 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. Conclusion These 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.http://link.springer.com/article/10.1186/s13195-019-0507-yTauPolyamine dysregulationHippocampusAlzheimer’s disease
spellingShingle Leslie A. Sandusky-Beltran
Andrii Kovalenko
Chao Ma
John Ivan T. Calahatian
Devon S. Placides
Mallory D. Watler
Jerry B. Hunt
April L. Darling
Jeremy D. Baker
Laura J. Blair
Mackenzie D. Martin
Sarah N. Fontaine
Chad A. Dickey
April L. Lussier
Edwin J. Weeber
Maj-Linda B. Selenica
Kevin R. Nash
Marcia N. Gordon
Dave Morgan
Daniel C. Lee
Spermidine/spermine-N 1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response
Alzheimer’s Research & Therapy
Tau
Polyamine dysregulation
Hippocampus
Alzheimer’s disease
title Spermidine/spermine-N 1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response
title_full Spermidine/spermine-N 1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response
title_fullStr Spermidine/spermine-N 1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response
title_full_unstemmed Spermidine/spermine-N 1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response
title_short Spermidine/spermine-N 1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response
title_sort spermidine spermine n 1 acetyltransferase ablation impacts tauopathy induced polyamine stress response
topic Tau
Polyamine dysregulation
Hippocampus
Alzheimer’s disease
url http://link.springer.com/article/10.1186/s13195-019-0507-y
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