University of Kentucky
Targeting Tau: Molecular Insights into SSAT1 and Polyamine Metabolism as Keys to Alzheimer’s Pathogenesis
Grade Level at Time of Presentation
Senior
Major
Neuroscience
Minor
Biology
Institution 24-25
University of Kentucky
KY House District #
6
KY Senate District #
27
Faculty Advisor/ Mentor
Daniel Lee, PhD
Department
Department of Neuroscience, Sanders-Brown Center on Aging
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions, with prevalence expected to double by 2050. Characterized by cognitive decline and neuronal loss, AD’s hallmark pathology includes the aggregation of Tau protein into neurofibrillary tangles, which are closely linked to disease severity. Despite extensive research, the mechanisms driving Tau aggregation remain incompletely understood, highlighting the need for innovative approaches to combat this devastating disease.
Polyamines, small aliphatic molecules essential for cellular function, are increasingly implicated in AD pathology. While polyamines initially play protective roles during cellular stress, their chronic dysregulation results in a polyamine stress response (PSR) that fuels neurodegeneration. Our research explores the relationship between the PSR and Tau pathology, focusing on spermidine/spermine N¹-acetyltransferase 1 (SSAT1), an enzyme traditionally recognized for polyamine acetylation. We have identified SSAT1 as a novel Tau acetyltransferase, uncovering a direct connection between polyamine metabolism and Tau aggregation.
Using Tau transgenic (PS19) mice crossed with SSAT1 knockouts, we demonstrate that SSAT1 ablation reduces acetylated Tau levels, attenuates PSR activity, and decreases Tau aggregation. These findings support a “two-hit” mechanism: SSAT1 promotes Tau aggregation through direct acetylation and exacerbates neurodegeneration by amplifying the PSR. This dual role of SSAT1 offers new insight into the molecular drivers of AD.
This research identifies SSAT1 as a promising therapeutic target, paving the way for novel strategies to mitigate Tau pathology and slow disease progression. By exploring the intersection of Tau pathology and polyamine metabolism, our work contributes to a deeper understanding of AD and offers hope for improved treatment approaches that could benefit millions affected by this disease.
Targeting Tau: Molecular Insights into SSAT1 and Polyamine Metabolism as Keys to Alzheimer’s Pathogenesis
Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions, with prevalence expected to double by 2050. Characterized by cognitive decline and neuronal loss, AD’s hallmark pathology includes the aggregation of Tau protein into neurofibrillary tangles, which are closely linked to disease severity. Despite extensive research, the mechanisms driving Tau aggregation remain incompletely understood, highlighting the need for innovative approaches to combat this devastating disease.
Polyamines, small aliphatic molecules essential for cellular function, are increasingly implicated in AD pathology. While polyamines initially play protective roles during cellular stress, their chronic dysregulation results in a polyamine stress response (PSR) that fuels neurodegeneration. Our research explores the relationship between the PSR and Tau pathology, focusing on spermidine/spermine N¹-acetyltransferase 1 (SSAT1), an enzyme traditionally recognized for polyamine acetylation. We have identified SSAT1 as a novel Tau acetyltransferase, uncovering a direct connection between polyamine metabolism and Tau aggregation.
Using Tau transgenic (PS19) mice crossed with SSAT1 knockouts, we demonstrate that SSAT1 ablation reduces acetylated Tau levels, attenuates PSR activity, and decreases Tau aggregation. These findings support a “two-hit” mechanism: SSAT1 promotes Tau aggregation through direct acetylation and exacerbates neurodegeneration by amplifying the PSR. This dual role of SSAT1 offers new insight into the molecular drivers of AD.
This research identifies SSAT1 as a promising therapeutic target, paving the way for novel strategies to mitigate Tau pathology and slow disease progression. By exploring the intersection of Tau pathology and polyamine metabolism, our work contributes to a deeper understanding of AD and offers hope for improved treatment approaches that could benefit millions affected by this disease.