Tier 3 — preclinical

The deacetylase SIRT6 reduces amyloid pathology and supports cognition in mice by reducing the stability of APP in neurons

Rong Cheng, Ning Bai, Shuhui Liu, Xiong Zhao, Bo Jiang, Wendong Guo, Sunrun Cao, Jingwei Liu, Na Li, Xiaoman Li, Xuan Wu, Fei Yi, Zhuo Wang, Qiqiang Guo, Jiayi Wei, Ming Bai, Xiaoyou Jiang, Xiaoyu Song, Zhuo Wang, Qi Miao, Difei Wang, Yu Di, Hua Liu, Liu Cao
Science Signaling 2024 17(866):eado1035

Bibliography

PubMed
PMID 39656860
DOI
10.1126/scisignal.ado1035

Study snapshot

DesignNeuronal/cell mechanism plus pharmacological intervention in APP/PS1 Alzheimer-model mice.
ModelMouse hippocampal neurons, transfected human cells and APP/PS1 mice.
SamplePreclinical cell and mouse cohorts.
InterventionSIRT6 mechanistic manipulation and systemic pharmacological SIRT6 activation.
DurationPreclinical Alzheimer-model intervention.
EndpointsAPP acetylation; APP ubiquitination/degradation; Amyloid pathology; Cognitive deficits; SIRT6 abundance in cortex/hippocampus

What the study showed, in plain terms

SIRT6 deacetylated amyloid precursor protein (APP), promoting its ubiquitination and degradation. Importantly, systemic pharmacological SIRT6 activation improved amyloid pathology and cognitive deficits in APP/PS1 mice.

Key findings

SIRT6 interacted with and deacetylated APP at Lys649-651, destabilizing APP. Pharmacological SIRT6 activation ameliorated amyloid pathology and cognitive deficits in an Alzheimer mouse model.

What this study can and cannot tell us

Preclinical Alzheimer-model evidence; no human dementia efficacy trial and no evidence that oral fucoidan or DoNotAge SIRT6Activator reproduces the CNS pharmacological effect.

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Editorial review

Reviewed by the Biohack Blueprint research team

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability