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SIRT6 prevent chronic cerebral hypoperfusion induced cognitive impairment by remodeling mitochondrial dynamics in a

Yong Du1, Jiaqing He2, Yanni Xu1

  • 1Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, 710032, China.

Journal of Translational Medicine
|August 25, 2024
PubMed

Insights

Sirtuin 6 (SIRT6) protects against vascular dementia (VaD) by preventing neuronal damage caused by chronic cerebral hypoperfusion (CCH). Enhancing SIRT6 activity offers a potential therapeutic strategy for cognitive impairment in VaD patients.

Area of Science:

  • Neuroscience
  • Cellular Biology
  • Gerontology

Background:

  • Vascular dementia (VaD) is a common dementia linked to chronic cerebral hypoperfusion (CCH).
  • The precise mechanisms driving VaD pathogenesis and effective treatments remain unclear.
  • Sirtuin 6 (SIRT6) is involved in crucial cellular processes like metabolism, DNA repair, and aging.

Purpose of the Study:

  • To investigate the role of Sirtuin 6 (SIRT6) in the context of vascular dementia (VaD) induced by chronic cerebral hypoperfusion (CCH).
  • To explore SIRT6's potential as a therapeutic target for mitigating cognitive deficits associated with VaD.

Main Methods:

  • Utilized a bilateral common carotid artery stenosis (BCAS) mouse model to simulate chronic cerebral hypoperfusion (CCH).
  • Assessed neuronal SIRT6 protein levels following CCH.
  • Examined the effects of neuron-specific Sirt6 gene ablation and SIRT6 agonist (MDL-800) treatment on neuronal damage and cognitive function.
  • Investigated the molecular mechanisms involving mitochondrial dynamics and the STAT5-PGAM5-Drp1 signaling pathway.
  • Correlated monocyte SIRT6 gene expression with cognitive outcomes in human patients with asymptomatic carotid stenosis.

Main Results:

  • Neuronal SIRT6 protein expression significantly decreased following CCH.
  • Neuron-specific Sirt6 ablation worsened neuronal damage and cognitive deficits in the VaD model.
  • SIRT6 agonist treatment (MDL-800) reduced neuronal loss and improved neurological recovery.
  • SIRT6 was found to inhibit excessive mitochondrial fission by suppressing the CCH-induced STAT5-PGAM5-Drp1 pathway.
  • Monocyte SIRT6 expression in human patients correlated with cognitive status.

Conclusions:

  • SIRT6 plays a protective role against cognitive impairment induced by chronic cerebral hypoperfusion (CCH).
  • SIRT6 mitigates VaD by regulating mitochondrial dynamics via the STAT5-PGAM5-Drp1 signaling pathway.
  • Targeting SIRT6 represents a promising therapeutic avenue for vascular dementia.

Keywords:
Chronic cerebral hypoperfusionCognitive impairmentDrp1Mitochondrial dynamicsSIRT6

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