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Area of Science:

  • Neuroscience
  • Cardiovascular Research
  • Pharmacology

Background:

  • Sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially for type 2 diabetes, show heart failure benefits.
  • Cerebral hypoperfusion is an early symptom of Alzheimer's disease and related dementias (AD/ADRD).
  • Previous studies indicated SGLT2 inhibitors improve brain perfusion and cognition in diabetes-related ADRD rats.

Purpose of the Study:

  • To investigate if SGLT2 inhibition benefits brain perfusion and cognition in Alzheimer's disease (AD) models.
  • To determine if these benefits occur independently of glucose control.

Main Methods:

  • TgF344-AD rats received luseogliflozin (SGLT2 inhibitor) or vehicle for 3 months.
  • Cognitive function assessed via eight-arm water maze.
  • Cerebral vascular function evaluated using pressure myography and laser-Doppler flowmetry; transcriptomic analysis of VSMCs.

Main Results:

  • Luseogliflozin did not alter body weight, plasma glucose, or HbA1c in AD rats.
  • SGLT2 inhibition significantly improved learning and memory in AD rats.
  • Impaired myogenic responses and cerebral blood flow autoregulation were normalized by SGLT2 inhibition.

Conclusions:

  • SGLT2 inhibition protects cognitive function in AD by enhancing cerebral blood flow autoregulation.
  • The mechanism involves improved cerebrovascular function, not glucose regulation.
  • Cerebral perfusion enhancement presents a potential therapeutic strategy for AD/ADRD.