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Amyloid-β-dependent compromise of microvascular structure and function in a model of Alzheimer's disease

Adrienne Dorr1, Bhupinder Sahota, Lakshminarayan V Chinta

  • 1Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario, Canada.

Brain : a Journal of Neurology
|October 16, 2012
PubMed

Insights

Alzheimer's disease involves amyloid-β peptide buildup in brain blood vessels, impairing their structure and function. Scyllo-inositol treatment reversed these microvascular changes in a mouse model, offering therapeutic potential.

Area of Science:

  • Neuroscience
  • Cerebrovascular Biology
  • Alzheimer's Disease Research

Background:

  • Alzheimer's disease (AD) is frequently associated with cerebral amyloid angiopathy (CAA), characterized by amyloid-β (Aβ) peptide deposition in leptomeningeal and cortical arterioles.
  • This Aβ accumulation is hypothesized to stem from impaired clearance of parenchymal Aβ peptides.
  • Understanding the impact of Aβ on cerebrovascular structure and function is crucial for AD pathogenesis.

Purpose of the Study:

  • To investigate the in situ structural and functional alterations of cortical microvasculature in the TgCRND8 transgenic mouse model of AD.
  • To evaluate the therapeutic potential of scyllo-inositol in ameliorating Aβ-induced cerebrovascular deficits.

Main Methods:

  • Utilized the TgCRND8 transgenic mouse model, which overexpresses mutant amyloid precursor protein, to study AD-related changes.
  • Assessed cortical microvascular structure (tortuosity, calibre) and function (transit times, reactivity to hypercapnia) in vivo.
  • Administered scyllo-inositol post-weaning to assess its effects on Aβ oligomerization, fibrillization, and cerebrovascular parameters.

Main Results:

  • Cortical arterioles in TgCRND8 mice exhibited increased tortuosity and decreased calibre with advancing Aβ accumulation.
  • Significant functional impairments were observed, including increased microvascular network dispersion, prolonged transit times, and reduced reactivity to hypercapnia.
  • Post-weaning administration of scyllo-inositol effectively rescued both structural and functional deficits in the cortical microvasculature.

Conclusions:

  • Microvascular impairment in the brain is directly correlated with amyloid-β accumulation in this AD model.
  • Targeting cerebrovascular amyloid angiopathy clearance presents a promising strategy for AD diagnosis, progression monitoring, and therapeutic intervention.
  • Scyllo-inositol demonstrates potential as a therapeutic agent by mitigating Aβ-induced cerebrovascular damage.

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