Chronic cerebral hypoperfusion shifts the equilibrium of amyloid β oligomers to aggregation-prone species with higher molecular weight

Sci Rep. 2019 Feb 26;9(1):2827. doi: 10.1038/s41598-019-39494-7.

Abstract

Epidemiological studies have shown that atherosclerotic risk factors accelerate the pathological process underlying Alzheimer's disease (AD) via chronic cerebral hypoperfusion. In this study, we aimed to clarify the mechanisms by which cerebral hypoperfusion may exacerbate AD pathology. We applied bilateral common carotid artery stenosis (BCAS) to a mice model of AD and evaluated how the equilibrium of amyloid β oligomers respond to hypoperfusion. BCAS accelerated amyloid β (Aβ) convergence to the aggregation seed, facilitating the growth of Aβ plaques, but without changing the total Aβ amount in the brain. Furthermore, Aβ oligomers with high molecular weight increased in the brain of BCAS-operated mice. Considering Aβ is in an equilibrium among monomeric, oligomeric, and aggregation forms, our data suggest that cerebral hypoperfusion after BCAS shifted this equilibrium to a state where a greater number of Aβ molecules participate in Aβ assemblies to form aggregation-prone Aβ oligomers with high molecular weight. The reduced blood flow in the cerebral arteries due to BCAS attenuated the dynamics of the interstitial fluid leading to congestion, which may have facilitated Aβ aggregation. We suggest that cerebral hypoperfusion may accelerate AD by enhancing the tendency of Aβ to become aggregation-prone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / etiology
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain Ischemia / complications
  • Brain Ischemia / metabolism*
  • Carotid Stenosis
  • Disease Models, Animal
  • Male
  • Mice
  • Molecular Weight
  • Plaque, Amyloid / metabolism*

Substances

  • Amyloid beta-Peptides