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Basic Science and Pathogenesis.

Xinyi Zhang1, Siyan Zhong1, Shuai Zhao1

  • 1Department of Neurology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

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|December 23, 2025
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Summary
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Chronic cerebral hypoperfusion (CCH) accelerates Alzheimer's disease tau pathology by increasing aspartate endopeptidase (AEP) and I2 PP2A. This study investigates the mechanisms by which CCH enhances tau propagation and phosphorylation.

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Area of Science:

  • Neuroscience
  • Pathology
  • Biochemistry

Background:

  • Alzheimer's disease (AD) pathogenesis is multifactorial, with neurofibrillary tangles (NFTs) being a key pathological hallmark.
  • Chronic cerebral hypoperfusion (CCH) is known to precede and potentially accelerate tau pathology, but the underlying mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the effects of CCH on tau propagation and phosphorylation.
  • To elucidate the role of aspartate endopeptidase (AEP) and I2 PP2A in CCH-induced tau pathology.

Main Methods:

  • Tau-HEK293 cells were subjected to oxygen-glucose deprivation (OGD) to mimic CCH conditions and assess tau aggregation.
  • PS19 mice received tau PFF injections and unilateral common carotid artery occlusion (UCCAO) to model CCH and examine tau pathology.
  • Western blotting and immunofluorescence were used to analyze tau pathology, AEP, I2 PP2A, BBB proteins, and microglial activation.

Main Results:

  • OGD treatment increased tau aggregates, AEP, and I2 PP2A in tau-HEK293 cells.
  • CCH in PS19 mice enhanced tau pathology by increasing insoluble tau phosphorylation, with elevated AEP and I2 PP2A levels.
  • CCH altered AEP and I2 PP2A subcellular localization, affected tight junction proteins, activated microglia, and modified gene expression profiles.

Conclusions:

  • The findings suggest that AEP and I2 PP2A are involved in CCH-induced tau hyperphosphorylation and propagation.
  • CCH exacerbates Alzheimer's disease-like tau pathology through mechanisms involving AEP and I2 PP2A.