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Updated: Nov 21, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Deciphering Alzheimer's Disease Pathogenic Pathway: Role of Chronic Brain Hypoperfusion on p-Tau and mTOR
1Department of Psychology, University of Texas at Austin, Austin, TX, USA.
Insights
Chronic brain hypoperfusion (CBH) drives Alzheimer's disease (AD) by increasing tau phosphorylation, damaging axonal transport, and impairing memory. This review details the nine-step biomolecular pathway from CBH to AD onset.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Chronic brain hypoperfusion (CBH) is a key feature in Alzheimer's disease (AD) pathogenesis.
- The vascular hypothesis of AD, proposed in 1993, links CBH to AD development.
- The collective role of pathological elements in AD onset driven by CBH requires further examination.
Purpose of the Study:
- To review new biomolecular findings supporting the hemodynamic role of CBH in Alzheimer's disease (AD).
- To consolidate the analysis of pathological phases contributing to cognitive decline and AD onset.
- To elucidate a nine-step chronological biomolecular pathway from CBH to AD.
Main Methods:
- Review of new biomolecular findings in AD models.
- Consolidated analysis of pathological phases.
- Chronological summarization of AD pathogenesis.
Main Results:
- CBH increases tau phosphorylation (p-Tau) in the hippocampus and cortex of AD mice.
- CBH damages fast axonal transport and increases mammalian target of rapamycin (mTOR) signaling.
- CBH impairs learning-memory function and promotes neurofibrillary tangle formation.
Conclusions:
- CBH plays a critical hemodynamic role in the pathway to Alzheimer's disease.
- Interconnected pathological events driven by CBH contribute to neurodegeneration and cognitive decline.
- Understanding this nine-step pathway offers insights into AD onset and potential therapeutic targets.
Abstract:
This review examines new biomolecular findings that lend support to the hemodynamic role played by chronic brain hypoperfusion (CBH) in driving a pathway to Alzheimer's disease (AD). CBH is a common clinical feature of AD and the current topic of intense investigation in AD models. CBH is also the basis for the vascular hypothesis of AD which we originally proposed in 1993. New biomolecular findings reveal the interplay of CBH in increasing tau phosphorylation (p-Tau) in the hippocampus and cortex of AD mice, damaging fast axonal transport, increasing signaling of mammalian target of rapamycin (mTOR), impairing learning-memory function, and promoting the formation of neurofibrillary tangles, a neuropathologic hallmark of AD. These pathologic elements have been singularly linked with neurodegeneration and AD but their abnormal, collective participation during brain aging have not been fully examined. The format for this review will provide a consolidated analysis of each pathologic phase contributing to cognitive decline and AD onset, summarized in nine chronological steps. These steps galvanize each factor's active participation and contribution in constructing a biomolecular pathway to AD onset generated by CBH.
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