Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer’s disease mice
Open accessAbstract
Cerebral hypoperfusion and impaired autophagy are two etiological factors that have been identified as being associated with the development of Alzheimer’s disease (AD). Nevertheless, the exact relationships among these pathological processes remain unknown. To elucidate the impact of cerebral hypoperfusion in AD, we created a unilateral common carotid artery occlusion (UCCAO) model by occluding the left common carotid artery in both young and old 3xTg-AD mice. Two months after occlusion, we found that ligation increases phospho-Tau (p-Tau) at Serine 199/202 in the hippocampus of 3-month-old AD mice, compared to sham-operated AD mice; whereas, there is no change in the wild type (WT) mice after ligation. Moreover, cerebral hypoperfusion led to significant increase of p-Tau in both the hippocampus and cortex of 16-month-old AD mice and WT mice. Notably, we did not detect any change in Aβ 42 level in either young or old AD and WT mice after ligation. Interestingly, we observed a downregulation of LC3-II in the cortex of aged AD mice and WT mice after ligation. Our results suggest that elevated p-Tau and reduced autophagy are major cellular changes that are associated with hypoperfusion in AD. Therefore, targeting p-Tau and autophagy pathways may ameliorate hypoperfusion-induced brain damage in AD.
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Preclinical studies have reported an Aβ-independent relationship between cerebrovascular dysfunction and tau.
“Several preclinical studies also reported such Aβ‐independent relationship between cerebrovascular dysfunction and tau. 40 , 41”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [40]
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- Authors
- Qiu, L., Ng, G., Tan, E. K., Liao, P., Kandiah, N., & Zeng, L.
- Affiliations
- National Neuroscience Institute (SG)
- Singapore General Hospital (SG)
- Duke-NUS Medical School (SG)
- Corresponding author
- Liao, Ping
- Kandiah, Nagaendran
- Zeng, Li
- Venue
- Scientific Reports
- Published
- 2016-04-06
- Volume
- 6
- Issue
- 1
- Pages
- 23964-23964
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4822118
- OpenAlex
- W2317915347
- Cited by
- 115
- References
- 49
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 10 · 2023: 13 · 2022: 9 · 2021: 14 · 2020: 17 · 2019: 11 · 2018: 18 · 2017: 4 · 2016: 1
- FWCI
- 9.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- National Research Foundation
- National Research Foundation Singapore
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, cerebral hypoperfusion, tau hyperphosphorylation, autophagy, 3xTg-AD mice, common carotid artery occlusion, hippocampus, LC3-II, amyloid-beta 42, aging, cerebral ischemia
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Autophagy, Brain Ischemia, Chronic Disease, Disease Models, Animal, Female, Frontal Lobe, Hippocampus, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Microtubule-Associated Proteins, Peptide Fragments, Phosphorylation, Immunoblotting, Amyloid beta-Peptides, tau Proteins, Mice, 129 Strain
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