title: Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer's disease mice.
abstract: 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 Aβ42 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.
authors.affiliation: Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Calcium Signaling Laboratory, Research Department, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433.
authors.forename: Gandi
authors.initials: G
authors.lastname: Ng
authors.affiliation: Department of Neurology, National Neuroscience Institute, SGH Campus, Singapore 169856.|Research Department, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433.|Neuroscience &Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Eng King
authors.initials: EK
authors.lastname: Tan
authors.affiliation: Calcium Signaling Laboratory, Research Department, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433.
authors.forename: Ping
authors.initials: P
authors.lastname: Liao
authors.affiliation: Neurology Department, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433.
authors.forename: Nagaendran
authors.initials: N
authors.lastname: Kandiah
authors.affiliation: Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433.|Neuroscience &Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Li
authors.initials: L
authors.lastname: Zeng
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins