title: Chronic cerebral hypoperfusion induces memory deficits and facilitates Aβ generation in C57BL/6J mice.
abstract: Alzheimer's disease (AD) is the most common type of dementia frequently responsible for cognitive decline in the elderly. The etiology and molecular mechanism of AD pathogenesis remain inconclusive. Aging and vascular factors are important independent causes and contributors to sporadic AD. Clinical imaging studies showed that cerebral blood flow decreases before cognitive impairment in patients with AD. To investigate the effect of chronic cerebral hypoperfusion (CCH) on cognitive impairment and morphological features, we developed a new manner of CCH mouse model by narrowing bilateral common carotid arteries. Mice started to manifest spatial memory deficits 1month after the surgery and exhibited behavioral changes in a time-dependent manner. Mice also presented memory deficits accompanied with morphological changes at the neuronal and synaptic levels. CCH damaged the normal neuronal morphology and significantly reduced the expression level of PSD95. CCH activated astrocytes, increased the co-expression of GFAP and AQP4, and destroyed the blood-brain barrier (BBB). Furthermore, CCH facilitated intracellular and extracellular Aβ deposition by up-regulating γ-secretase and β-secretase levels. Our results showed good reproducibility of post-CCH pathological processes, which are characterized by neuronal apoptosis, axonal abnormalities, glial activation, BBB damage, amyloid deposition, and cognitive dysfunction; these processes may be used to decipher the complex interplay and pathological process between CCH and AD. This study provides laboratory evidence for the prevention and treatment of cognitive malfunction and AD.
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Lingxi
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yehong
authors.initials: Y
authors.lastname: Du
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China; Department of Anatomy, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Kejian
authors.initials: K
authors.lastname: Wang
authors.affiliation: Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Xu
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Shifang
authors.initials: S
authors.lastname: Luo
authors.affiliation: Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China; Department of Anatomy, Chongqing Medical University, Chongqing 400016, China. Electronic address: guiqionghe@126.com.
authors.forename: Guiqiong
authors.initials: G
authors.lastname: He
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications* / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004797:Enzyme-Linked Immunosorbent Assay; D019922:GAP-43 Protein / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008569:Memory Disorders / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009419:Nerve Tissue Proteins / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C508903:Aph-1 protein, rat; D051401:Aquaporin 4; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D019922:GAP-43 Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D014404:Tubulin; D019938:Cyclin D1; D051528:Guanylate Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: APP; Alzheimer's disease; Aβ; Chronic cerebral hypoperfusion; Cognitive impairment