Experimental microembolism induces localized neuritic pathology in guinea pig cerebrum

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// Jian-Ming Li 1,2 , Yan Cai 1 , Fei Liu 3 , La Yang 2 , Xia Hu 1 , Peter R. Patrylo 4 , Huaibin Cai 5 , Xue-Gang Luo 1 , Dong Xiao 6 and Xiao-Xin Yan 1 1 Department of Anatomy and Neurobiology, Central South University School of Basic Medical Science, Changsha, Hunan, China 2 Neuroscience Research Center, Changsha Medical University, Changsha, Hunan, China 3 Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China 4 Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University School of Medicine, Carbondale, Illinois, USA 5 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA 6 State Key Laboratory of Coal Resources and Safe Mining, China University of Mining and Technology, Xuzhou, Jiangsu, China Correspondence to: Xiao-Xin Yan, email: // Keywords : Alzheimer’s disease, amyloid pathology, axonal pathology, brain aging, silent stroke Received : January 21, 2015 Accepted : February 20, 2015 Published : March 14, 2015 Abstract Microbleeds are a common finding in aged human brains. In Alzheimer’s disease (AD), neuritic plaques composed of β-amyloid (Aβ) deposits and dystrophic neurites occur frequently around cerebral vasculature, raising a compelling question as to whether, and if so, how, microvascular abnormality and amyloid/neuritic pathology might be causally related. Here we used a guinea pig model of cerebral microembolism to explore a potential inductive effect of vascular injury on neuritic and amyloid pathogenesis. Brains were examined 7-30 days after experimental microvascular embolization occupying ~0.5% of total cortical area. Compared to sham-operated controls, glial fibrillary acidic protein immunoreactivity was increased in the embolized cerebrum, evidently around intracortical vasculature. Swollen/sprouting neurites exhibiting increased reactivity of nicotinamide adenine dinucleotide phosphate diaphorase, parvalbumin, vesicular glutamate transporter 1 and choline acetyltransferase appeared locally in the embolized brains in proximity to intracortical vasculature. The embolization-induced swollen/sprouting neurites were also robustly immunoreactive for β-amyloid precursor protein and β-secretase-1, the substrate and initiating enzyme for Aβ genesis. These experimental data suggest that microvascular injury can induce multisystem neuritic pathology associated with an enhanced amyloidogenic potential in wild-type mammalian brain.