Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity.

Autor: Olajide OJ; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria. olajide.oj@unilorin.edu.ng.; Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Canada. olajide.oj@unilorin.edu.ng., Gbadamosi IT; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.; Central Research Laboratories Ltd, 132b University Road, Ilorin, Nigeria., Yawson EO; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.; Department of Anatomy, Faculty of Basic Medical Sciences, Redeemer's University, Ede, Nigeria., Arogundade T; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.; Department of Anatomy, Faculty of Basic Medical Sciences, Adeleke University, Ede, Nigeria., Lewu FS; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria., Ogunrinola KY; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.; Department of Anatomy, School of Post-Basic Nursing, University of Ilorin Teaching Hospital, Ilorin, Nigeria., Adigun OO; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria., Bamisi O; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.; Department of Anatomy, Faculty of Basic Medical Sciences, Ekiti State University, Ado Ekiti, Nigeria., Lambe E; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria., Arietarhire LO; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria., Oluyomi OO; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria., Idowu OK; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria., Kareem R; Department of Anatomy, Division of Neurobiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Nigeria., Asogwa NT; Central Research Laboratories Ltd, 132b University Road, Ilorin, Nigeria.; Department of Biochemistry, Faculty of Life Sciences, University of Ilorin, Ilorin, Nigeria., Adeniyi PA; Department of Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, LA, USA.
Jazyk: angličtina
Zdroj: Journal of molecular neuroscience : MN [J Mol Neurosci] 2021 Jun; Vol. 71 (6), pp. 1205-1220. Date of Electronic Publication: 2021 Jan 08.
DOI: 10.1007/s12031-020-01747-w
Abstrakt: The hallmarks of Alzheimer's disease (AD) pathology include senile plaques accumulation and neurofibrillary tangles, which is thought to underlie synaptic failure. Recent evidence however supports that synaptic failure in AD may instead be instigated by enhanced N-methyl-D-aspartate (NMDA) activity, via a reciprocal relationship between soluble amyloid-β (Aβ) accumulation and increased glutamate agonist. While previous studies have shown Aβ-mediated alterations to the glutamatergic system during AD, the underlying etiology of excitotoxic glutamate-induced changes has not been explored. Here, we investigated the acute effects of stereotaxic dentate gyrus (DG) glutamate injection on behavior and molecular expression of specific proteins and neurochemicals modulating hippocampal functions. Dependence of glutamate-mediated effects on NMDA receptor (NMDAR) hyperactivation was tested using NMDARs antagonist memantine. DG of Wistar rats (12-weeks-old) were bilaterally microinjected with glutamate (500 mM) with or without daily intraperitoneal (i.p.) memantine injection (20 mg/kg) for 14 days, while controls received either intrahippocampal/i.p. PBS or i.p. memantine. Behavioral characterization in open field and Y-maze revealed that glutamate evoked anxiogenic responses and perturbed spatial memory were inhibited by memantine. In glutamate-treated rats, increased NO expression was accompanied by marked reduction in profiles of glutathione-s-transferase and glutathione peroxidase. Similarly, glutamate-mediated increase in acetylcholinesterase expression corroborated downregulation of synaptophysin and PSD-95, coupled with initiation of reactive astrogliosis (GFAP). While neurofilament immunolocalization/immunoexpression was unperturbed, we found glutamate-mediated reduction in neurogenic markers Ki67 and PCNA immunoexpression, with a decrease in NR2B protein expression, whereas mGluR1 remains unchanged. In addition, increased expression of apoptotic regulatory proteins p53 and Bax was seen in glutamate infused rats, corroborating chromatolytic degeneration of granule neurons in the DG. Interestingly, memantine abrogated most of the degenerative changes associated with glutamate excitotoxicity in this study. Taken together, our findings causally link acute glutamate dyshomeostasis in the DG with development of AD-related behavioral impairment and molecular neurodegeneration.
Databáze: MEDLINE
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