Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity
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Date
2021-01-08
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Springer
Abstract
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, glutamatemediated 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.
Description
Keywords
Alzheimer’s disease, Dentate gyrus, Excitotoxicity, Glutamate, Memantine, NMDAR
Citation
Olajide OJ, Gbadamosi IT, Yawson EO, Arogundade T, Lewu FS, Ogunrinola KY, Adigun OO, Bamisi O, Lambe E, Arietarhire LO, Oluyomi OO, Idowu OK, Kareem R, Asogwa NT, Adeniyi PA. Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity. J Mol Neurosci. 2021 Jun;71(6):1205-1220. doi: 10.1007/s12031-020-01747-w. Epub 2021 Jan 8. PMID: 33420680