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

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,...

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Published in:	Journal of molecular neuroscience Vol. 71; no. 6; pp. 1205 - 1220
Main Authors:	Olajide, Olayemi Joseph, Gbadamosi, Ismail Tayo, Yawson, Emmanuel Olusola, Arogundade, Tolulope, Lewu, Folashade Susan, Ogunrinola, Kehinde Yomi, Adigun, Oluwaseun Olaniyi, Bamisi, Olawande, Lambe, Ezra, Arietarhire, Leviticus Ogbenevurinrin, Oluyomi, Olushola Oladapo, Idowu, Olumayowa Kolawole, Kareem, Rukayat, Asogwa, Nnaemeka Tobechukwu, Adeniyi, Philip Adeyemi
Format:	Journal Article
Language:	English
Published:	New York Springer US 01-06-2021 Springer Nature B.V
Subjects:	Accumulation Acetylcholinesterase Acute effects Alzheimer's disease Apoptosis BAX protein Biomedical and Life Sciences Biomedicine Cell Biology Degeneration Dentate gyrus Etiology Excitotoxicity Glial fibrillary acidic protein Gliosis Glutamatergic transmission Glutamic acid receptors Glutamic acid receptors (ionotropic) Glutamic acid receptors (metabotropic) Glutathione Glutathione peroxidase Glutathione transferase Granule cells Hippocampus Impairment Injection Memantine Memory tasks N-Methyl-D-aspartic acid receptors Neurochemistry Neurodegeneration Neurodegenerative diseases Neurofibrillary tangles Neurology Neurosciences Pathogenesis Peroxidase Proteins Proteomics Reduction Senile plaques Spatial analysis NMDAR Dentate gyrus Memantine Alzheimer’s disease Glutamate Excitotoxicity
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Summary:	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.
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ISSN:	0895-8696 1559-1166
DOI:	10.1007/s12031-020-01747-w