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Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity
Olajide OJ, Gbadamosi IT, Yawson EO, Arogundade T, Lewu FS, Ogunrinola KY, Adigun OO, Bamisi O et al.. Journal of molecular neuroscience : MN, 2021-01-08
Topic: Amyloid, tau and blood-test diagnosis
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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APA 7th
Olajide, O. J., Gbadamosi, I. T., Yawson, E. O., Arogundade, T., Lewu, F. S., Ogunrinola, K. Y., et al. (2021). Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity. Journal of molecular neuroscience : MN. https://doi.org/10.1007/s12031-020-01747-w
Vancouver
Olajide OJ, Gbadamosi IT, Yawson EO, Arogundade T, Lewu FS, Ogunrinola KY, et al. Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity. Journal of molecular neuroscience : MN. 2021. doi:10.1007/s12031-020-01747-w. PMID: 33420680.
BibTeX
@article{olajide2021-33420680,
author = {Olajide, O. J. and Gbadamosi, I. T. and Yawson, E. O. and Arogundade, T. and Lewu, F. S. and Ogunrinola, K. Y. and Adigun, O. O. and Bamisi, O. and others},
title = {{Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity}},
journal = {Journal of molecular neuroscience : MN},
year = {2021},
doi = {10.1007/s12031-020-01747-w},
pmid = {33420680},
url = {https://doi.org/10.1007/s12031-020-01747-w}
}
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Key findings
- Behavioral characterization in open field and Y-maze revealed that glutamate evoked anxiogenic responses and perturbed spatial memory were inhibited by memantine.
- 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.
- 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.
Why it matters
In rats given glutamate injections into the dentate gyrus, memantine inhibited the anxiogenic responses and perturbed spatial memory that glutamate evoked, and memantine also abrogated most of the degenerative changes associated with glutamate. This animal study suggests glutamate excitotoxicity through NMDA receptor hyperactivation is involved in Alzheimer-like pathogenesis, but it does not establish a treatment, cure, or prevention for human Alzheimer's disease.
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Study details
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of molecular neuroscience : MN) |
| Journal's citation record | 1 / 4 | Journal of Molecular Neuroscience: journal h-index 118 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 4 / 7 | Cited 55 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 7.9 citations a year over 7 year(s) since 2021 |
| Impact for its field and year | 3 / 6 | Cited 3.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 2 / 4 | Cited 33 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Philip Adeyemi Adeniyi: h-index 12 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Louisiana State University: institution h-index 856 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 33420680) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 39 / 100 | — |
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