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The Dual Role of Glutamatergic Neurotransmission in Alzheimer’s Disease: From Pathophysiology to Pharmacotherapy

Bukke, Vidyasagar Naik, Archana, Moola, Villani, Rosanna, Romano, Antonino Davide, Wawrzyniak, Agata, Balawender, Krzysztof, Orkisz, Stanislaw, Beggiato, Sarah, Serviddio, Gaetano, Cassano, Tommaso·2020·International Journal of Molecular Sciences
DOI 10.3390/ijms21207452PMC PMC7589203
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Abstract

Alzheimer’s disease (AD) is an age-related dementia and neurodegenerative disorder, characterized by Aβ and tau protein deposition impairing learning, memory and suppressing synaptic plasticity of neurons. Increasing evidence suggests that there is a link between the glucose and glutamate alterations with age that down-regulates glucose utilization reducing glutamate levels in AD patients. Deviations in brain energy metabolism reinforce the development of AD by hampering glutamate levels in the brain. Glutamate is a nonessential amino acid and the major excitatory neurotransmitter synthesized from glucose. Alterations in cerebral glucose and glutamate levels precede the deposition of Aβ plaques. In the brain, over 40% of neuronal synapses are glutamatergic and disturbances in glutamatergic function have been implicated in pathophysiology of AD. Nevertheless, targeting the glutamatergic system seems to be a promising strategy to develop novel, improved therapeutics for AD. Here, we review data supporting the involvement of the glutamatergic system in AD pathophysiology as well as the efficacy of glutamatergic agents in this neurodegenerative disorder. We also discuss exciting new prospects for the development of improved therapeutics for this devastating disorder.

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  • In Alzheimer's disease, beta-amyloid (Aβ) accumulates within synapses, impairing neurotransmitter release, receptor signalling, and dendritic spine stability, strongly implicating Aβ in synaptic pathology.

    “In AD, beta-amyloid (Aβ) accumulates within synapses, impairing neurotransmitter release, receptor signalling, and dendritic spine stability, strongly implicating Aβ in synaptic pathology [7, 28].”

    From Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer’s disease mouse model (2025) · cites this paper as [7]

    The Introduction reports Aβ species at synapses and describes their synaptotoxic effects. Section 3.3 links Aβ to altered receptor signalling and dendritic spine collapse. However, it says Aβ enhances glutamate release from presynaptic neurons rather than impairing neurotransmitter release. (LLM, conf=0.88)

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Metadata

Authors
Bukke, V. N., Archana, M., Villani, R., Romano, A. D., Wawrzyniak, A., Balawender, K., Orkisz, S., Beggiato, S., Serviddio, G., & Cassano, T.
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2020-10-09
Volume
21
Issue
20
Pages
7452
ISSN
1422-0067
DOI
10.3390/ijms21207452
PMC
PMC7589203
Cited by
161
References
26
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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