Glutamate Receptor Dysregulation and Platelet Glutamate Dynamics in Alzheimer’s and Parkinson’s Diseases: Insights into Current Medications

Abstract

Two of the most prevalent neurodegenerative disorders (NDDs), Alzheimer’s disease (AD) and Parkinson’s disease (PD), present significant challenges to healthcare systems worldwide. While the etiologies of AD and PD differ, both diseases share commonalities in synaptic dysfunction, thereby focusing attention on the role of neurotransmitters. The possible functions that platelets may play in neurodegenerative illnesses including PD and AD are becoming more acknowledged. In AD, platelets have been investigated for their ability to generate amyloid-ß (Aß) peptides, contributing to the formation of neurotoxic plaques. Moreover, platelets are considered biomarkers for early AD diagnosis. In PD, platelets have been studied for their involvement in oxidative stress and mitochondrial dysfunction, which are key factors in the disease’s pathogenesis. Emerging research shows that platelets, which release glutamate upon activation, also play a role in these disorders. Decreased glutamate uptake in platelets has been observed in Alzheimer’s and Parkinson’s patients, pointing to a systemic dysfunction in glutamate handling. This paper aims to elucidate the critical role that glutamate receptors play in the pathophysiology of both AD and PD. Utilizing data from clinical trials, animal models, and cellular studies, we reviewed how glutamate receptors dysfunction contributes to neurodegenerative (ND) processes such as excitotoxicity, synaptic loss, and cognitive impairment. The paper also reviews all current medications including glutamate receptor antagonists for AD and PD, highlighting their mode of action and limitations. A deeper understanding of glutamate receptor involvement including its systemic regulation by platelets could open new avenues for more effective treatments, potentially slowing disease progression and improving patient outcomes.

KYNA Ameliorates Glutamate Toxicity of HAND by Enhancing Glutamate Uptake in A2 Astrocytes

“…Furthermore, under normal physiological conditions, astrocytes maintain glutamate homeostasis by taking up the vast majority of free glutamate released from neuronal synapses via glutamate transporter proteins (EAATs) [7]. However, glutamate toxicity is one of the triggers for neurodegenerative diseases, such as HAND and AD [8,9]. HIV-1 gp120 may therefore impair the glutamate uptake capacity of astrocytes, thereby mediating the occurrence of glutamate toxicity in HAND, but the specific mechanism by which gp120 impairs the glutamate uptake capacity of astrocytes has not yet been reported.…”