Metabotropic glutamate receptors: the potential for therapeutic applications in Alzheimer's disease

: Glutamate, the major excitatory neurotramitter in the brain exerts its effects via both ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs). There are three subgroups of mGluRs, pre-synaptic Group II and Group III mGluRs and post-synaptic Group I mGluRs. mGluRs are ubiquitously expressed in the brain and their activation is poised upstream of a myriad of signaling pathways, resulting in their implication in the pathogenesis of various neurodegenerative diseases including, Alzheimer’s disease (AD). While the exact mechanism of AD etiology remains elusive, β-amyloid (Aβ) plaques and hyperphosphorylated tau tangles remain the histopathological hallmarks of AD. Though less electrically excitable, neuroglia are a major non-neuronal cell type in the brain and are composed of astrocytes, microglia, and oligodendrocytes. Astrocytes, microglia, and oligodendrocytes provide structural and metabolic support, active immune defence, and axonal support and sheathing, respectively. Interestingly, Aβ and hyperphosphorylated tau are known to disrupt the neuroglial homeostasis in the brain, pushing them towards a more neurotoxic state. In this review, we discuss what is currently known regarding the expression patterns of various mGluRs in neuroglia and how Aβ and tau alter the normal mGluR function in the neuroglia and contribute to the pathophysiology of AD.

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Metabotropic Glutamate Receptors in Alzheimer’s Disease Synaptic Dysfunction: Therapeutic Opportunities and Hope for the Future

Journal of Alzheimer s Disease ◽

10.3233/jad-201146 ◽

2020 ◽

Vol 78 (4) ◽

pp. 1345-1361

Author(s):

Akriti Srivastava ◽

Brati Das ◽

Annie Y. Yao ◽

Riqiang Yan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Early Event ◽

Metabotropic Glutamate ◽

Cognitive Improvement

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence of neuritic plaques and neurofibrillary tangles. The impaired synaptic plasticity and dendritic loss at the synaptic level is an early event associated with the AD pathogenesis. The abnormal accumulation of soluble oligomeric amyloid-β (Aβ), the major toxic component in amyloid plaques, is viewed to trigger synaptic dysfunctions through binding to several presynaptic and postsynaptic partners and thus to disrupt synaptic transmission. Over time, the abnormalities in neural transmission will result in cognitive deficits, which are commonly manifested as memory loss in AD patients. Synaptic plasticity is regulated through glutamate transmission, which is mediated by various glutamate receptors. Here we review recent progresses in the study of metabotropic glutamate receptors (mGluRs) in AD cognition. We will discuss the role of mGluRs in synaptic plasticity and their modulation as a possible strategy for AD cognitive improvement.

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The Implication of Glial Metabotropic Glutamate Receptors in Alzheimer’s Disease

Current Neuropharmacology ◽

10.2174/1570159x20666211223140303 ◽

2021 ◽

Vol 20 ◽

Author(s):

Izabella B. Q. de Lima ◽

Fabíola M. Ribeiro

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glutamate Receptors ◽

Disease Progression ◽

Glial Cells ◽

Metabotropic Glutamate Receptors ◽

Underlying Disease ◽

App Processing ◽

Metabotropic Glutamate ◽

Brain Functions

: Alzheimer’s disease (AD) was first identified more than 100 years ago and, yet, aspects pertaining its origin as well as the mechanisms underlying disease progression are not well known. To this date, there is no therapeutic approach or disease modifying drug that could halt or at least delay disease progression. Until recently, glial cells were seen as secondary actors in brain homeostasis. Although this view was gradually refuted and the relevance of glial cells for the most diverse brain functions such as synaptic plasticity and neurotransmission was vastly proved, many aspects of its functioning as well as its role in pathological conditions remain poorly understood. Metabotropic glutamate receptors (mGluRs) in glial cells were shown to be involved in neuroinflammation and neurotoxicity. Besides its relevance for glial function, glutamatergic receptors are also central in the pathology of AD and recent studies have shown that glial mGluRs play a role in the establishment and progression of AD. Glial mGluRs influence AD-related alterations in Ca2+ signalling, APP processing and Aβ burden, as well as AD-related neurodegeneration. However, different types of mGluRs play different roles, depending on the cell type and brain region that is being analysed. Therefore, in this review we focus on the current understanding of glial mGluRs and their implication in AD, providing an insight for future therapeutics and identifying existing research gaps worth investigating.

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Activation of group II metabotropic glutamate receptors underlies microglial reactivity and neurotoxicity following stimulation with chromogranin A, a peptide up-regulated in Alzheimer's disease

Journal of Neurochemistry ◽

10.1046/j.1471-4159.2002.01062.x ◽

2004 ◽

Vol 82 (5) ◽

pp. 1179-1191 ◽

Cited By ~ 94

Author(s):

D. L. Taylor ◽

L. T. Diemel ◽

M. L. Cuzner ◽

J. M. Pocock

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glutamate Receptors ◽

Chromogranin A ◽

Metabotropic Glutamate Receptors ◽

Metabotropic Glutamate ◽

Group Ii

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Group 1 Metabotropic Glutamate Receptors in Neurological and Psychiatric Diseases: Mechanisms and Prospective

The Neuroscientist ◽

10.1177/10738584211021018 ◽

2021 ◽

pp. 107385842110210

Author(s):

Li-Da Su ◽

Na Wang ◽

Junhai Han ◽

Ying Shen

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Fine Tuning ◽

Psychiatric Diseases ◽

Metabotropic Glutamate ◽

Group 1

Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors that are activated by glutamate in the central nervous system (CNS). Basically, mGluRs contribute to fine-tuning of synaptic efficacy and control the accuracy and sharpness of neurotransmission. Among eight subtypes, mGluR1 and mGluR5 belong to group 1 (Gp1) family, and are implicated in multiple CNS disorders, such as Alzheimer’s disease, autism, Parkinson’s disease, and so on. In the present review, we systematically discussed underlying mechanisms and prospective of Gp1 mGluRs in a group of neurological and psychiatric diseases, including Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder, epilepsy, Huntington’s disease, intellectual disability, Down’s syndrome, Rett syndrome, attention-deficit hyperactivity disorder, addiction, anxiety, nociception, schizophrenia, and depression, in order to provide more insights into the therapeutic potential of Gp1 mGluRs.

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