Recent Insights on Glutamatergic Dysfunction in Alzheimer’s Disease and Therapeutic Implications

Abstract

Alzheimer’s disease (AD) poses a critical public health challenge, and there is an urgent need for novel treatment options. Glutamate, the principal excitatory neurotransmitter in the human brain, plays a critical role in mediating cognitive and behavioral functions; and clinical symptoms in AD patients are highly correlated with the loss of glutamatergic synapses. In this review, we highlight how dysregulated glutamatergic mechanisms can underpin cognitive and behavioral impairments and contribute to the progression of AD via complex interactions with neuronal and neural network hyperactivity, Aβ, tau, glial dysfunction, and other disease-associated factors. We focus on the tripartite synapse, where glutamatergic neurotransmission occurs, and evidence elucidating how the tripartite synapse can be pathologically altered in AD. We also discuss promising therapeutic approaches that have the potential to rescue these deficits. These emerging data support the development of novel glutamatergic drug candidates as compelling approaches for treating AD.

Walnut-Derived Peptides Ameliorate Scopolamine-Induced Memory Impairments in a Mouse Model via Activation of Peroxisome Proliferator-Activated Receptor γ-Mediated Excitotoxicity

“…The clinical symptoms of patients with AD are most closely correlated to the loss of glutamatergic synapses in neuropathological examinations. 1 The fundamental reason for the synaptic loss of glutamate is that excessive glutamate in the intercellular space stimulates long-term activation of glutamate receptors, leading to excitatory toxicity and, ultimately, to loss of neuronal synaptic function and cell death. Excitotoxicity may underlie chronic neuronal loss in neurodegenerative diseases.…”

“…The pathological changes in AD are complex and diverse, with patients generally experiencing neuronal loss, synaptic dysfunction (such as synaptic loss and prominent plasticity defects), extracellular β-amyloid (Aβ) deposition, which forms amyloid plaques, and abnormal phosphorylation of tau protein, which forms intracellular neuronal fiber tangles. The clinical symptoms of patients with AD are most closely correlated to the loss of glutamatergic synapses in neuropathological examinations . The fundamental reason for the synaptic loss of glutamate is that excessive glutamate in the intercellular space stimulates long-term activation of glutamate receptors, leading to excitatory toxicity and, ultimately, to loss of neuronal synaptic function and cell death.…”

Hippocampal mGluR5 levels are comparable in Alzheimer’s and control brains, and divergently influenced by amyloid and tau in control brain

“…Alzheimer’s disease (AD) is pathologically characterized by the aberrant accumulation of amyloid-beta (Aβ), tau tangles, neuroinflammation, and synaptic dysfunctions (9, 32, 35). Synaptic degeneration and neurotransmitter receptor alterations play critical roles in the progression of AD (54, 72). Glutamatergic neurons form the main excitatory system in the brain and play a pivotal role in many neurophysiological functions.…”

Multitargeted Virtual Screening and Molecular Simulation of Natural Product-like Compounds against GSK3β, NMDA-Receptor, and BACE-1 for the Management of Alzheimer’s Disease

“…Furthermore, the deposition of amyloid plaques and oxidative stress can result in the hyperactivation of GSK3β, which increases the phosphorylation of tau proteins and potentiate the formation of neurofibrillary tangles [4]. Moreover, the hyperactivation of NMDA-receptor (NMDA) in combination with neurofibrillary tangles and amyloid plaques raises the release of glutamate, which could lead to excitotoxicity and neuronal death [5,6].…”