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

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.