Is EAAT2 a potential therapeutic intervention target for Alzheimer's disease?

Alzheimer's disease (AD) is the most common form of dementia worldwide, impairing memory and cognitive functions due to widespread neuronal death. The global incidence of this neurodegenerative disorder is predicted to increase rapidly in the near future. This growth in prevalence of AD will create a large burden for health systems worldwide. Further research into new therapeutic avenues is therefore crucial, given the extremely limited treatment options currently available for AD. The dysfunction and aggregation of two proteins, amyloid-beta (Aβ) and tau, are typically considered the main pathological hallmarks that cause neuronal death in AD. However, numerous other cellular alterations occur, one of which is extensive damage to neurotransmitter systems. Glutamate is the primary excitatory neurotransmitter in the central nervous system and is responsible for the vast majority of excitatory neuron-to-neuron communication throughout the brain. Various receptors, enzymes, and transporters function together in a well-orchestrated manner to ensure glutamatergic homeostasis. The proper regulation of this system is critical for a normal cellular physiological state, given excess activation of glutamatergic postsynaptic receptors can cause glutamate excitotoxicity, which is heavily implicated in the pathogenesis of AD (Han et al., 2016; Yeung et al., 2021).