Role of calcineurin and ionotropic glutamate receptors in Alzheimer's disease: A systematic review

Abstract

• Calcineurin dysregulation contributes to synaptic dysfunction in AD. • Ionotropic glutamate receptors mediate excitotoxicity in neurodegeneration. • NMDA receptor hypofunction is linked to cognitive decline in Alzheimer's disease. • AMPA receptor alterations affect synaptic plasticity and memory formation. • Targeting calcineurin and iGluRs offers potential therapeutic strategies. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes. Calcineurin (CaN), a calcium/calmodulin-dependent serine/threonine phosphatase, is hyperactivated in AD, leading to enhanced neuroinflammation, synaptic dysfunction, and tau hyperphosphorylation. Similarly, the dysregulation of ionotropic glutamate receptors (iGluRs), particularly NMDA receptors in the context of AD, aggravates excitotoxicity, which in turn contributes to neuronal damage and cognitive deficits. Moreover, AMPA and kainate receptors also play significant roles in synaptic plasticity and neurodegeneration. The intricate interplay between CaN and iGluRs, specifically NMDA, AMPA, and kainate receptors, through various signaling pathways plays a crucial role in AD pathogenesis. Therapeutic approaches targeting the CaN-iGluR axis, including CaN inhibitors and iGluR modulators, have the potential to mitigate the progression of AD and improve cognitive functions associated with the disease. This systematic review aims to consolidate current knowledge on the molecular mechanisms underlying CaN and iGluR dysregulation in AD and discuss their potential as therapeutic targets. Future investigations should prioritize elucidating the precise interactions between CaN and iGluRs, as well as developing selective modulators to enhance the efficacy and safety of therapeutic interventions for AD.