Neurotransmitter receptors and cognitive dysfunction in Alzheimer's disease and Parkinson's disease

Abstract

Cognitive dysfunction is one of the most typical characteristics in various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (advanced stage). Although several mechanisms like neuronal apoptosis and inflammatory responses have been recognized to be involved in the pathogenesis of cognitive dysfunction in these diseases, recent studies on neurodegeneration and cognitive dysfunction have demonstrated a significant impact of receptor modulation on cognitive changes. The pathological alterations in various receptors appear to contribute to cognitive impairment and/or deterioration with correlation to diversified mechanisms. This article recapitulates the present understandings and concepts underlying the modulation of different receptors in human beings and various experimental models of Alzheimer's disease and Parkinson's disease as well as a conceptual update on the underlying mechanisms. Specific roles of serotonin, adrenaline, acetylcholine, dopamine receptors, and N-methyl-D-aspartate receptors in Alzheimer's disease and Parkinson's disease will be interactively discussed. Complex mechanisms involved in their signaling pathways in the cognitive dysfunction associated with the neurodegenerative diseases will also be addressed. Substantial evidence has suggested that those receptors are crucial neuroregulators contributing to cognitive pathology and complicated correlations exist between those receptors and the expression of cognitive capacities. The pathological alterations in the receptors would, therefore, contribute to cognitive impairments and/or deterioration in Alzheimer's disease and Parkinson's disease. Future research may shed light on new clues for the treatment of cognitive dysfunction in neurodegenerative diseases by targeting specific alterations in these receptors and their signal transduction pathways in the frontal-striatal, fronto-striato-thalamic, and mesolimbic circuitries.

Fig 1. Potential serotonin receptor-mediated signaling in AD

Stimulation of serotonin receptors potentially activates the secondary messenger, cAMP, and subsequently stimulates the PKA-mediated pathway in AD.

Fig 2. Proposed acetylcholine receptor-mediated pathways involved in AD

The activation of the acetylcholine receptor might elevate the cytoplasmic calcium inflow and trigger a series of calcium-dependent signaling processes such as CaMKII/IV and ERK/MAPK pathways.

Fig 3. Proposed dopamine receptor-mediated signaling pathways in cognitive dysfunction in PD

The simultaneous activation of dopamine receptors suppresses transmembrane Ca²⁺ currents and activates phospholipase C (PLC) and the calcium-dependent phosphatase calcineurin. ERK1/2/MAP, AKT and PKA signal pathways would be activated after the denervation of nigrostriatal dopaminergic neurons following dopamine receptor modulation.

Fig 4. Proposed NMDA receptor-mediated mechanisms in cognitive dysfunction in AD

In AD development, tau and amyloid plaques overactivate NMDA receptors and thus can cause Ca²⁺ overflow into dopaminergic neurons and activate several key enzymes, such as the calmodulin-dependent protein kinase kinase (CaMKK).