Involvement of Cholinergic, Adrenergic, and Glutamatergic Network Modulation with Cognitive Dysfunction in Alzheimer's Disease

Abstract

Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease. The number of AD cases has been rapidly growing worldwide. Several the related etiological hypotheses include atypical amyloid β (Aβ) deposition, neurofibrillary tangles of tau proteins inside neurons, disturbed neurotransmission, inflammation, and oxidative stress. During AD progression, aberrations in neurotransmission cause cognitive decline-the main symptom of AD. Here, we review the aberrant neurotransmission systems, including cholinergic, adrenergic, and glutamatergic network, and the interactions among these systems as they pertain to AD. We also discuss the key role of N-methyl-d-aspartate receptor (NMDAR) dysfunction in AD-associated cognitive impairment. Furthermore, we summarize the results of recent studies indicating that increasing glutamatergic neurotransmission through the alteration of NMDARs shows potential for treating cognitive decline in mild cognitive impairment or early stage AD. Future studies on the long-term efficiency of NMDA-enhancing strategies in the treatment of AD are warranted.

Keywords: Alzheimer’s disease; NMDAR; adrenergic; cholinergic; glutamatergic.

Figure 1

Proposed model of the mechanism of α1, α2, and βAR regulating NMDAR function. βAR enhances NMDAR currents through cAMP-PKA pathways, whereas α2AR reduces NMDAR activity by inhibiting the same pathway or presynaptic glutamate secretion. α1AR, which is a protein-coupled receptor, decreases NMDAR activity through PLC-IP3 signals.