The Impact of Neurotransmitters on the Neurobiology of Neurodegenerative Diseases

Abstract

Neurodegenerative diseases affect millions of people worldwide. Neurodegenerative diseases result from progressive damage to nerve cells in the brain or peripheral nervous system connections that are essential for cognition, coordination, strength, sensation, and mobility. Dysfunction of these brain and nerve functions is associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and motor neuron disease. In addition to these, 50% of people living with HIV develop a spectrum of cognitive, motor, and/or mood problems collectively referred to as HIV-Associated Neurocognitive Disorders (HAND) despite the widespread use of a combination of antiretroviral therapies. Neuroinflammation and neurotransmitter systems have a pathological correlation and play a critical role in developing neurodegenerative diseases. Each of these diseases has a unique pattern of dysregulation of the neurotransmitter system, which has been attributed to different forms of cell-specific neuronal loss. In this review, we will focus on a discussion of the regulation of dopaminergic and cholinergic systems, which are more commonly disturbed in neurodegenerative disorders. Additionally, we will provide evidence for the hypothesis that disturbances in neurotransmission contribute to the neuronal loss observed in neurodegenerative disorders. Further, we will highlight the critical role of dopamine as a mediator of neuronal injury and loss in the context of NeuroHIV. This review will highlight the need to further investigate neurotransmission systems for their role in the etiology of neurodegenerative disorders.

Keywords: Dopamine; HIV-1 Associated Neurocognitive Disorders; neurodegenerative diseases; neurotransmitters.

Figure 1

Two pathways are proposed for NT-mediated neuronal cell death and damage. The direct pathway involves neurotoxic metabolites or catabolites of NTs, which generate ROS, stimulating mitochondrial response. The indirect pathway involves the overactivation of G-protein coupled receptors to increase Ca²⁺ levels past physiologically normal levels, resulting in cellular stress responses and subsequent activation of mitochondrial-mediated apoptosis. Both pathways may facilitate synaptic injury through increased ROS formation. Molecular factors that contribute to the dysregulation of NT systems may mediate mild Neurocognitive Impairment (NCI) or neuronal cell death through the outlined pathways.

Figure 2

Hypothesized pathway for DA mediated HAND neurobiology. HIV-1 enters the CNS by infecting macrophages, which subsequently translocate across the blood–brain barrier. Once in the CNS, viral replication takes place in infected macrophages in the basal ganglia. HIV proteins such as Tat and gp120 are then released from infected cells into the extracellular space. Extracellular Tat can directly block DA and NE transporter activity (red “X”), subsequently increasing extracellular DA levels (dashed arrow). DA may then increase viral replication in macrophages and promote the release of inflammatory cytokines from macrophages, presenting a pathway by which the NT DA mediates neurotoxicity in subcortical brain regions containing dopaminergic neurons. Additionally, extracellular gp120 interacts with CXCR5 and CCR5 receptors in microglia and macrophages, which also contributes to neurotoxicity through activation of the NLRP3-inflammasome.