The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

Abstract

The elderly population is growing worldwide, with important health and socioeconomic implications. Clinical and experimental studies on aging have uncovered numerous changes in the brain, such as decreased neurogenesis, increased synaptic defects, greater metabolic stress, and enhanced inflammation. These changes are associated with cognitive decline and neurobehavioral deficits. Although aging is not a disease, it is a significant risk factor for functional worsening, affective impairment, disease exaggeration, dementia, and general disease susceptibility. Conversely, life events related to mental stress and trauma can also lead to accelerated age-associated disorders and dementia. Here, we review human studies and studies on mice and rats, such as those modeling human neurodegenerative diseases, that have helped elucidate (1) the dynamics and mechanisms underlying the biological and pathological aging of the main projecting systems in the brain (glutamatergic, cholinergic, and dopaminergic) and (2) the effect of defective glutamatergic, cholinergic, and dopaminergic projection on disabilities associated with aging and neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Detailed knowledge of the mechanisms of age-related diseases can be an important element in the development of effective ways of treatment. In this context, we briefly analyze which adverse changes associated with neurodegenerative diseases in the cholinergic, glutaminergic and dopaminergic systems could be targeted by therapeutic strategies developed as a result of our better understanding of these damaging mechanisms.

Role of Cholinergic Signaling in Alzheimer’s Disease

“…Although aging is not a disease, it is an important risk factor for deterioration of function, mood disorders, disease exaggeration, dementia and general disease susceptibility. In addition, life events related to mental stress and trauma can also lead to accelerated age-related diseases including AD [ 94 ]. Individuals with post-traumatic stress disorder (PTSD) are also a risk of developing various forms of dementia [ 95 ].…”

Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems

“…Aging is associated with a loss of dopaminergic function, which may originate from defects on multiple components, including loss of dopamine-producing neurons, atrophy of projection brain regions, and reduced density of dopamine receptors. These alterations result in the efficiency of dopaminergic projecting systems declines slowly during physiological aging ( Ciampa et al, 2021 ; Gasiorowska et al, 2021 ). Cumulative evidence suggests that impaired dopaminergic neurotransmission is also involved in the pathological development of a variety of neurological disorders, including AD ( Martorana and Koch, 2014 ; D’Amelio et al, 2018 ).…”

Disrupting Neurons and Glial Cells Oneness in the Brain—The Possible Causal Role of Herpes Simplex Virus Type 1 (HSV-1) in Alzheimer’s Disease

“…Activation of the glial cells, the major mediators of neuroinflammation [ 88 ], and infiltration of the CNS with inflammatory cells, serve to eliminate infected cells and inhibit viral expansion; however, immense and/or persisting inflammation can lead to pathological outcomes. For example, it is inflammation as a defense reaction and result of innate immune responses that can contribute to the secretion of Aβ by glial cells and neurons; however, Aβ accumulation, as well as NFTs formation, can lead to astrocytosis and microgliosis [ 89 ], and ultimately activate and deepen the neuroinflammatory state that has a significant share in the progression of AD. This renders inflammation in neurodegenerative diseases the meaning of the double-edged sword [ 90 , 91 ].…”

“…Dopaminergic hypofunction was also observed as a repercussion of the acute HSV brain infection in rabbits [ 260 ]. Damage through loss of neurons and cholinergic phenotype to the cholinergic system, which is involved in memory and learning, is considered to be among the earliest events during AD etiology [ 89 ], while the loss of dopaminergic neurons pertains to cognitive decline symptoms in a mouse model of AD [ 261 ], and structural alterations of the dopaminergic system strongly condition behavioral symptomatology in AD patients, as reviewed by D’Amelio et al [ 262 ].…”