The significance of the cholinergic system in the brain during aging and in Alzheimer's disease

Acetylcholine is widely distributed in the nervous system and has been implicated to play a critical role in cerebral cortical development, cortical activity, controlling cerebral blood flow and sleep-wake cycle as well as in modulating cognitive performances and learning and memory processes. Cholinergic neurons of the basal forebrain complex have been described to undergo moderate degenerative changes during aging, resulting in cholinergic hypofunction that has been related to the progressing memory deficits with aging. Basal forebrain cholinergic cell loss is also a consistent feature of Alzheimer's disease, which has been suggested to cause, at least partly, the cognitive deficits observed, and has led to the formulation of the cholinergic hypotheses of geriatric memory dysfunction. Impaired cortical cholinergic neurotransmission may also contribute to beta-amyloid plaque pathology and increase phosphorylation of tau protein the main component of neurofibrillar tangles in Alzheimer's disease. Understanding the molecular mechanisms underlying the interrelationship between cortical cholinergic dysfunction, beta-amyloid formation and deposition, and tau pathology in Alzheimer's disease, would allow to derive potential treatment strategies to pharmacologically intervene in the disease-causing signaling cascade.