Neurochemical deficits in pathological brain aging: specificity and possible relevance for treatment strategies

Normal brain aging is accompanied by the losses of certain neuronal populations and the appearance of structures such as neuronal plaques and neurofibrillary tangles. Additionally, various neurotransmitter systems are altered in the elderly, although marked variations are observed between individuals, suggesting important differences between successful and unsuccessful aging. In certain pathological conditions, only certain features of normal aging are exacerbated. For example, the densities of forebrain cholinergic neurons are markedly decreased in cortical and hippocampal (but not striatal) areas in Alzheimer's disease. We discuss here the comparative alterations of cholinergic markers in certain neurological disorders such as Alzheimer's disease, Parkinson's disease, and the combined pathology. Differential alterations of brain cholinergic profile are observed in each disorder, this most likely having functional significance. We also found that muscarinic receptors of the M2 subtype act as negative autoreceptors to decrease brain acetylcholine release, whereas nicotinic agonists induced the opposite effect. This suggests that blockade of negative M2 or stimulation of positive nicotinic autoreceptors could have beneficial effects in Alzheimer's disease. Additionally, modulation of heteroreceptor activation such as the serotonergic or interleukin-2 sites located on or in proximity to cholinergic nerve terminals could offer alternate strategies for the treatment of cholinergic deficits in pathological brain aging.