Two of the principal abnormalities that occur in the brains of aged individuals and, to a greater extent, subjects with Alzheimer's disease (AD) are degeneration of basal forebrain cholinergic neurons and the degeneration of cholinergic neurons contributes to the mild memory deficits that occur in some aged individuals and to the severe impairments documented in subjects with AD. The demonstration of age- and disease- associated alterations in neurons of the basal forebrain cholinergic system has led to the use of cholinomimetic strategies to treat affected patients. Interpretation of the results of these therapies has been controversial. In part, the failure to respond to cholinomimetic therapies may result from the use of agents that do not target the distinct muscarinic receptor subtypes. Newly developed antibodies that differentiate these receptors will be used to analyze levels and distributions of muscarinic receptor subtypes in the basal forebrain, hippocampus, and neocortex of controls (10-80 years of age) and neuropsychologically characterized aged individuals from our Alzheimer's Disease Research Center and the Baltimore Longitudinal Study of Aging. Levels of specific muscarinic receptor subtypes will be correlated with clinical findings. The results of these studies are essential for the design of new agonist-antagonist strategies to treat individuals with symptomatic dysfunction of basal forebrain cholinergic circuits. A second pathological hallmark of aging and AD is the deposition of the 4-kiloDalton beta-amyloid peptide (beta/A4) in brain parenchyma and around blood vessels. Beta/A4, derived from the amyloid precursor protein (APP), and, in some cases of familial AD and in cases of hereditary cerebral hemorrhage with amyloid (Dutch type), there are mutations within APP at amino acids 642 and 618, respectively. The pathogenic roles of these mutations will be investigated in transgenic mice using techniques that have proved successful in our studies of aged nonhuman primates and individuals with AD.
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