Cholinergic Systems in Models of Alzheimer's Disease

DESCRIPTION OF PROJECT IN NONTECHNICAL TERMINOLOGY AD is the most common cause of dementia in adult life and represents a health problem of major proportions. Cases of AD show evidence of dysfunction/degeneration of specific populations of neurons, and basal forebrain cholinergic neurons are one of the principal populations affected by this disease. Thus, mechanisms associated with the survival or degeneration/death of specific populations of neurons are not well understood and are insufficient to design rational therapies to promote the survival and functions of vulnerable neurons. Because complex processes are difficult to investigate in autopsy-derived brain tissues from patients with end-stage disease, our studies focus on models: monkeys with experimental injury of basal forebrain cholinergic neurons; and aged nonhuman primates that show behavioral and brain abnormalities similar to those occurring in elderly humans and in patients with AD. The goals of this proposal are: to correlate age-associated alterations in basal forebrain neurons with changes in cholinergic markers and with behavioral imp airments documented in a cohort of aged nonhuman pr imates (Specific Aim 1); to delineate the distribution of cholinergic muscarinic receptor subtypes so that it should be possible to design more effective cholinomimetic therapies (Specific Aim 2); to determine whether neurotrophic factors (i.e., NGF) influence the long-term survival of experimentally injured basal forebrain cholinergic neurons (Specific Aim 3); and to test the efficacy of rhNGF on age-associated behavioral abnormalities in old monkeys (Specific Aim 4). These investigations will provide essential information to allow for the development of new therapies designed to improve the functions of patients who have impairments associated with diseased neurons of the basal forebrain cholinergic system.