Changes in cognitive function, including a decline in various aspects of memory, occur as part of normal aging. However, a far more dramatic memory impairment occurs as a result of certain age-related diseases including Alzheimer's disease (AD) and, in fact, forms its major behavioral symptomatological axis. Neurochemically, the most striking and consistent marker of AD is a widespread depletion of the cholinergic enzymes choline acetyltransferase (CAT) and acetylcholinesterase (AChE) in various cortical and limbic regions. At the same time, neuropathological evidence is accumulating to show that neurons in the nucleus basal of Meynert (NB) and the associated substantia innominata (SI) undergo extensive degeneration in patients with AD. These areas of the basal forebrain contain CAT and AChE positive cells which are known to project to widespread areas of the cerebral cortex and limbic system. The relationship between these neurochemical and neuropathological markers and the steady decline of cognitive function in patients with AD is the principal question addressed in this proposal.
Four specific aims of this proposal are 1) to assess the behavioral effects of bilateral lesions of the SI-NB in the rhesus monkey. Four tests of associative and recognition memory which we have found to be sensitive to monkeys with limbic system lesions and to patients with AD will be used. 2) To measure the extent of loss in cholinergic activity in the basal forebrain, cerebral cortex and limbic system in these same monkeys using histochemical, biochemical and immunocytochemical techniques. 3) To correlate the exent of loss in cholinergic activity with the degree of memory impairment and 4) to assess the potential of transplanting cholinergic tissue from the basal forebrain of neonatal monkeys into either the site of lesion and/or into identified areas of cholinergic depletion in the brain of animals with demonstrated memory impairment following SI-NB damage. The efficacy of transplants will be determined by assessing the degree of behavioral recovery on the memory tasks and by measuring the extent of recovery of cholinergic activity in the transplant and target sites. Characterizing the behavioral and neurochemical deficits which may follow SI-NB lesions in monkeys would be a first step in establishing a working animal model of AD.
