Continuing the search for cholinergic factors in cognitive dysfunction

The objective of the experiments reported here was to explore three hypotheses regarding cholinergic processes underlying the development of progressive degenerative dementia (PDD). One possibility involved the downregulation of muscarinic receptors (mAChR) with aging, thus reducing the capability of the cholinergic system to support normal memory and other cognitive functions. The results of downregulation to 10% of normal produced only a temporary effect, the system having the capability to repair the damage. A second hypothesis predicted that a chronic hypocholinergic state can produce structural changes that are reflected in persisting cognitive dysfunctions. Chronic administration of a false cholinergic transmitter in the diets of weanling rats mimicked such a state which, if maintained for a protracted period, produced many of the features of PDD in humans. When the diet was returned to normal, biochemical and physiological processes recovered fully. However, memory impairment continued. This suggested the possibility that the behavioral losses were mediated by persisting morphological changes in the CNS. The third hypothesis proposes that these changes may be due to cell loss resulting from impaired phospholipid metabolism. Changes in sphingomyelin, one of the two major Ch-containing lipids in cell membranes, could increase amounts of ceramide, an inducer of programmed cell death (apoptosis). Tests of this hypothesis are nearing completion.