IMPAIRMENT OF BASAL FOREBRAIN CHOLINERGIC NEURONS ASSOCIATED WITH AGING AND LONG-TERM LOSS OF OVARIAN-FUNCTION

Recent studies suggest that women are at greater risk for Alzheimer's disease than men and that estrogen replacement can help to reduce the risk and severity of Alzheimer's-related dementia in postmenopausal wo men. We have hypothesized that the increased risk for Alzheimer's-rela ted dementia is due, in part, to the loss of ovarian function in postm enopausal women and to the effects that decreased levels of ovarian ho rmones have on basal forebrain cholinergic function. In the present st udy, the effects of aging and ovariectomy on cholinergic neurons in th e rat basal forebrain were examined to determine (1) whether aging dif ferentially affects cholinergic neurons in the basal forebrain of male s vs females, and (2) whether long-term loss of ovarian function produ ces deficits in basal forebrain cholinergic function beyond those asso ciated with aging and sex. In part I of the study, gonadally intact ma le and female rats were sacrificed at 13, 19, and 25 months of age and the effects of aging on cholinergic neurons in the medial septum (MS) and nucleus basalis magnocellularis (NBM) were compared. In part II o f the study, female rats were ovariectomized at 13 months of age and t hen sacrificed 3 and 6 months later along with gonadally intact, age-m atched controls. Adjacent sections through the MS and NBM were process ed for either immunocytochemical detection of choline acetyltransferas e (ChAT) and p75NTR-Like immunoreactivity or for in situ hybridization detection and quantification of ChAT and trkA mRNA. Results from part I revealed no significant effects of age on the relative size or dens ity of cholinergic neurons in the MS and NBM of gonadally intact anima ls. Likewise, no significant effects on the relative numbers of cholin ergic neurons expressing p75NTR protein were detected. However, a sign ificant decrease in trkA mRNA was detected in the MS of gonadally inta ct females, but not males, between 13 and 25 months of age. No signifi cant effects of aging on ChAT mRNA were detected. Results from part II revealed significant decreases in both ChAT and trkA mRNA in the MS a nd NBM of female rats sacrificed 6 months, but not 3 months, following ovariectomy relative to age-matched, gonadally intact controls. Short -term estrogen replacement initiated 6 months following ovariectomy an d administered for 3 days prior to sacrifice partially restored ChAT m RNA levels in the MS and trkA mRNA levels in the NBM. These findings s uggest that ovarian hormones play a role in maintaining normal levels of ChAT and trkA expression in the MS and NBM. The fact that ChAT mRNA was decreased in the MS and NBM at 6 months following ovariectomy sug gests that long-term loss of ovarian function produces a decrease in t he functional status of basal forebrain cholinergic neurons projecting to the hippocampus and cortex. In addition, we hypothesize that the d ecreases in trkA mRNA detected both in the MS as a function of aging, and in the MS and NBM in response to ovariectomy, reflect decreases in the production of high affinity nerve growth factor (NGF) receptors, and a decrease in the responsiveness of the cholinergic neurons to end ogenous NGF. This, in turn, may increase the susceptibility of the cho linergic neurons to the effects of aging and disease and thereby contr ibute to basal forebrain cholinergic decline. We conclude that long-te rm loss of ovarian function combined with aging has a negative impact on basal forebrain cholinergic neurons. These effects may contribute t o the risk and severity of cognitive decline associated with aging and Alzheimer's disease in postmenopausal women. (C) 1998 Academic Press.