Cholinergic ventral forebrain grafts into the neocortex improve passive avoidance memory in a rat model of Alzheimer disease.

Abstract

The memory dysfunction of Alzheimer disease has been associated with a cortical cholinergic deficiency and loss of cholinergic neurons of the nucleus basalis of Meynert. This cholinergic component of Alzheimer disease can be modeled in the rat by ibotenic acid lesions of the cholinergic nucleus basalis magnocellularis. The (15,16) or cholinergic (17) systems in rats with NBM lesions. In the present study, we examined the ability of embryonic neurons from the cholinergic ventral forebrain to reinnervate the neocortex of animals with NBM lesions. We show that such grafts survive and ameliorate a memory deficit caused by lesions in the rats as measured in a passive avoidance paradigm.The long time course of transplantation experiments requires the use of animals with stable lesions, large enough to preclude compensatory sprouting. Large bilateral lesions of the NBM in the rat produce profound disruption of appetitive behaviors, which may be attributable to damage to adjacent hypothalamic and pallidal structures, and which often have fatal consequences. By contrast, large unilateral NBM lesions leave one side intact to maintain normal eating and drinking, have no detectable effect on spontaneous locomotor activity, and provide an internal control for biochemical and histochemical assessment. Thirty-three female Sprague--Dawley rats (180-210 g) received unilateral ibotenic acid lesions at two sites in the right NBM (see Fig. 1). Such lesions spare fibers of passage (18); indeed, identical injections of ibotenic acid directly into the more ventrally located median forebrain bundle completely spare the ascending catecholaminergic fibers (19). Manipulations were restricted to one side of the brain and to animals of one sex in order to reduce possible sources of variability. Eight of the injected animals were killed 1 week later for biochemical assay of ChoAcTase (20); the lesions reduced ChoAcTase content in dorsolateral frontal and parietal cortex to 43.2% ± 5.4% and 41.2% +± 3.2% (mean ± SEM), respectively, of intact contralateral levels. This corresponds to a decrease in measured activity from 16.24 to 6.83 nmol of acetylcholine synthesized per mg of protein per hr and from 15.74 to 6.38 nmol per mg of protein per hr in the two respective sites. Since cortical undercutting indicates that 20-50% of cortical ChoAcTase is derived from intrinsic cortical neurons (21), this suggests that these NBM lesions are nearly complete. The remaining 25 rats with lesions were subdivided into three groups 1 week after surgery. Twelve animals received transplants of cholinergic-rich tissue dissected from the developing ventral forebrain (including septum, diagonal band, nucleus basalis precursors) of 15-to 16-mm long (crown-rump) Sprague--Dawley rat embryos and dissociated to a single-cell suspension (1 ventral forebrain per 10-,ul suspension) as described elsewhere (22). Each animal received two 2-,ul aliquots of cell suspension stereotaxically injected into dorsolateral frontal and parietal cortex ipsilateral to the lesio...

Induction of Memory and Cortical Cholinergic Neurochemical Recovery with Combine Fetal Transplantation and GM1 Treatments in Rats with Lesions of the NBM

“…6 for review]. Those studies that have used unilateral lesions generally are in agree ment with the results derived from bilateral experiments in reporting passive avoidance deficits [5,7,9], There fore, the present demonstration of a 72-hour retention deficit on passive avoidance induced by unilateral nbM lesions is fully consistent with previously published data.…”

Par-4 Inhibits Choline Uptake by Interacting with CHT1 and Reducing Its Incorporation on the Plasma Membrane

“…For example, basal forebrain cholinergic neurons are involved in learning and memory processes, and hypoactivity of the cholinergic system may be directly responsible for the cognitive deficit in Alzheimer's disease (AD) 1 (4 -8). Reductions in choline acetyltransferase (ChAT) activity and a profound loss of cholinergic neurons in the nucleus basalis magnocellularis have been observed in AD brain (5)(6)(7)(8)(9)(10)(11)(12). High affinity choline uptake is generally believed to be the rate-limiting step in acetylcholine synthesis in cholinergic neurons and is essential for cholinergic transmission in the central nervous system (13)(14)(15)(16).…”

Embryonic Stem Cell in the Therapy of Neurodegenerative Diseases

“…When cholinergicrich tissue and peripheral cholinergic neurons were transplanted into an AD rat model with nbM lesions, memory improvement which indicated a partial neuronal rescue has been found in these animal models. However, it is difficult to get enough donor cells, no clinical trials in AD patients have been initiated with this method (Fine et al, 1985). When ESCs as donor cells transplanted directly in AD animal model, it usually resulted in teratomas formation instead of producing neurons (Ringdén et al, 2003;Wang et al, 2006).…”