Journal of Neuroscience, Vol 10, 3801-3813, Copyright © 1990 by Society for Neuroscience
Mouse nerve growth factor prevents degeneration of axotomized basal forebrain cholinergic neurons in the monkey
VE Koliatsos, HJ Nauta, RE Clatterbuck, DM Holtzman, WC Mobley and DL Price
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2182.
NGF, a trophic polypeptide, is necessary for the normal development and
survival of certain populations of neurons in the CNS and PNS. In the CNS,
cholinergic neurons of the basal forebrain magnocellular complex (BFMC) are
prominent targets of NGF. During rat development, NGF increases the
activity of ChAT in these neurons. In adult rats with experimental injury
of axons in the fimbria-fornix, NGF prevents degenerative changes in
axotomized cholinergic BFMC neurons in the medial septal nucleus (MSN).
Because the amino acid sequences of NGF and its receptor (NGF-R) are highly
conserved across species, we hypothesized that mouse NGF would also prevent
degeneration of cholinergic BFMC neurons in nonhuman primates. Therefore,
the present study was designed to test whether fimbria-fornix lesions
result in retrograde degenerative changes in basal forebrain cholinergic
neurons in macaques, whether these changes are prevented by mouse NGF, and
whether the protective effect of NGF is selective for cholinergic neurons
of the basal forebrain. Following unilateral complete transection of the
fornix, animals were allowed to survive for 2 weeks, during which time half
of the subjects received intraventricular NGF in vehicle and the other half
received vehicle alone. In animals receiving vehicle alone, there was a 55%
reduction in the number of ChAT- immunoreactive cell bodies within the MSN
ipsilateral to the lesion; loss of immunoreactive somata was more severe in
caudal planes of the MSN. Remaining immunoreactive neurons appeared smaller
than those in control, unoperated animals. In Nissl stains, there was no
apparent loss of basophilic profiles in the MSN, but cells showed reduced
size and intensity of basophilia. Treatment with NGF almost completely
prevented reductions in the number and size of cholinergic neurons and had
a significant general effect in preventing atrophy in basophilic
magnocellular neurons of the MSN, though some basophilic neurons in the MSN
did not appear to respond to NGF. Adjacent 7-microns-thick sections stained
with ChAT and NGF-R immunocytochemistry revealed that these markers are
strictly colocalized in individual neurons in the MSN in controls and in
both groups of experimental animals. Thus, mouse NGF profoundly influences
the process of axotomy-induced retrograde degeneration in cholinergic BFMC
neurons in primates. The in vivo effectiveness of mouse NGF on primate BFMC
neurons suggests that mouse or human recombinant NGF may be useful in
ameliorating the ACh- dependent, age-associated memory impairments that
occur in nonhuman primates.(ABSTRACT TRUNCATED AT 400 WORDS)
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