Human nerve growth factor prevents degeneration of basal forebrain cholinergic neurons in primates.
Basal forebrain cholinergic neurons respond to nerve growth factor (NGF), and it has been suggested that the administration of NGF might prevent their degeneration in patients with Alzheimer's disease. One major prerequisite to be fulfilled before the consideration of clinical trials of NGF in patients with Alzheimer's disease is the demonstration that human NGF affects basal forebrain cholinergic neurons in primates. In the present study, we used a recombinant human nerve growth factor (rhNGF), which we previously showed to be active on rat basal forebrain cholinergic neurons, in nonhuman primates with a unilateral transection of the fornix (a well-established model for the induction of retrograde degenerative changes in septal cholinergic neurons). After the lesion, one group of animals received rhNGF and a second group received vehicle solution for 2 weeks. In animals receiving vehicle, the medial septal nucleus ipsilateral to the lesion showed reductions in number (55%) and size of cell bodies immunoreactive for NGF receptor and choline acetyltransferase. In Nissl stains, many cells showed reduced size and basophilia. The rhNGF completely prevented alterations in the number and size of NGF receptor- and choline acetyltransferase-immunoreactive neurons in the medial septal nucleus and reversed atrophy in a subpopulation of large, basophilic medial septal nucleus neurons, as identified by Nissl stains. The effects of rhNGF were identical to those of mouse NGF, which we have previously used in the same primate lesion paradigm. The restoration of the phenotype of injured cholinergic septal neurons by rhNGF in the monkey raises the possibility that this factor may be used to ameliorate acetylcholine-dependent memory impairments that occur in aged nonhuman primates. In concert, results of the present investigation provide critical information for the future use of NGF in patients with neurological disorders that affect NGF-responsive cells in the peripheral and central nervous systems.
Koliatsos
V E
VE
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2181.
Clatterbuck
R E
RE
Nauta
H J
HJ
Knüsel
B
B
Burton
L E
LE
Hefti
F F
FF
Mobley
W C
WC
Price
D L
DL
D000110:Acetylcholinesterase / Q000032:analysis; D000818:Animals; D015415:Biomarkers; D016923:Cell Death / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000032:analysis; D002799:Cholinergic Fibers / Q000187:drug effects; D003864:Depression, Chemical; D006624:Hippocampus / Q000293:injuries; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D009410:Nerve Degeneration / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D012686:Septal Nuclei / Q000187:drug effects*
D015415:Biomarkers; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase