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Departments of Neurology (Drs. Holtzman, Li, and Mobley) and Pediatrics (Drs. Epstein and Mobley) and the Neuroscience Program (Dr. Mobley), University of California, San Francisco, and the Department of Neurosciences (Drs. Chen and Gage), University of California, San Diego, La Jolla, CA.
Atrophy and dysfunction of certain neurons, including cholinergic neurons in the basal forebrain, are key features of the neuropathology of Alzheimer's disease (AD). Since all individuals with Down syndrome (DS) develop AD neuropathology by the 4th decade, we reasoned that a genetic model of DS, the trisomy 16 (Ts 16) mouse, may provide an animal model to study the neurodegeneration in AD. Ts 16 mice fail to survive birth; to evaluate neurons for long periods in vivo required transplantation of fetal tissue. We previously demonstrated that Ts 16 basal fore-brain cholinergic neurons (BFCNs) undergo age-related atrophy similar to DS and AD, and now show that a specific neurotrophic factor, nerve growth factor (NGF), acts to reverse Ts 16-induced atrophy of BFCNs and stimulates hypertrophy of these cells. As NGF levels were not decreased in the host, abnormalities intrinsic to Ts 16 BFCNs presumably caused the atrophy. Our results suggest that NGF may be useful in reversing cholinergic neurodegeneration in DS and AD.
Address correspondence and reprint requests to Dr. David M. Holtzman, Department of Neurology, University of California, San Francisco, 505 Parnassus Ave., M-794, Box 0114, San Francisco, CA 94143.
Supported by NIH grants AGO0445 (D.M.H.), AGO8938 (C.J.E. and W.C.M.), NS24054, AG10672 (W.C.M.), and AGO6088 (F.H.G.). D.M.H. was also supported by an Ameiican Academy of Neurology Neuropharmacology research fellowship award.
Presented in part at the 44th annual meeting of the American Academy of Neurology, San Diego, CA, May 1992, by David M. Holtzman, MD, as recipient of the 1992 S. Weir Mitchell Award.
Received March 4, 1993. Accepted for publication in final form May 12, 1993
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