Targeted intraparenchymal delivery of human NGF by gene transfer to the primate basal forebrain for 3 months does not accelerate β-amyloid plaque deposition
Nerve growth factor therapy has been proposed as a potential means of preventing degeneration of basal forebrain cholinergic neurons in Alzheimer's disease and thereby improving cognition. However, NGF has been reported to upregulate expression of the 13-amyloid precursor protein, which in turn could accelerate deposition of 'mature' β-amyloid in the brain. To address this possibility, the brains of 16 adult and aged rhesus monkeys were examined for 13-amyloid plaque deposition in the presence or absence of NGF treatment. Six aged monkeys received intraparenchymal grafts into the cholinergic basal forebrain of autologous cells genetically modified to secrete NGF, six aged monkeys received intraparenchymal grafts of autologous control cells expressing the reporter gene β-galactosidase, and four adult nonoperated monkeys served as additional controls. All brains were examined for expression of mature 13-amyloid using an antibody recognizing amino acids 1-40 of the β-amyloid peptide. Amyloid plaques were systematically quantified in representative sections of the temporal, frontal, cingulate, insular, and parietal cortices and in the amygdala and hippocampus. Results disclosed that aging resulted in an increase in amyloid plaque formation: no plaques at all were detected in nonaged monkeys, whereas a mean of 20 ± 13 plaques per section were present in control-aged monkeys. Aged subjects with intraparenchymal NGF-secreting grafts for 3 months contained a mean of 29 ± 14 plaques per section, an amount that did not differ significantly from controlaged monkeys (P = 0.66). Thus, 3 months of intraparenchymal NGF delivery did not significantly increase β-amyloid deposition.
13-amyloid, Aging, Alzheimer's disease, Gene therapy, Nerve growth factor, Neurotrophin, β-APP
Digital Object Identifier (DOI)
Tuszynski, Mark H.; Smith, David E.; Roberts, Jeffrey; McKay, Heather; and Mufson, Elliott, "Targeted intraparenchymal delivery of human NGF by gene transfer to the primate basal forebrain for 3 months does not accelerate β-amyloid plaque deposition" (1998). Translational Neuroscience. 1965.