DIFFUSION NGF & BIOLOGICAL RESPONSE FROM BASAL FOREBRAIN CHOLINERGIC NEURONS

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Significance NGF regulates the phenotype of basal forebrain cholinergic neurons (BFCN) and can promote BFCN survival following injury or age-related degeneration. NGF may therefore be useful in treating the cholinergic component of neuronal loss in Alzheimer's disease. However, intracerebroventricular infusions of NGF cause substantial adverse effects from non-targeted systems; thus, local and intraparenchymal delivery of NGF to BFCNs is necessary. Objectives To determine whether intraparenchymal (IP) infusions of NGF diffuse for distances sufficient to elicit neurotrophic effects from the extensive population of BFCNs in the primate, adult rhesus monkeys (n=4) between the ages of 7 and 19 years received continuous infusions of NGF [1.0 mg/ml x 12 ml/day] for 3 days into either the striatum or nucleus basalis magnocellularis (NBM). Brain sections were immunolabeled for NGF [Mufson et al., 1994], and CSF and serum samples were assayed for NGF protein content using a two-site ELISA. Results NGF delivered IP diffused in a spherical distribution over 6-10 mm and accessed a majority of NBM neurons. Only slight amounts of NGF were detected in the CSF after IP. Future Directions Thus, intraparenchymal brain infusions of NGF diffuse extensively while raising CSF levels only slightly. These results further support the concept that direct IP infusions may provide an alternative to ICV infusions for delivering trophic factors chronically into the CNS. KEY WORDS aging, Alzheimer's, neurotrophic factor FUNDING NIH Grant AG10435