Overexpression of neurotrophin receptor p75 contributes to the excitotoxin-induced cholinergic neuronal death in rat basal forebrain

Both excitotoxicity and altered trophic factor support have been implicated in the pathogenesis of Alzheimer's disease. To determine whether stimulati on of p75, the low-affinity receptor for nerve growth factor, contributes t o the excitotoxin-induced apoptotic death of cholinergic neurons, we examin ed the effect of unilateral kainic acid (KA; PBS vehicle, 1.25, 2.5 and 5.0 nmol) administration into rat basal forebrain on neuronal loss and p75 exp ression. KA (2.5 nmol) destroyed 43% of Nissl-stained neurons and 70% of ch oline acetyltransferase (ChAT)-positive neurons 5 days after injection. Aga rose gel electrophoresis revealed that KA (2.5 nmol) induced local intemucl eosomal DNA fragmentation after 6-48 h. Immunohistochemical analysis furthe r showed that KA (2.5 nmol) augmented p75 immunoreactivity at a time when t erminal transferase-mediated deoxyuridine trophosphate (d-UTP)-digoxigenin nick end labeling (TUNEL)-positive nuclei were increased. Many fragmented n uclei were co-labeled with ChAT antibody. The chronic administration of ant i-rat p75 or the protein synthesis inhibitor, cycloheximide, but not anti-h uman p75, substantially reduced the KA-induced destruction of cholinergic n eurons and the induction of internucleosomal DNA fragmentation. Anti-rat p7 5, but not cycloheximide, also reversed the spatial memory impairment produ ced by KA. These findings suggest that overexpression of p75 contributes to the excitotoxin-induced death of rat basal forebrain cholinergic neurons b y an apoptotic-like mechanism. (C) 2000 Published by Elsevier Science B.V. All rights reserved.