title: Overexpression of neurotrophin receptor p75 contributes to the excitotoxin-induced cholinergic neuronal death in rat basal forebrain.
abstract: Both excitotoxicity and altered trophic factor support have been implicated in the pathogenesis of Alzheimer's disease. To determine whether stimulation of p75, the low-affinity receptor for nerve growth factor, contributes to the excitotoxin-induced apoptotic death of cholinergic neurons, we examined 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 expression. KA (2. 5 nmol) destroyed 43% of Nissl-stained neurons and 70% of choline acetyltransferase (ChAT)-positive neurons 5 days after injection. Agarose gel electrophoresis revealed that KA (2.5 nmol) induced local internucleosomal DNA fragmentation after 6-48 h. Immunohistochemical analysis further showed that KA (2.5 nmol) augmented p75 immunoreactivity at a time when terminal transferase-mediated deoxyuridine trophosphate (d-UTP)-digoxigenin nick end labeling (TUNEL)-positive nuclei were increased. Many fragmented nuclei were co-labeled with ChAT antibody. The chronic administration of anti-rat p75 or the protein synthesis inhibitor, cycloheximide, but not anti-human p75, substantially reduced the KA-induced destruction of cholinergic neurons and the induction of internucleosomal DNA fragmentation. Anti-rat p75, but not cycloheximide, also reversed the spatial memory impairment produced by KA. These findings suggest that overexpression of p75 contributes to the excitotoxin-induced death of rat basal forebrain cholinergic neurons by an apoptotic-like mechanism.
authors.affiliation: Experimental Therapeutics Branch, Building 10, Room 5C103, National Institute of Neurological Disorders and Stroke, NIH, Bldg. 10, Room 5C211, 90900 Rockville Pike, Bethesda, MD, USA. jdoh@helix.nih.gov
authors.forename: J D
authors.initials: JD
authors.lastname: Oh
authors.forename: K
authors.initials: K
authors.lastname: Chartisathian
authors.forename: T N
authors.initials: TN
authors.lastname: Chase
authors.forename: L L
authors.initials: LL
authors.lastname: Butcher
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D007608:Kainic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D008845:Microinjections; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D000906:Antibodies; D018696:Neuroprotective Agents; D009498:Neurotoxins; D020800:Receptor, Nerve Growth Factor; D003513:Cycloheximide; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine; D007608:Kainic Acid