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 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.
Oh
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JD
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
Chartisathian
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Chase
T N
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Butcher
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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*
D000906:Antibodies; D018696:Neuroprotective Agents; D009498:Neurotoxins; D020800:Receptor, Nerve Growth Factor; D003513:Cycloheximide; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine; D007608:Kainic Acid