Destruction of the cholinergic basal forebrain using immunotoxin to rat NGF receptor: modeling the cholinergic degeneration of Alzheimer's disease.
Degeneration of cholinergic neurons in the basal forebrain (CBF) is a prominent neuropathological feature of Alzheimer's disease and is thought responsible for some cognitive deficits seen in patients. An animal model of pure CBF degeneration would be valuable for analysis of the function of these neurons and testing therapeutic strategies. CBF neurons express receptors for nerve growth factor. In order to selectively destroy these neurons, we developed an immunotoxin using monoclonal antibody (192 IgG) to rat NGF receptor (p75NGFr) armed with the ribosome inactivating protein, saporin. In vitro 192-saporin was highly toxic to neurons expressing p75NGFr. Intraventricular injections of 192-saporin destroyed the CBF and impaired passive avoidance learning. These results indicate that 192-saporin treated rats can be used to model a key feature of Alzheimer's disease and that anti-neuronal immunotoxins are a powerful approach to selective neural lesioning.
Wiley
R G
RG
Laboratory of Experimental Neurology, DVAMC, Nashville, TN 37212-2637, USA.
Berbos
T G
TG
Deckwerth
T L
TL
Johnson
E M
EM
Lappi
D A
DA
D000544:Alzheimer Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity*; D001362:Avoidance Learning / Q000502:physiology; D001479:Basal Ganglia / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology*; D002452:Cell Count; D002478:Cells, Cultured; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000276:immunology; D000922:Immunotoxins / Q000008:administration & dosage / Q000633:toxicity*; D007276:Injections, Intraventricular; D007859:Learning Disabilities / Q000139:chemically induced; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000276:immunology; D009699:N-Glycosyl Hydrolases; D009474:Neurons / Q000187:drug effects; D010940:Plant Proteins / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects* / Q000276:immunology; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D012688:Septum Pellucidum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D013377:Substantia Innominata / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology
C085696:192 IgG-saporin; D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D007074:Immunoglobulin G; D000922:Immunotoxins; D008562:Membrane Glycoproteins; C085346:OX7-saporin; D010940:Plant Proteins; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; D000076985:Saporins