Reduced transport of [125I]nerve growth factor by cholinergic neurons and down-regulated TrkA expression in the medial septum of aged rats.
Basal forebrain cholinergic neurons atrophy and degenerate in aging and Alzheimer's disease for unknown reasons. In this study, aged male Sprague-Dawley rats (26-30 months old) showed a significant 31% reduction in the number of septal cholinergic neurons which take up and retrogradely transport 125I-labelled nerve growth factor injected into their target hippocampus, as compared with young adult rats (three to six months old). In aged rats, cholinergic neurons not transporting nerve growth factor were severely atrophied and had a significant 60% reduction in mean cross-sectional area as compared with [125I]nerve growth factor transporting neurons. These changes were accompanied by a significant 43% decline in relative levels of messenger RNA encoding the high affinity nerve growth factor receptor TrkA, in the septal region of aged rats. There was no difference between young and aged rats in messenger RNA levels encoding the low affinity nerve growth factor receptor, p75NGFR. These findings suggest that aged basal forebrain cholinergic neurons exhibit a reduced capacity to sustain receptor mediated uptake and retrograde transport of target-derived neurotrophin. This reduced capacity is associated with severe neuronal atrophy and may contribute to the pronounced vulnerability of these neurons to degeneration in aging and Alzheimer's disease.
Cooper
J D
JD
MRC Cambridge Centre for Brain Repair, University of Cambridge, U.K.
Lindholm
D
D
Sofroniew
M V
MV
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001284:Atrophy; D001370:Axonal Transport; D002799:Cholinergic Fibers / Q000378:metabolism*; D015536:Down-Regulation; D006624:Hippocampus; D007267:Injections; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D012688:Septum Pellucidum / Q000378:metabolism* / Q000473:pathology
D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA