Alzheimer's disease and NGF signaling.
Age-related degeneration of basal forebrain cholinergic neurons (BFCNs) occurs early and contributes significantly to cognitive decline in Alzheimer's disease (AD). Proper function and morphology of BFCNs depends on the supply of nerve growth factor (NGF) from the cortex and the hippocampus. A large number of experiments have shown that decreased supply of NGF at the level of BFCN cell bodies leads to loss of neuronal markers and shrinkage, mimicking what is observed in AD. The delivery of sufficient amounts of NGF signal to BFCN cell bodies depends on the effective participation of several factors including sufficient synthesis and release of NGF, adequate synthesis and expression of NGF receptors by BFCNs, normal signaling and retrograde transport of NGF-receptor complex, and finally effective induction of gene expression by NGF. In the past few years it has become clear that decreased amounts of NGF at the level of BFCN cell bodies is largely due to failed retrograde transport rather than decreased synthesis, binding or expression of NGF receptors in the BFCN terminals. We will discuss in vivo evidence supporting decreased retrograde transport of NGF in a mouse model with BFCN degeneration, and will attempt to match these findings with our studies in postmortem human AD brain. We will speculate about the possible mechanisms of failed NGF retrograde transport and its relationship to AD pathology.
Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA. asalehi@stanford.edu
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Salehi
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Delcroix
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Swaab
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002799:Cholinergic Fibers / Q000473:pathology; D002875:Chromosomes / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000473:pathology; D016548:Prosencephalon / Q000473:pathology; D015398:Signal Transduction; D014314:Trisomy
D009414:Nerve Growth Factors