Neurotoxic and neurotrophic roles of proNGF and the receptor sortilin in the adult and ageing nervous system

The precursor form of the nerve growth factor (proNGF), forms a heterotrimeric complex with the receptors p75 and sortilin; this complex has been implicated in neuron cell death. However, it is not known whether proNGF and the receptors p75 and sortilin contribute to age‐ and disease‐related neurode...

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Bibliographic Details
Published in:The European journal of neuroscience 2008-04, Vol.27 (8), p.2103-2114
Main Authors: Al-Shawi, Raya, Hafner, Angela, Olson, Jessica, Chun, Soyon, Raza, Saba, Thrasivoulou, Christopher, Lovestone, Simon, Killick, Richard, Simons, Paul, Cowen, Timothy
Format: Article
Language:English
Subjects:
Adaptor Proteins, Vesicular Transport
Aged
Aging - physiology
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Alzheimer's disease
Animals
atrophy
basal forebrain
Blotting, Western
Caloric Restriction
Cells, Cultured
Humans
Immunohistochemistry
Male
Membrane Glycoproteins - metabolism
Mice
Microscopy, Confocal
Nerve Degeneration - physiopathology
Nerve Growth Factor - metabolism
Nerve Tissue Proteins - metabolism
neuron cell death
Neurons - metabolism
Organ Culture Techniques
p75
Prosencephalon - metabolism
Rats
Rats, Sprague-Dawley
Receptors, Nerve Growth Factor - metabolism
sympathetic neurons
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Summary:The precursor form of the nerve growth factor (proNGF), forms a heterotrimeric complex with the receptors p75 and sortilin; this complex has been implicated in neuron cell death. However, it is not known whether proNGF and the receptors p75 and sortilin contribute to age‐ and disease‐related neurodegeneration. Here we show that proNGF induces cell death in subpopulations of basal forebrain and peripheral sympathetic neurons of old, but not of young, adult rodents. In contrast, proNGF appears to induce neurite outgrowth rather than cell death of young adult sympathetic neurons. We have examined the neurotoxic role of proNGF in old age, and find that proNGF protein is elevated during ageing in the projection areas of some populations of vulnerable central and peripheral neurons; caloric restriction, which has known neuroprotective effects, partially prevents these increases. Sortilin was found to play a significant part in the observed patterns of age‐related proNGF‐mediated neurotoxicity. In particular, survival of aged neurons was rescued by neurotensin, an alternative sortilin ligand that blocks the sortilin‐mediated effects of proNGF. Furthermore, sortilin immunoreactivity increases markedly in ageing rodent basal forebrain and sympathetic neurons; in contrast, p75 levels are either unchanged or reduced. From these data we propose that selective age‐related neuronal atrophy and neurodegeneration may be mediated by increased sortilin expression in neurons, together with elevated levels of proNGF expression in some targets.
ISSN:0953-816X
1460-9568
DOI:10.1111/j.1460-9568.2008.06152.x