Region-Specific Neurotrophin Imbalances in Alzheimer Disease

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Abstract
NERVE GROWTH factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5) are members of the neurotrophin gene family that support the survival, differentiation, maintenance, and repair of vertebrate neurons.1 Nerve growth factor supports the cholinergic neurons of the basal forebrain system.2 Brain-derived neurotrophic factor supports cholinergic, dopaminergic, 5-hydroxytryptamine, and neuropeptides containing neurons.3- 6 Neurotrophin 3 was shown to prevent the death of adult central noradrenergic neurons in vivo.7 Neuronal loss in Alzheimer disease (AD) includes the cholinergic neurons of the basal forebrain system, as well as neurons of the noradrenergic and serotonergic system.8 Previous reports demonstrated increased levels of NGF in cortical and subcortical brain areas including the frontal and parietal cortices and the hippocampus.9- 11 These increases were attributed to both reduced uptake and retrograde transport of NGF to NGF-sensitive cell bodies, since expression and protein levels of the NGF high-affinity receptor trkA were reduced in target regions of basal forebrain cholinergic neurons, such as the cortical association areas.12- 15 In contrast, BDNF messenger RNA levels were reported to be decreased in hippocampal neurons16 and BDNF protein levels were reported to be decreased in the entorhinal cortex of patients with AD.17 These results pointed to an opposite involvement of NGF and BDNF, which are both associated with trophic support of cholinergic neurons of the basal forebrain system, in the neuropathology of AD. To further explore the differential involvement of neurotrophins in AD, we quantitated protein levels of NGF, BDNF, NT-3, and NT-4/5 in well-characterized, rapid-autopsy–derived AD postmortem hippocampus, frontal and parietal cortices, and cerebellum, and compared them with age-matched control tissue. In addition, to control for potential effects of alterations in tissue wet weight on neurotrophin concentrations, we calculated neurotrophin/NT-3 ratios.