Degeneration Of Basal Forebrain Neurons Research Articles

ProNGF elicits retrograde axonal degeneration of basal forebrain neurons through p75NTR and induction of amyloid precursor protein.

Basal forebrain cholinergic neurons (BFCNs) extend long projections to multiple regions in the brain to regulate cognitive functions. Degeneration of BFCNs is seen with aging, after brain injury, and in neurodegenerative disorders. An increase in the amount of the immature proform of nerve growth factor (proNGF) in the cerebral cortex results in retrograde degeneration of BFCNs through activation of proNGF receptor p75NTR. Here, we investigated the signaling cascades initiated at the axon terminal that mediate proNGF-induced retrograde degeneration. We found that local axonal protein synthesis and retrograde transport mediated proNGF-induced degeneration initiated from the axon terminal. Analysis of the nascent axonal proteome revealed that proNGF stimulation of axonal terminals triggered the synthesis of numerous proteins within the axon, and pathway analysis showed that amyloid precursor protein (APP) was a key upstream regulator in cultured BFCNs and in mice. Our findings reveal a functional role for APP in mediating BFCN axonal degeneration and cell death induced by proNGF.

Sustained, long-lasting inhibition of nitric oxide synthase aggravates the neural damage in some models of excitotoxic brain injury

Brain nitric oxide (NO) can be a mediator of physiological and neuroprotective actions and an effector of neural damage. The effectiveness of acute or chronic inhibition of NO production in in vivo experiments of neurotoxicity/neuroprotection is controversial. We report here on the effects of a chronic, sustained inhibition of nitric oxide synthase (NOS) on the neurodegenerative damage caused by three different excitotoxic lesions. The damage caused by intrastriatal injection of ibotenic or kainic acid was aggravated in rats subjected to chronic NOS inhibition. On the contrary, the drop of cortical cholinergic input consequent to ibotenic acid-mediated degeneration of basal forebrain neurons was not altered by chronic NOS inhibition. The worsening of the damage was not related to any overt differential sensitivity to excitotoxicity of NOS-containing striatal neurons under conditions of NOS inhibition. These results suggest that, contrary to what has been often reported for short-term, mild inhibition of NO production, chronic and sustained NOS inhibition may exacerbate neuropathology. Thus, long-lasting shortage of NO may be detrimental when neuroprotective mechanisms related to the physiological action of this free radical are severely impaired. Although we cannot exclude that inhibition of the endothelial NOS isoform could have contributed to the worsening of neuropathology, differences among the paradigms of neurotoxicity used in the present study suggest a primary involvement of the neuronal NOS isoform. In view of the potential therapeutic use of NOS inhibitors, the effects of a too drastic alteration of the balance between neuroprotective and neurodegenerative actions of NO should be carefully considered.

The aged monkey basal forebrain: rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor.

Six Rhesus monkeys between 24 and 29 years of age received unilateral transections of the fornix. Three monkeys then received intraventricular transplants of polymer-encapsulated baby hamster kidney (BHK) fibroblasts that had been genetically modified to secrete human nerve growth factor (hNGF). The remaining three monkeys received identical grafts except the cells were not modified to secrete hNGF. Monkeys receiving the fornix transection and control grafts displayed extensive reductions in the number of choline acetyltransferase- (57-75%) and p75 NGF receptor- (53%) immunoreactive medial septal neurons ipsilateral to the lesion/implant. In contrast, monkeys receiving transplants of encapsulated hNGF-secreting cells display only a modest loss of choline acetyltransferase- (0-36%) and p75 NGF receptor-(7-22.4%) immunoreactive septal neurons. Additionally, all monkeys receiving the hNGF-secreting implants, but none receiving control implants, displayed robust sprouting of cholinergic fibers within the septum ipsilateral to the transplant. Just prior to sacrifice, the capsules were retrieved and found to contain viable BHK cells releasing biologically relevant levels of hNGF. These data demonstrate that hNGF can provide trophic and tropic influences to aged primate basal forebrain neurons undergoing lesion-induced degeneration, supporting the contention that hNGF may prevent the degeneration of basal forebrain neurons in Alzheimer disease.

Nerve growth factor and Alzheimer's disease.

Nerve growth factor (NGF) is a well-characterized protein that exerts pharmacological effects on a group of cholinergic neurons known to atrophy in Alzheimer's disease (AD). Considerable evidence from animal studies suggests that NGF may be useful in reversing, halting, or at least slowing the progression of AD-related cholinergic basal forebrain atrophy, perhaps even attenuating the cognitive deficit associated with the disorder. However, many questions remain concerning the role of NGF in AD. Levels of the low-affinity receptor for NGF appear to be at least stable in AD basal forebrain, and the recent finding of AD-related increases in cortical NGF brings into question whether endogenous NGF levels are related to the observed cholinergic atrophy and whether additional NGF will be useful in treating this disorder. Evidence regarding the localization of NGF within the central nervous system and its presumed role in maintaining basal forebrain cholinergic neurons is summarized, followed by a synopsis of the relevant aspects of AD neuropathology. The available data regarding levels of NGF and its receptor in the AD brain, as well as potential roles for NGF in the pathogenesis and treatment of AD, are also reviewed. NGF and its low affinity receptor are abundantly present within the AD brain, although this does not rule out an NGF-related mechanism in the degeneration of basal forebrain neurons, nor does it eliminate the possibility that exogenous NGF may be successfully used to treat AD. Further studies of the degree and distribution of NGF within the human brain in normal aging and in AD, and of the possible relationship between target NGF levels and the status of basal forebrain neurons in vivo, are necessary before engaging in clinical trials.

Galanin antagonizes acetylcholine on a memory task in basal forebrain-lesioned rats.

Galanin coexists with acetylcholine in medial septal neurons projecting to the ventral hippocampus, a projection thought to modulate memory functions. Neurochemical lesions of the nucleus basalis-medial septal area in rats impaired choice accuracy on a delayed alternation t-maze task. Acetylcholine (7.5 or 10 micrograms intraventricularly or 1 micrograms micro-injected into the ventral hippocampus) significantly improved performance in the lesioned rats. Atropine (5 mg/kg intraperitoneally or 10 micrograms intraventricularly), but not mecamylamine (3 mg/kg intraperitoneally or 20 micrograms intraventricularly), blocked this action of acetylcholine, suggesting involvement of a muscarinic receptor. Galanin (100-500 ng intraventricularly or 200 ng into the ventral hippocampus) attenuated the ability of acetylcholine to reverse the deficit in working memory in the lesioned rats. The antagonistic interaction between galanin and acetylcholine suggests that endogenous galanin may inhibit cholinergic function in memory processes, particularly in pathologies such as Alzheimer disease that involve degeneration of basal forebrain neurons.

Age-related loss of nerve growth factor sensitivity in rat basal forebrain neurons

Nerve growth factor (NGF) has recently been implicated as a trophic agent in the survival and maintenance of basal forebrain cholinergic neurons. To test the hypothesis that NGF may play a role in the age-related degeneration of basal forebrain neurons and decline of cerebral cholinergic function, we have used a monoclonal antibody to the NGF receptor, 192 IgG, to immunocytochemically visualize and compare rat basal forebrain neurons responsive to NGF in aged (30 months) and young adult (10 months) rats. In a subpopulation of aged rats, NGF receptor-immunoreactive cells in the basal forebrain appear vacuolated and shrunken, and the neuropil staining is markedly reduced. While no substantial decline in cell density is apparent in Nissl-stained sections, the number of NGF receptor-positive cell profiles within the vertical limb of diagonal band nuclei is reduced by an average of 32% in aged rats. Marked reduction in the expression of NGF receptors in aged rats may signify loss of capacity of the basal forebrain neurons to bind and transport NGF from their terminals in the hippocampus and cortex, subsequent decrease in NGF delivered to the cell bodies, and eventual cellular dysfunction and death of neurons in aging.