A dual mechanism linking NGF/proNGF imbalance and early inflammation to Alzheimer's disease neurodegeneration in the AD11 anti-NGF mouse model

The neurotrophin Nerve Growth Factor (NGF) is essential for the maintenance and differentiation of basal forebrain cholinergic neurons. Since basal forebrain cholinergic neurons represent one major neuronal population affected and progressively degenerating in Alzheimer's disease (AD), interest has grown for NGF as a potential therapeutic agent in neurodegenerative disorders linked to aging, particularly for AD. However, no evidence was available, to link, in a cause-effect manner, deficits in NGF signalling to the broader activation in the Alzheimer's cascade, besides cholinergic deficits. The phenotypic analysis of the AD11 anti-NGF transgenic mouse, obtained by the "neuroantibodies" phenotypic protein knock out strategy, allowed demonstrating a direct causal link between NGF deprivation and AD pathology. Since then, extensive mechanistic studies on the AD11 model provided a new twist to the concept that alterations in NGF transport and signalling play a crucial role in sporadic Alzheimer's neurodegeneration, leading to the hypothesis of "Neurotrophic imbalance" as an upstream driver for sporadic AD. The results obtained with the AD11 anti-NGF mice highlight the fact that the particular mode of NGF neutralization, with an NGF antibody expressed in the brain, selectively interfering with mature NGF versus unprocessed proNGF, plays a major role in the mechanism of neurodegeneration, and could lead to new insights into the mechanisms of human sporadic AD. Here, we will review (1) the renewed neurotrophic imbalance hypothesis for AD and (2) the mechanisms underlying the neurodegenerative phenotype of AD11 anti-NGF mice.     

Towards non invasive nerve growth factor therapies for Alzheimer's disease

In the past thirty years, nerve growth factor (NGF) has received much attention for its potential role as a therapeutic agent for Alzheimer's disease (AD) due to its neurotrophic activities on basal forebrain cholinergic neurons. This attention has been renewed by recent findings that provide new causal links between defects in NGF signaling, transport or processing to the activation of the amyloidogenic route and, more generally, to AD neurodegeneration. Thus, the concept of therapeutic administration of human recombinant NGF in AD patients has a strong rationale, being further validated by recent and ongoing clinical trials with a gene-therapy approach. However, the widespread clinical application of gene or cell-therapy strategies for the delivery of NGF to AD patients seems unpractical, and it would be more advantageous to have non-invasive methods, that should also limit the adverse effects of NGF in activating nociceptive responses. This review will describe: 1) the data from preclinical and clinical studies underlying the rationale of NGF as a potential therapeutic agent for AD; and 2) the alternative strategies to reach adequate concentrations of NGF in relevant brain areas while preventing the onset of adverse effects.     

Impact of the NGF maturation and degradation pathway on the cortical cholinergic system phenotype

Cortical cholinergic atrophy plays a significant role in the cognitive loss seen with aging and in Alzheimer's disease (AD), but the mechanisms leading to it remain unresolved. Nerve growth factor (NGF) is the neurotrophin responsible for the phenotypic maintenance of basal forebrain cholinergic neurons in the mature and fully differentiated CNS. In consequence, its implication in cholinergic atrophy has been suspected; however, no mechanistic explanation has been provided. We have previously shown that the precursor of NGF (proNGF) is cleaved extracellularly by plasmin to form mature NGF (mNGF) and that mNGF is degraded by matrix metalloproteinase 9. Using cognitive-behavioral tests, Western blotting, and confocal and electron microscopy, this study demonstrates that a pharmacologically induced chronic failure in extracellular NGF maturation leads to a reduction in mNGF levels, proNGF accumulation, cholinergic degeneration, and cognitive impairment in rats. It also shows that inhibiting NGF degradation increases endogenous levels of the mature neurotrophin and increases the density of cortical cholinergic boutons. Together, the data point to a mechanism explaining cholinergic loss in neurodegenerative conditions such as AD and provide a potential therapeutic target for the protection or restoration of this CNS transmitter system in aging and AD.     

β/A4-Amyloid increases nerve growth factor production in rat primary hippocampal astrocyte cultures

Nerve growth factor (NGF), a member of the neurotrophin family, is an essential mediator of neuronal activity and synaptic plasticity of basal forebrain cholinergic neurons (BFCN). In processes of chronic degeneration of BFCN like in Alzheimer's disease (AD), characterized among others by amyloid containing plaques, NGF has been shown to improve cognitive decline and rescue BFCN but also to reduce survival of hippocampal neurons via p75 neurotrophin receptor (p75). Little is known about the mechanisms of NGF regulation in glial cells under pathological conditions in AD. This study investigates the influence of amyloid administration on the NGF protein secretion in rat primary hippocampal astrocytes. Astrocytes were stimulated with "aged" beta/A4-Amyloid (1-40), and NGF was measured in different fractions, such as supernatant, vesicles, and cytosol fraction. Treatment with amyloid at a final concentration of 10 microM for 72 h led to increased NGF protein levels up to 30-fold increase compared to unstimulated controls. This observation may be an endogenous neuroprotective mechanism possibly contributing to a delay of amyloid-dependent loss of cholinergic neurons or contribute to accelerated neuronal death by activation of p75 within Alzheimer pathology.     

The cholinergic system, nerve growth factor and the cytoskeleton

Cholinergic neurons of the basal forebrain provide the major cholinergic innervation to the cortex and hippocampus, and play a key role in memory and attentional processes. Dysfunction of basal forebrain cholinergic neurons (BFCN) is a cardinal feature of Alzheimer's disease (AD) and correlates with cognitive decline. Survival of BFCN neurons depends upon binding of nerve growth factor (NGF), which is synthesized and secreted by cells in the cortex and hippocampus, with high-affinity (TrkA) and low-affinity (p75^NTR) neurotrophin receptors produced within BFCN neurons. NGF released from target cells activates TrkA on axon terminals and triggers activation of PI3K/Akt, MEK/ERK, and PLCγ (phospholipase C) signaling pathways. The signal then travels retrogradely along axon to cell body to promote neuronal survival. However, the nature of the retrograde signal remains mysterious. p75^NTR receptors could mediate a fundamentally different signaling pathway leading to apoptic cell death. Dysfunction of NGF and its receptors has been suggested to underlie the selective degeneration of the BFCN in end stage Alzheimer disease. In this regard, NGF, the founding member of the neurotrophin family, has generated great interest as a potential target for the treatment of AD. This review focuses on NGF-cholinergic dependency, NGF/receptor binding, signal transduction, retrograde transport, regulation of specific cellular endpoints, and the potential involvement of cytoskeleton dysfunction in defected NGF signaling.     

Production of nerve growth factor by beta-amyloid-stimulated astrocytes induces p75NTR-dependent tau hyperphosphorylation in cultured hippocampal neurons

Reactive astrocytes surround amyloid depositions and degenerating neurons in Alzheimer's disease (AD). It has been previously shown that beta-amyloid peptide induces inflammatory-like responses in astrocytes, leading to neuronal pathology. Reactive astrocytes up-regulate nerve growth factor (NGF), which can modulate neuronal survival by signaling through TrkA or p75 neurotrophin receptor (p75NTR). Here, we analyzed whether soluble Abeta peptide 25-35 (Abeta) stimulated astrocytic NGF expression, modulating the survival of cultured embryonic hippocampal neurons. Hippocampal astrocytes incubated with Abeta up-regulated NGF expression and release to the culture medium. Abeta-stimulated astrocytes increased tau phosphorylation and reduced the survival of cocultured hippocampal neurons. Neuronal death and tau phosphorylation were reproduced by conditioned media from Abeta-stimulated astrocytes and prevented by caspase inhibitors or blocking antibodies to NGF or p75NTR. Moreover, exogenous NGF was sufficient to induce tau hyperphosphorylation and death of hippocampal neurons, a phenomenon that was potentiated by a low steady-state concentration of nitric oxide. Our findings show that Abeta-activated astrocytes potently stimulate NGF secretion, which in turn causes the death of p75-expressing hippocampal neurons, through a mechanism regulated by nitric oxide. These results suggest a potential role for astrocyte-derived NGF in the progression of AD.     

The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease

Dysfunction of nerve growth factor (NGF) and its high (TrkA) and low (p75NTR) affinity receptors has been suggested to underlie the selective degeneration of the nucleus basalis (NB) cholinergic cortical projection neurons in end stage Alzheimer disease (AD). Whether the NGF system is dysfunctional during the prodromal stages of AD has only recently been evaluated. Surprisingly, the number of choline acetyltransferase-containing neurons remains stable despite a significant reduction in NGF receptor-positive cells in people with mild cognitive impairment (MCI), suggesting a phenotypic NGF receptor downregulation but not a frank loss of NB neurons during prodromal AD. Moreover, there is a loss of cortical TrkA in the face of stable p75NTR and increased proNGF levels, the precursor molecule of mature NGF, in early AD. Depending upon the cellular context these changes may result in increased pro-apoptotic signaling, cell survival, or a defect in retrograde transport mechanisms. Alterations in NGF and its receptors within the cholinotrophic NB system in early AD suggest that NGF-mediated cell signaling is required for the longterm survival of these neurons. Therapeutic neurotrophic intervention might delay or prevent NB neuron degeneration and preserve cholinergic cortical function during prodromal AD.     

NGF-cholinergic dependency in brain aging, MCI and Alzheimer's disease

Forebrain cholinergic neurons are highly dependent on nerve growth factor (NGF) for phenotype maintenance. We have established that in addition to "target-derived" NGF neurotrophic stimulation, cholinergic neurons also respond dose-dependently, to intra-parenchymal NGF administration in the somato-dendritic region of the nucleus Basalis, thus illustrating the potential of alternative reparative therapies which would by-pass the undesirable effects of diffuse neurotrophin application. Moreover, our lab has also observed that the steady-state number of cortical cholinergic synapses is dependent on continuous NGF supply, as anti-NGF monoclonal antibodies and TrkA receptor antagonists deplete pre-existing cholinergic bouton numbers. Furthermore, the application of either NGF or TrkA NGF-mimetic agonists successfully rescues the age-dependent loss of cortical cholinergic boutons in aged-impaired rats. The vulnerability of the cortical cholinergic system has also been demonstrated in transgenic animal models of the Alzheimer's disease (AD) amyloid pathology. It is of interest to note however, that an up-regulation of cholinergic presynaptic boutons has been observed in certain transgenic mouse models prior to plaque formation. This observation is similar to the visibly increased immunoreactivity of cortical and hippocampal choline acetyltransferase (ChAT) fibers in patients with Mild Cognitive Impairment (MCI). A series of ex-vivo experiments conducted by our group have demonstrated that contrary to popular belief, proNGF, as opposed to mature NGF, is released from the cerebral cortex in an activity-dependent manner. In addition, proNGF appears to be released with a series of pro-enzymes and enzymes, which are involved in its subsequent maturation to NGF and degradation in the extracellular space. Given that proNGF is known to be upregulated in AD patients a dysregulation in the maturation or degradation of mature NGF might explain the preferential vulnerability of the cholinergic system in the AD pathology.     

Cholinotrophic molecular substrates of mild cognitive impairment in the elderly

Cholinergic nucleus basalis (NB) neurons provide the major cholinergic innervation to the cortical mantle, are selectively vulnerable in late stage Alzheimer's disease (AD) and require the neurotrophin, nerve growth factor (NGF) and its receptors (TrkA and p75(NTR)), for their survival. The molecular events underlying the demise of these neurons in AD were investigated using tissue harvested from participants in a longitudinal clinical pathological study of aging and AD who agreed to an annual clinical evaluation providing a categorization of no cognitive impairment (NCI), mild cognitive impairment (MCI) or AD and postmortem brain donation. Although the number of choline acetyltransferase (ChAT)-positive neurons was unchanged, TrkA and p75(NTR) receptor-containing neurons, which co-localize with ChAT, were significantly reduced in the NB of subjects with MCI and AD compared to those with NCI. These observations indicate a phenotypic down-regulation rather than frank NB neuronal degeneration in MCI. Expression profiling of single cholinergic NB neurons revealed TrkA but not p75(NTR) mRNA is reduced in MCI, suggesting that decreased neurotrophin responsiveness may be an early biomarker for AD. The NGF precursor molecule, proNGF, is increased in the cortex in MCI and AD. Since proNGF accumulates in the presence of reduced cortical TrkA and sustained levels of p75(NTR), a shift in the balance between cell survival and death molecules may occur in prodromal AD. Coincident with these phenomena, brain derived neurotrophic factor (BDNF) and its precursor molecule, proBDNF, are reduced in the MCI cortex, potentially depriving CBF neurons of additional trophic factor support. Moreover, there is a shift in the ratio of 3 repeat tau to 4 repeat tau gene expression, whereas total tau message is stable in NB neurons during the disease process. These data suggest there is a shift in cholinotrophic molecular events in MCI and early AD which may lead to cell dysfunction and eventual cell death over the course of the disease. These findings support the concept that from a neurotrophic pathobiologic perspective, MCI is already early AD.     

Neurotrophin receptor-based strategies for Alzheimer's disease

The traditional perspective of applying neurotrophins in the context of Alzheimer's disease is based on the premise that neurotrophins are capable of upregulating cholinergic function and of rendering neurons less vulnerable to certain processes causing degeneration. Factors limiting the therapeutic application of neurotrophin proteins include their poor pharmacological properties and their pleiotropic effects mediated by interaction with Trk, p75NTR and sortilin receptors. Recent studies suggesting and that pro-forms of neurotrophins accumulating in Alzheimer's and other pathological states cause cell death, that p75NTR modulates amyloid beta- and injury-induced neurodegeneration and that small molecules can be created that bind specifically to individual neurotrophin receptors point to novel strategies by which neurotrophin receptors might be targeted in Alzheimer's and other neuropathological states.     

sAPPalpha enhances the transdifferentiation of adult bone marrow progenitor cells to neuronal phenotypes

The remediation of neurodegeneration and cognitive decline in Alzheimer's Disease (AD) remains a challenge to basic scientists and clinicians. It has been suggested that adult bone marrow stem cells can transdifferentiate into different neuronal phenotypes. Here we demonstrate that the alpha-secretase-cleaved fragment of the amyloid precursor protein (sAPPalpha), a potent neurotrophic factor, potentiates the nerve growth factor (NGF)/retinoic acid (RA) induced transdifferentiation of bone marrow-derived adult progenitor cells (MAPCs) into neural progenitor cells and, more specifically, enhances their terminal differentiation into a cholinergic-like neuronal phenotype. The addition of sAPPalpha to NGF/RA-stimulated MAPCs resulted in their conversion to neuronal-like cells as evidenced by the extension of neurites and the appearance of immature synaptic complexes. MAPCs differentiated in the presence of sAPPalpha and NGF/RA exhibited a 40% to as much as 75% increase in neuronal proteins including NeuN, beta-tubulin III, NFM, and synaptophysin, compared to MAPCs differentiated by NGF/RA alone. This process was accompanied by an increase in the levels of choline acetyltransferase, a marker of cholinergic neurons, compared to those of GABAergic and dopaminergic neuronal subtypes. MAPCs immunopositive for sAPPalpha were identified within the septohippocampal system of transgenic PS/APP mice injected intravenously with sAPPalpha-transfected MAPCs and found in close proximity to the cerebral vasculature. Given that in AD cholinergic neurons are severely vulnerable to neurodegeneration and that the levels of sAPPalpha are significantly reduced, these findings suggest the combined use of sAPPalpha and MAPCs offers a new and potentially powerful therapeutic strategy for AD treatment.     

Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas

BACKGROUND: 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 of specific neuronal populations, including those that are affected by neurodegeneration in Alzheimer disease (AD). OBJECTIVE: To determine whether neurotrophin protein levels are altered in the AD-affected brain compared with control brains. METHODS: We quantitated protein levels of NGF, BDNF, NT-3, and NT-4/5, and calculated neurotrophin/NT-3 ratios in AD-affected postmortem hippocampus, frontal and parietal cortex, and cerebellum, and compared them with age-matched control tissue (patients with AD/controls: hippocampus, 9/9 cases; frontal cortex, 19/9; parietal cortex, 8/5; and cerebellum, 5/7, respectively). We applied highly sensitive and specific enzyme-linked immunosorbent assays in rapid-autopsy-derived brain tissue (mean+/-SD postmortem interval, 2. 57+/-1.75 h, n=71) to minimize postmortem proteolytic activity. RESULTS: Levels of BDNF were significantly reduced in hippocampus and parietal cortex (P<.001, and P<.01) as well as BDNF/NT-3 ratios in frontal and parietal cortices (P<.05, and P<.01) in the group with AD compared with the control group. Levels of NGF and NGF/NT-3 ratio were significantly elevated in the group with AD compared with the control group in the hippocampus and frontal cortex (P<.001). Levels of NT-4/5 and the NT-4/NT-3 ratio were slightly reduced in hippocampus and cerebellum in the group with AD compared with the control group (P<.05). In contrast, the levels of NT-3 were unchanged in all brain regions investigated. CONCLUSION: Decreased levels of BDNF may constitute a lack of trophic support and, thus, may contribute to the degeneration of specific neuronal populations in the AD-affected brain, including the basal forebrain cholinergic system. Arch Neurol. 2000.     

P75 neurotrophin receptor in the nucleus basalis of meynert in relation to age, sex, and Alzheimer's disease

In a previous study we showed that the staining of tyrosine kinase receptors (trks), which are high-affinity neurotrophin receptors (NTRs), is strongly diminished in the nucleus basalis of Meynert (NBM) of Alzheimer's disease (AD) patients, which may explain the lack of effect of NGF therapy in AD patients so far. Since the literature regarding the expression of low-affinity NTRs was rather controversial, the aim of the present study was to examine (i) possible changes in the staining of low-affinity NTRs, i.e., p75 in the human NBM, an area that is severely affected in AD; and (ii) alterations of these receptors in relation to risk factors for AD, e. g., age, sex, and menopause. Brain material of 31 controls and 30 AD patients was obtained at autopsy, embedded in paraffin, and stained immunocytochemically. Using an image analysis system, we quantified p75 immunoreactivity in both cell bodies and fibers at the level of the NBM. Our results showed a significant diminishment of p75 immunoreactivity in both cell bodies and fibers of NBM neurons in AD. We did not find any relationship between age or sex and the expression of p75 receptor in cell bodies. However, there was a clearly positive relationship between age and fiber staining in AD patients which suggests the occurrence of a p75 transport disorder as an early event in the process of AD. These observations and the earlier reported decreased staining of trk receptors show that degeneration of NBM neurons in AD is associated with a decreased neurotrophin responsiveness of NBM neurons in AD and that therapeutic strategies should be directed toward upregulation of receptors or facilitation of transport before an effect of neurotrophins in AD may be expected.     

Aluminum disrupts the pro-inflammatory cytokine/neurotrophin balance in primary brain rotation-mediated aggregate cultures: possible role in neurodegeneration

The etiology of human neurodegenerative diseases including Alzheimer's disease (AD) is exceedingly complex and our understanding of the mechanisms involved is far from complete. The experimental neurotoxicology of aluminum has been shown to recapitulate many of the pathophysiological features of AD and therefore represents a useful model to study the mechanisms involved in neurodegeneration. The present study investigated the effects of aluminum maltolate (Al-maltol) on the delicate balance that exists between pro-inflammatory cytokines and neurotrophins using primary brain rotation-mediated aggregate cultures. Aggregates were treated with Al-maltol (5-150 microM) on day 15 in vitro for 72 h. Cell death increased in a time- and concentration-dependent manner reaching significance in aggregates treated with 150 microM Al-maltol in 48 h and 50 microM by 72 h. Analysis of gene expression at 72 h revealed a concentration-dependent increase in tumor necrosis factor alpha (TNFalpha) and macrophage inflammatory protein-1alpha (MIP-1alpha) suggestive of a state of inflammation. In contrast, a dramatic concentration-dependent decrease in the expression of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) was observed. In fact, NGF expression could not be detected in aggregates treated with 50 and 150 microM Al-maltol. These changes in gene expression correlated with a decrease in aggregate size and an increase in neurodegeneration as indicated by Fluoro-Jade B staining. The results indicated a differential regulation of pro-inflammatory cytokines and neurotrophins in brain tissue following treatment with Al-maltol. Such findings provide insight into the possible involvement of deregulation of the cytokine/neurotrophin balance in the etiology of neurodegeneration.     

Time window in cholinomimetic ability to rescue long-term potentiation in neurodegenerating anti-nerve growth factor mice

A deficit in cortical cholinergic synaptic transmission is a common feature of cognitive and behavioral impairment observed in neurodegenerative pathologies. AD11 transgenic mice producing blocking antibodies against Nerve Growth Factor (NGF) are characterized by a progressive neurodegenerative phenotype defined by the deposition of amyloid peptide, intracellular neurofibrillary tangles and by a marked cholinergic depletion. We exploited AD11 mice to develop a functional assay to investigate the impact of cholinergic deficit on cortical synaptic plasticity impairment at different neurodegenerative stages. In particular, we investigated the time course of long-term potentiation (LTP) impairment in neocortex of AD11 mice and potential rescue by acute pharmacological treatment with Acetylcholine (ACh) or the cholinergic agonist Galantamine (GAL). We showed that LTP starts being absent in AD11 mice at 2 months, an age corresponding to early neurodegenerative stage characterized by the first observed decrease in number of basal forebrain cholinergic neurons (BFCNs) without overt cortical neurodegeneration. We demonstrated that acute ACh or GAL treatment fully reverts LTP impairment in 2 month old AD11 mice. In contrast, cholinergic treatment failed to recover synaptic plasticity deficit in aged (9-10 months) AD11 mice characterized by a severe cortical neurodegeneration.     

Differential regulation of neurotrophin expression in basal forebrain astrocytes by neuronal signals

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3) promote the function and/or survival of basal forebrain (BF) cholinergic neurons in vivo and in culture. The neurotrophin source is commonly thought to be targets of cholinergic neurons and the possibility that local glial sources support cholinergic neurons has not been well examined. These sources, however, may be critical to BF neurons before or even after they reach their targets. We investigated neurotrophin expression in BF astrocytes and its regulation by neural signals. Solution hybridization and immunocytochemical assays revealed that NGF, BDNF, and NT(3) mRNA and proteins were expressed in cultured BF astrocytes. To investigate roles of neuronal signals in neurotrophin regulation, effects of K(+), glutamate, and the cholinergic agonist carbachol were examined. These stimuli affected neurotrophin expression differentially. KCl increased BDNF mRNA but did not alter NGF or NT(3) mRNA. The effect was blocked by nifedipine, suggesting that it was mediated by L-type voltage-dependent calcium currents. Carbachol also increased BDNF mRNA levels without changing NGF or NT(3). Effects were blocked by the muscarinic antagonist, atropine. In contrast, glutamate increased both NGF and BDNF mRNA. NT(3) mRNA again was unaffected. The metabotropic agonist trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) reproduced glutamate effects, whereas kainate or N-methyl-D-aspartate (NMDA) plus glycine did not. Lack of antagonism by ionotropic antagonists and blockade of glutamate effects by metabotropic antagonists confirmed metabotropic mediation. We suggest that BF astrocytes are local sources of neurotrophins for BF cholinergic neurons during development and are regulated differentially by specific neuronal signals. Critical neuronal-glial interactions may underlie basal forebrain function.     

Cholinergic system during the progression of Alzheimer's disease: therapeutic implications

Alzheimer's disease (AD) is characterized by a progressive phenotypic downregulation of markers within cholinergic basal forebrain (CBF) neurons, frank CBF cell loss and reduced cortical choline acetyltransferase activity associated with cognitive decline. Delaying CBF neurodegeneration or minimizing its consequences is the mechanism of action for most currently available drug treatments for cognitive dysfunction in AD. Growing evidence suggests that imbalances in the expression of NGF, its precursor proNGF and the high (TrkA) and low (p75(NTR)) affinity NGF receptors are crucial factors underlying CBF dysfunction in AD. Drugs that maintain a homeostatic balance between TrkA and p75(NTR) may slow the onset of AD. A NGF gene therapy trial reduced cognitive decline and stimulated cholinergic fiber growth in humans with mild AD. Drugs treating the multiple pathologies and clinical symptoms in AD (e.g., M1 cholinoceptor and/or galaninergic drugs) should be considered for a more comprehensive treatment approach for cholinergic dysfunction.     

Is there nicotinic modulation of nerve growth factor? Implications for cholinergic therapies in Alzheimer's disease.

Studies on the neurobiology of nerve growth factor (NGF) reveal a diverse range of actions. Through alterations in gene expression, NGF is important in maintaining and regulating the phenotype of neurons that express the high-affinity receptor, trkA. Nerve growth factor also has a rapid action, revealed by its role in pain signaling in bladder and in skin. In the central nervous system (CNS), NGF has an intimate relationship with the cholinergic system. It promotes cholinergic neuron survival after experimental injury but also maintains and regulates the phenotype of uninjured cholinergic neurons. In addition to these effects mediated by gene expression, NGF has a rapid neurotransmitter-like action to regulate cholinergic neurotransmission and neuronal excitability. Consistent with its actions on the cholinergic system, NGF can enhance function in animals with cholinergic lesions and has been proposed to be useful in humans with Alzheimer's disease (AD); however, the problems of CNS delivery and of side effects (particularly pain) limit the clinical efficacy of NGF. Drug treatment strategies to enhance production of NGF in the CNS may be useful in the treatment of AD. Nicotine is one such agent, which, when administered directly to the hippocampus in rats, produces long-lasting elevation of NGF production.