Nerve Growth Factor and Alzheimer's Disease

Scott, Samuel A.; Crutcher, Keith A.

doi:10.1515/revneuro.1994.5.3.179

Cited by 88 publications

(55 citation statements)

References 446 publications

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“…For this reason, it is particularly significant that AD11 mice expressing anti-NGF antibodies (18) develop an age-dependent neurodegeneration that is highly reminiscent of AD (19)(20)(21). This finding strengthens the previously suggested connection between NGF and AD (34,35) and shows that reducing the availability of NGF to its target cells (14,19,36,37) can represent one significant pathway leading to sporadic AD.…”

Section: Discussionsupporting

confidence: 59%

Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice

Capsoni

Giannotta

Cattaneo

2002

Proc. Natl. Acad. Sci. U.S.A.

198

132

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Phenotypic knockout of nerve growth factor (NGF) activity in transgenic anti-NGF mice (AD11 mice) results in a progressive neurodegenerative phenotype resembling Alzheimer's disease. In this article, we examine whether and how the progressive neurodegenerative phenotype of AD11 mice could be prevented or ameliorated by pharmacological treatments with NGF or the cholinergic agonist galantamine, at a relatively early phase of Alzheimer's disease-like neurodegeneration. We demonstrate that the neurodegeneration induced by the expression of anti-NGF antibodies in AD11 mice can be largely reversed by NGF delivery through an olfactory route.A loss of basal forebrain cholinergic neurons (BFCNs) underlies the behavioral and cognitive deficits observed in Alzheimer's disease (AD) (1). The cholinergic phenotype of BFCNs is influenced by nerve growth factor (NGF) (2-4), which promotes the survival and differentiation of BFCNs during development and adulthood (5-10). Consequently, it has been suggested that a decrease in NGF function could contribute to the onset of AD. In AD brains, the levels of NGF mRNA are unchanged (11, 12), whereas increased levels of NGF protein can be detected in the cortex and hippocampus (13-16), associated to a decreased amount of NGF in the BF (17). A deficit in NGF activity has been obtained in a transgenic model (AD11 mice) (18), in which a recombinant anti-NGF antibody is secreted by neuronal and glial cells and neutralizes the activity of NGF in the extracellular space. Aged AD11 mice display a neurodegenerative phenotype characterized by behavioral deficits linked to cholinergic atrophy, neuronal loss, tau hyperphosphorylation and insolubility, abnormalities of the neuronal cytoskeleton reminiscent of tangles (19), ␤-amyloid plaques [from the endogenous amyloid precursor protein (APP) gene] (20), and deficits in cortical synaptic plasticity (21). AD11 mice recapitulate many of the neurodegenerative markers that characterize AD and therefore represent a comprehensive model for sporadic AD.To gain further insights into the mechanisms whereby blocking NGF activity with an antibody leads to an AD-like neurodegeneration and to further validate AD11 mice as a model for human sporadic AD, we investigated the extent to which the NGF deficit and the ensuing cholinergic deficit are causally linked to the observed neurodegeneration. We examined whether and how the neurodegenerative phenotype of AD11 mice could be prevented or ameliorated by pharmacological treatments with NGF or cholinergic agonists, at a relatively early phase of AD-like neurodegeneration. MethodsAnti-NGF AD11 Mice. AD11 anti-NGF mice were produced as described (18). Double transgenic mice expressing functional anti-NGF antibodies were obtained by crossing single transgenic mice expressing only the light chain (CMV-VK ␣D11) with single transgenic mice expressing only the heavy chain (CMV-VH ␣D11) (18).Pharmacological Treatments. LT4 (L-thyroxine) was administered according to the schedule and dosages shown to produce the maximal incr...

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Section: Discussionsupporting

confidence: 59%

Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice

Capsoni

Giannotta

Cattaneo

2002

Proc. Natl. Acad. Sci. U.S.A.

198

132

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“…Age-related reductions in NGF production in the cortex have not been reported either in the context of normal or pathological aging (52)(53)(54)(55). On the other hand, reductions in expression of neurotrophin receptors in basal forebrain cholinergic neurons have been reported in Alzheimer's disease (56,57) but not in normal aging.…”

Section: Discussionmentioning

confidence: 98%

Nontropic actions of neurotrophins: Subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation

Conner

Darracq

Roberts³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

106

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Normal aging is associated with a significant reduction in cognitive function across primate species. However, the structural and molecular basis for this age-related decline in neural function has yet to be defined clearly. Extensive cell loss does not occur as a consequence of normal aging in human and nonhuman primate species. More recent studies have demonstrated significant reductions in functional neuronal markers in subcortical brain regions in primates as a consequence of aging, including dopaminergic and cholinergic systems, although corresponding losses in cortical innervation from these neurons have not been investigated. In the present study, we report that aging is associated with a significant 25% reduction in cortical innervation by cholinergic systems in rhesus monkeys (P < 0.001). Further, these age-related reductions are ameliorated by cellular delivery of human nerve growth factor to cholinergic somata in the basal forebrain, restoring levels of cholinergic innervation in the cortex to those of young monkeys (P ‫؍‬ 0.89). Thus, (i) aging is associated with a significant reduction in cortical cholinergic innervation; (ii) this reduction is reversible by growth-factor delivery; and (iii) growth factors can remodel axonal terminal fields at a distance, representing a nontropic action of growth factors in modulating adult neuronal structure and function (i.e., administration of growth factors to cholinergic somata significantly increases axon density in terminal fields). These findings are relevant to potential clinical uses of growth factors to treat neurological disorders.aging ͉ Alzheimer's disease ͉ gene therapy ͉ plasticity ͉ cholinergic systems

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“…Moreover, intracerebral implantation of NGF-secreting cell lines has also been shown to promote neurotial survival after experimental lesions (46). Clinical studies pubhshed in the last 10 years seetn also to support the hypothesis that NGF, along with other neurotrophins may play a pivotal role in human forebrain cliolitiergic deficits, including aging and Alzheimer's disease (AD) (47)(48)(49)(50)(51).…”

Section: Ngf and The Nervous Systemmentioning

confidence: 99%

The expanding role of nerve growth factor: from neurotrophic activity to immunologic diseases

Aloe

Bracci-Laudiero

Бонини

et al. 1997

Allergy

203

127

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Numerous studies published in the last 10–15 years have shown that nerve growth factor (NGF), a polypeptide originally discovered in connection with its neurotrophic activity, also acts on cells of the immune system. NGF has been found in various immune organs including the spleen, lymph nodes, and thymus, and cells such as mast cells, eosinophils, and B and T cells. The circulating levels of NGF increase in inflammatory responses, in various autoimmune diseases, in parasitic infections, and in allergic diseases. Stress‐related events both in animal models and in man also result in an increase of NGF, suggesting that this molecule is involved in neuroendocrine functions. The rapid release of NGF is part of an alerting signal in response to either psychologically stressful or anxiogenic conditions in response to homeostatic alteration. Thus, the inflammation and stress‐induced increase in NGF might alone or in association with other biologic mediators induce the activation of immune cells during immunologic insults. A clearer understanding of the role of NGF in these events may be useful to identify the mechanisms implicated in certain neuroimmune and immune dysfunctions.

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Nerve Growth Factor and Alzheimer's Disease

Cited by 88 publications

References 446 publications

Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice

Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice

Nontropic actions of neurotrophins: Subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation

The expanding role of nerve growth factor: from neurotrophic activity to immunologic diseases

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