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...
Brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the rat visual cortex of young and postnatal day 90 (P90) animals is developmentally regulated and influenced by visual experience. In the present paper we compared the expression of BDNF mRNA to the actual changes of BDNF protein occurring during postnatal development and verified whether BDNF protein distribution is controlled by visual activity. To achieve this aim we analysed BDNF mRNA and/or BDNF protein cellular distribution in the rat visual cortex at different postnatal ages by using immunohistochemistry and highly sensitive in situ hybridization. We found that before eye opening (P13), in all cortical layers a large number of visual cortical neurons contain BDNF mRNA with no detectable amount of BDNF protein. At later ages (P23 and P90), the number of BDNF-immunostained cells increases; most neurons are double labelled for BDNF mRNA and protein, and a small group of neurons is labelled only for BDNF protein. The cellular increase of BDNF immunolabelling is blocked in animals deprived of visual experience from birth (dark rearing), with a large population of neurons containing BDNF mRNA but not BDNF protein. This is similar to what is observed before eye opening. Exposure of dark-reared rats to a brief period (2 h) of light restores a good match between BDNF mRNA and BDNF protein cellular expression. We propose that visual experience controls the neuronal content of BDNF mRNA and BDNF protein in developing visual cortex.
Ganstigmine (CHF2819) is an acetylcholinesterase inhibitor that increases acetylcholine in rat hippocampus and ameliorates scopolamine-induced amnesia. In this article, we examined whether and how ganstigmine might prevent or rescue the neurodegenerative phenotype in AD11 antinerve growth factor (anti-NGF) mice, a transgenic model for Alzheimer's disease. The effects of ganstigmine were compared with those obtained after administration of donepezil. Results demonstrate that intraperitoneal and oral administration of ganstigmine and donepezil can reverse the cholinergic and behavioral deficit in AD11 mice but not the amyloid and phosphotau accumulation, uncovering different mechanisms leading to neurodegeneration in AD11 mice.
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