Search

It has been suggested that systemic infection, occurring during aging and chronic neurodegenerative diseases, can evoke an immune response that aggravates the progression of neurodegeneration and cognitive decline. It has been shown that the AD11 neurodegeneration mouse model, expressing a recombinant anti-nerve growth factor (NGF) antibody, shows a milder phenotype when housed in murine pathogen-free (MPF) conditions with respect to AD11 mice reared in conventional (CV) housing. AD10 mice, a variant of the anti-NGF AD11 model, expressing only an immunoglobulin light chain for the transgenic anti-NGF antibody, in the absence of the corresponding transgenic antibody chain VH, exhibit a complex neurodegenerative phenotype, similar to that of AD11 mice. Here we show that the AD10 transgenic mice, housed in murine pathogen-free conditions (MPF-AD10 mice), also display a milder behavioral and neurodegenerative phenotype compared to the corresponding mice kept under conventional housing conditions (CV-AD10). As a first step toward the identification of mechanisms underlying this difference, a differential gene expression profiling was performed on brains from CV-AD10 and MPF-AD10 mice, showing a decrease of the immune response and neuroinflammation gene expression in MPF-AD10 mice. Results suggest that the activation of the immune response gene expression in the CV-AD10, in a microbially unprotected environment, might contribute to a more severe and progressive neurodegenerative phenotype, compared to the MPF mice.

Autosomal dominant forms of familial Alzheimer's disease are linked to an aberrant processing of the amyloid-β protein precursor, which results in an increased production of amyloid-β (Aβ) peptides that first form oligomers and eventually aggregate in the form of extracellular amyloid plaques in the brain. The accumulation of Aβ peptides oligomers seems to correlate with alterations of synaptic transmission in experimental models of Alzheimer's disease. Whether Aβ aggregation disrupts synaptic function independently of amyloid plaques deposition still needs further research. Here we report an amyloid plaque-independent deficit of neuronal plasticity after short-term sensory deprivation in the visual system of 5XFAD mice.

Sortilin-related receptor with A-type repeats (SorLA, also known as LR11) has been implicated in Alzheimer's disease (AD). Thus, genetic studies associated SorLA gene variants with the risk of sporadic AD. Also, in vitro and in vivo studies showed that SorLA impairs processing of the amyloid-β protein precursor (AβPP) to amyloid-β. In particular, it has been found that loss of SorLA accelerates senile plaque deposition in mouse models overexpressing mutant forms of human AβPP and presenilin 1. Here we tested the possibility that SorLA deficiency also interferes with behavioral and neuropathological endpoints in an alternative murine AD model, the AD10 anti-nerve growth factor (NGF) mouse, in which amyloid-β accumulation derives from the altered processing of endogenous AβPP. In addition to alterations in AβPP processing, AD10 mice also show cholinergic deficit and tau hyperphosphorylation resulting in behavioral deficits in learning and memory paradigms. We found that the loss of SorLA not only exacerbates early amyloid pathology but, at the same time, protects from cholinergic deficit and from early phospho-tau mislocalization. The results show that in the AD10 anti-NGF mouse model the AβPP processing-related aspects of neurodegeneration can be dissociated from those related to tau posttranslational processing and to cholinergic phenotypic maintenance by modulation of SorLA expression. We suggest that SorLA regulates different aspects of neurodegeneration in a complex way, supporting the hypothesis that SorLA expression might be critical not only for amyloid-related pathology but also for other cellular processes altered in AD.

Several studies suggest that systemic infection occurring during aging and chronic neurodegenerative diseases can evoke an exaggerated immune response that contributes to the progression of neurodegeneration and cognitive decline. However, studies directly addressing the relationship between microbial environment and the onset of neurodegeneration in Alzheimer's disease animal models are lacking. Here we show that the onset of neurodegeneration that transgenic mice develop when raised in conventional husbandry slows down when raising anti-nerve growth factor transgenic mice in a murine pathogen free condition.

The identification of early and stage-specific biomarkers for Alzheimer's disease (AD) is critical, as the development of disease-modification therapies may depend on the discovery and validation of such markers. The identification of early reliable biomarkers depends on the development of new diagnostic algorithms to computationally exploit the information in large biological datasets. To identify potential biomarkers from mRNA expression profile data, we used the Logic Mining method for the unbiased analysis of a large microarray expression dataset from the anti-NGF AD11 transgenic mouse model. The gene expression profile of AD11 brain regions was investigated at different neurodegeneration stages by whole genome microarrays. A new implementation of the Logic Mining method was applied both to early (1-3 months) and late stage (6-15 months) expression data, coupled to standard statistical methods. A small number of "fingerprinting" formulas was isolated, encompassing mRNAs whose expression levels were able to discriminate between diseased and control mice. We selected three differential "signature" genes specific for the early stage (Nudt19, Arl16, Aph1b), five common to both groups (Slc15a2, Agpat5, Sox2ot, 2210015, D19Rik, Wdfy1), and seven specific for late stage (D14Ertd449, Tia1, Txnl4, 1810014B01Rik, Snhg3, Actl6a, Rnf25). We suggest these genes as potential biomarkers for the early and late stage of AD-like neurodegeneration in this model and conclude that Logic Mining is a powerful and reliable approach for large scale expression data analysis. Its application to large expression datasets from brain or peripheral human samples may facilitate the discovery of early and stage-specific AD biomarkers.

We previously showed that anti-nerve growth factor (NGF) antibodies expressed in transgenic mice (AD11) elicit a progressive neurodegeneration, comprising the triad of Alzheimer's disease (AD) hallmarks: cholinergic loss, tau hyperphosphorylation, and amyloid-beta peptide formation. However, since anti-NGF antibodies are produced both in the brain and in peripheral tissues of AD11 mice, the contribution of peripheral neutralization of NGF to the onset of brain neurodegeneration was still unexplored. To address this question, we characterized a line of transgenic mice (AD10) in which anti-NGF antibodies are obligatorily produced only in lymphocytes, being initially found in blood. In AD10 mice, peripheral NGF neutralization elicits shrinkage of superior cervical ganglia (immunosympathectomy) and, as a consequence of this, peripheral anti-NGF antibodies cross the blood brain barrier (BBB) and reach the brain, generating an NGF-dependent neurodegeneration, largely superimposable to that observed in AD11 mice. This demonstrates that peripherally originated anti-NGF antibodies can generate a neurodegeneration in the central nervous system of an animal model. Consistently, peripherally-delivered NGF is effective in preventing the onset of the central cholinergic deficit. These findings could have a direct relevance for some human sporadic AD cases, highlighting the role of the BBB disruption and suggesting a causally relevant role of circulating antibodies in AD pathology.

Nerve growth factor (NGF) has a great potential for the treatment of Alzheimer's disease. However, the therapeutic administration of NGF represents a significant challenge, due to the difficulty to deliver relevant doses to the brain, in a safe and non-invasive way. We previously demonstrated the efficacy of a non-invasive delivery of NGF to the brain in animal models, by an intranasal route. Recently, topical eye application of NGF was proposed, as an option for the delivery of NGF to the brain. Here, we compare the efficacy of the two delivery routes of hNGF-61, a recombinant traceable form of human NGF, in the mouse neurodegeneration model AD11. The intranasal administration appeared to be significantly more effective than the ocular one, in rescuing the neurodegenerative phenotypic hallmarks in AD11 mice. The ocular administration of hNGF-61 showed a more limited efficacy, even at higher doses. Thus, NGF nasal drops represent a viable and effective option to successfully deliver therapeutic NGF to the brain in a non-invasive manner.

Oligomeric amyloid-beta (Abeta) interferes with long-term potentiation (LTP) and cognitive processes, suggesting that Abeta peptides may play a role in the neuronal dysfunction which characterizes the early stages of Alzheimer's disease (AD). Multiple lines of evidence have highlighted RAGE (receptor for advanced glycation end-products) as a receptor involved in Abeta-induced neuronal and synaptic dysfunction. In the present study, we investigated the effect of oligomeric soluble Abeta1-42 on LTP elicited by the stimulation of different intracortical pathways in the mouse visual cortex. A variety of nanomolar concentrations (20-200 nM) of Abeta1-42 were able to inhibit LTP in cortical layer II-III induced by either white matter (WM-Layer II/III) or the layer II/III (horizontal pathway) stimulation, whereas the inhibition of LTP was more susceptible to Abeta1-42, which occurred at 20 nM of Abeta, when stimulating layer II-III horizontal pathway. Remarkably, cortical slices were resistant to nanomolar Abeta1-42 in the absence of RAGE (genetic deletion of RAGE) or blocking RAGE by RAGE antibody. These results indicate that nanomolar Abeta inhibits LTP expression in different neocortical circuits. Crucially, it is demonstrated that Abeta-induced reduction of LTP in different cortical pathways is mediated by RAGE.

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.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive memory deficits and cognitive decline. We explored the possibility that Environmental Enrichment (EE) may reduce the disease progression in a comprehensive mouse model for AD like neurodegeneration, the AD11 mice. AD11 mice, which express anti nerve growth factor (NGF) antibodies, develop an age dependent neurodegeneration which encompasses all hallmarks of human AD. We have tested the efficacy of EE starting from 2 months of age, that is before the onset of behavioural deficits in AD11 mice. At 7 months of age, visual recognition memory was tested with the Object Recognition Test (ORT), spatial memory with the Morris Water Maze (MWM) and the presence of AD pathological hallmarks (Abeta clusters, presence of hyperphosphorylated tau and cholinergic deficit) was assessed immunohistochemically. We found that in AD11 mice exposed to EE from 2 to 7 months of age performance in both memory tests was significantly better than in non EE AD11 mice and indistinguishable from that in wild-type mice of the same age. Exposure to EE from 2 to 7 months significantly reduce the appearance of AD neuropathological hallmarks. A group of AD11 mice was tested also at 12 months of age: we found that 12 months old AD11 mice exposed to EE from 2 to 7 months of age performed significantly better than non EE AD11 mice of the same age and did not differ from 12 months old wt mice. Thus, EE is able to prevent the onset of memory deficits up to at least 12 months of age and to restrain the progression of neurodegeneration in a mouse model of AD.

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.

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.