Project description:Alzheimer's disease (AD) is the most common form of dementia. Over fifty years of intense research have revealed many key elements of the biology of this neurodegenerative disorder. However, our understanding of the molecular bases of the disease is still incomplete, and the available medical treatments for AD are mainly symptomatic and hardly effective. Indeed, the robustness of biological systems have revealed that the modulation of a single target is unlikely to yield the desired outcome, and we should move from gene-centric to systemic therapeutic strategies. Here, we present the complete characterization of three murine models of AD at different stages of the disease (i.e. onset, progression and advanced). To identify genotype-to-phenotype relationships, we combine the cognitive assessment of these mice with histological analyses and a full transcriptional and protein quantification profiling from hippocampus. Comparison between the gene and protein expression trends observed in AD progression and physiological ageing exposed certain commonalities, such as the upregulation of microglial and inflammation markers. However, although there is an accelerated ageing in AD models, there are other factors specifically associated with A_ pathology. Despite the clear correlation between mRNA and protein levels of the dysregulated genes, we discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable. Indeed, we show that at least two of these proteins, namely lfit3 and Syt11, co-localize with A_ plaques in the brain. Finally, we derive specific A_-related molecular AD signatures, and we look for drugs able to globally revert them. We found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing A_ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels.

Project description:Proctor2013 - Effect of Aβ immunisation in Alzheimer's disease (deterministic version) Extension of a previously published stochastic model (designed to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau ( BIOMD0000000286, BIOMD0000000462)) to include the main processes involved in passive and active immunisation against Aβ and then to demonstrate the effects of this intervention on soluble Aβ. This is the deterministic version of the model, the stochastic version is BIOMD0000000634. This model is described in the article: Investigating interventions in Alzheimer's disease with computer simulation models. Proctor CJ, Boche D, Gray DA, Nicoll JA. PLoS ONE 2013; 8(9): e73631 Abstract: Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies. This model is hosted on BioModels Database and identified by: BIOMD0000000488. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

			Action	DRS
	2484_PA_iTRAQ_SP3_Multiconsesus_PSMs.txt	Txt
	2484_PA_iTRAQ_batch1_06Da.msf	Msf
	2484_PA_iTRAQ_batch1_FrGroup_10_SP3.raw	Raw
	2484_PA_iTRAQ_batch1_FrGroup_11_SP3.raw	Raw
	2484_PA_iTRAQ_batch1_FrGroup_12_SP3.raw	Raw

Dataset Information

Identification and drug-induced reversion of molecular signatures of Alzheimer´s disease onset and progression in AppNL-G-F, AppNL-F and 3xTg-AD mouse models

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