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: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 Aβ 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 Aβ plaques in the brain. Finally, we derive specific Aβ-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 Aβ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels.

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:BackgroundIn spite of many years of research, our understanding of the molecular bases of Alzheimer's disease (AD) is still incomplete, and the medical treatments available mainly target the disease symptoms and are hardly effective. Indeed, the modulation of a single target (e.g., β-secretase) has proven to be insufficient to significantly alter the physiopathology of the disease, and we should therefore move from gene-centric to systemic therapeutic strategies, where AD-related changes are modulated globally.MethodsHere we present the complete characterization of three murine models of AD at different stages of the disease (i.e., onset, progression and advanced). We combined the cognitive assessment of these mice with histological analyses and full transcriptional and protein quantification profiling of the hippocampus. Additionally, we derived specific Aβ-related molecular AD signatures and looked for drugs able to globally revert them.ResultsWe found that AD models show accelerated aging and that factors specifically associated with Aβ pathology are involved. We discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable, and showed that at least two of them (i.e., lfit3 and Syt11) co-localize with Aβ plaques in the brain. Finally, we found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aβ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels.ConclusionsThe characterization of three AD mouse models at different disease stages provides an unprecedented view of AD pathology and how this differs from physiological aging. Moreover, our computational strategy to chemically revert AD signatures has shown that NSAID and anti-hypertensive drugs may still have an opportunity as anti-AD agents, challenging previous reports.

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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