Transcriptome profiling of mouse brain microglia in Cnp null mice with 5xFAD background
Ontology highlight
ABSTRACT: Alzheimer’s disease (AD) is the most common form of dementia and neurodegenerative disease with increasing prevalence due to longer lifespan in the human population. Why aging constitutes the greatest risk factor for development of AD, however, remains poorly understood. Aging markedly affects oligodendrocytes and the structural integrity of their myelin sheaths which also causes secondary tissue inflammation. We propose a mechanistic link between aging-associated myelin dysfunction and the deposition of Amyloid-ß (Aß) as primary neuropathological hallmark of early AD and hypothesized that breakdown of myelin - especially in cortical regions – is an upstream driver of amyloid deposition in AD. Here, we show that in transgenic mouse models of AD, genetically induced myelin defects by Cnp or Plp1 depletion, as well as direct demyelination are potent drivers of amyloid deposition in vivo as shown by light sheet microscopy imaging. At transcriptomic level, bulk and single-cell RNA sequencing revealed successfully induced disease-associated-microglia (DAM)-like phenotypes in Cnp-/- animals. These activated microglia, however, are primarily engaged with myelin seemingly preventing the protective reactions of the microglia pool to Aß plaques. Our work, therefore, identifies myelin aging as a previously overlooked risk factor for AD and makes the case for myelin health-directed therapies in AD.
Project description:The aim of the dataset is to identify cell heterogeneity changes under myelin abnormalities. Alzheimer’s disease (AD) is the most common form of dementia and neurodegenerative disease with increasing prevalence due to longer lifespan in the human population. Why aging constitutes the greatest risk factor for development of AD, however, remains poorly understood. Aging markedly affects oligodendrocytes and the structural integrity of their myelin sheaths which also causes secondary tissue inflammation. We propose a mechanistic link between aging-associated myelin dysfunction and the deposition of Amyloid-ß (Aß) as primary neuropathological hallmark of early AD and hypothesized that breakdown of myelin - especially in cortical regions – is an upstream driver of amyloid deposition in AD. Here, we show that in transgenic mouse models of AD, genetically induced myelin defects by Cnp or Plp1 depletion, as well as direct demyelination are potent drivers of amyloid deposition in vivo as shown by light sheet microscopy imaging. At transcriptomic level, bulk and single-cell RNA sequencing revealed successfully induced disease-associated-microglia (DAM)-like phenotypes in Cnp-/- animals. These activated microglia, however, are primarily engaged with myelin seemingly preventing the protective reactions of the microglia pool to Aß plaques. Our work, therefore, identifies myelin aging as a previously overlooked risk factor for AD and makes the case for myelin health-directed therapies in AD.
Project description:The aim of the dataset is to identify cell heterogeneity changes under myelin abnormalities. Alzheimer’s disease (AD) is the most common form of dementia and neurodegenerative disease with increasing prevalence due to longer lifespan in the human population. Why aging constitutes the greatest risk factor for development of AD, however, remains poorly understood. Aging markedly affects oligodendrocytes and the structural integrity of their myelin sheaths which also causes secondary tissue inflammation. We propose a mechanistic link between aging-associated myelin dysfunction and the deposition of Amyloid-ß (Aß) as primary neuropathological hallmark of early AD and hypothesized that breakdown of myelin - especially in cortical regions – is an upstream driver of amyloid deposition in AD. Here, we show that in transgenic mouse models of AD, genetically induced myelin defects by Cnp or Plp1 depletion, as well as direct demyelination are potent drivers of amyloid deposition in vivo as shown by light sheet microscopy imaging. At transcriptomic level, bulk and single-cell RNA sequencing revealed successfully induced disease-associated-microglia (DAM)-like phenotypes in Cnp-/- animals. These activated microglia, however, are primarily engaged with myelin seemingly preventing the protective reactions of the microglia pool to Aß plaques. Our work, therefore, identifies myelin aging as a previously overlooked risk factor for AD and makes the case for myelin health-directed therapies in AD.
Project description:The accumulation of amyloid-ß (Aß) peptides in the brain is a crucial step in the pathogenesis of Alzheimer`s disease (AD). Several studies indicate that microglia cells in the brain have the ability to internalize Aß by phagocytosis and might therefore play a protective role in AD. However, the mechanisms underlying Aß clearance remain unresolved. We have found that small molecule inhibitors of the ubiquitous glycogen synthase kinase 3ß (GSK3ß) stimulate the uptake of Aß by human THP-1 monocytes and primary murine microglia cells. To investigate how GSK3ß inhibitors might stimulate Aß uptake, we conducted microarray-based gene expression analyses of THP-1 cells after treatment with three different GSK3ß inhibitors. We identified a subset of genes similarly altered by all three inhibitors, including chemokines and surface receptors that have been linked to the regulation of microglial activation and phagocytosis.
Project description:Alzheimer’s Disease (AD) is the most common form of dementia and a leading global cause of human mortality and morbidity. Amyloid plaques of the amyloid beta (Aß) peptide are a universal pathological hallmark of AD and rare mutations in Aß can cause familial forms of AD (fAD). However, hundreds of additional mutations in Aß of uncertain significance are likely to exist in the human population, making clinical interpretation of genetic variation a difficult challenge even in this short peptide. Here, we use deep mutagenesis to quantify the effects of all possible single nucleotide variants and thousands of double mutations on the ability of Aß to nucleate amyloid fibrils in vivo. This data provides the first comprehensive view of how mutations alter the nucleation of an amyloid, reveals a modular organisation of mutational effects in Aß, and demonstrates the importance of charge in preventing nucleation. Moreover, the in vivo nucleation data, unlike computational predictors, accurately discriminates the known dominant fAD mutations. These results illustrate how deep mutagenesis can be used to genetically validate assays as discovery platforms. They also further prioritize nucleation as the critical biochemical event to target in order to prevent and treat AD.
Project description:Puri2010 - Mathematical Modeling for the
Pathogenesis of Alzheimer's Disease
Puri2010 - Mathematical Modeling for the Pathogenesis of
Alzheimer's Disease
Encoded non-curated model. Issues:
- Confusing replacement of
α16
when t = 3 years
- Confusing 4th rate equation
This model is described in the article:
Mathematical modeling for
the pathogenesis of Alzheimer's disease.
Puri IK, Li L.
PLoS ONE 2010; 5(12): e15176
Abstract:
Despite extensive research, the pathogenesis of
neurodegenerative Alzheimer's disease (AD) still eludes our
comprehension. This is largely due to complex and dynamic
cross-talks that occur among multiple cell types throughout the
aging process. We present a mathematical model that helps
define critical components of AD pathogenesis based on
differential rate equations that represent the known
cross-talks involving microglia, astroglia, neurons, and
amyloid-? (A?). We demonstrate that the inflammatory activation
of microglia serves as a key node for progressive
neurodegeneration. Our analysis reveals that targeting
microglia may hold potential promise in the prevention and
treatment of AD.
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Project description:Amyloid-ß (Aß) plaques are pathological hallmarks of Alzheimer disease. However, the precise neuropathological changes that occur in brain in response to amyloid deposition are largely unknown. To study the molecular mechanism(s) responsible for Aß-mediated neuropathology, we performed a gene expression analysis on frontal neocortical brain tissue of APPPS1 mice compared to their littermate controls.
Project description:Amyloid-ß (Aß) plaques are pathological hallmarks of Alzheimer disease. However, the precise neuropathological changes that occur in brain in response to amyloid deposition are largely unknown. To study the molecular mechanism(s) responsible for Aß-mediated neuropathology, we performed a gene expression analysis on laser-microdissected brain tissue of Tg2576 mice compared to their littermate controls.
Project description:The APPSwe/PS1dE9 (APP/PS1) mouse ß-amyloidopathy mouse model exhibits extracellular Aß deposition, particularly in the neocortex and hippocampus, increasing steadily from about 6 months, with reactive astrogliosis and synapse loss occurring proximal to plaques. We crossed APP/PS1 mice onto genetically modified mice which lack microglia (Csf1r ∆FIRE/∆FIRE) to assess whether Aß plaque deposition and downstream events are altered in brains lacking microglia.
Project description:The APPSwe/PS1dE9 (APP/PS1) ß-amyloidopathy mouse model exhibits extracellular Aß deposition increasing steadily from about 6 months, particularly in the neocortex and hippocampus, with reactive astrogliosis and synapse loss occurring proximal to plaques. We crossed APP/PS1 mice onto genetically modified mice which lack microglia (Csf1r ∆FIRE/∆FIRE) to assess whether Aß plaque deposition and downstream events are altered in brains lacking microglia.
Project description:Microglia are involved in Alzheimer’s disease (AD) by adopting activated phenotypes. How ageing in the absence or presence of β-amyloid (Aβ) deposition in different brain areas affects this response and whether sex and AD risk genes are involved, remains however largely unknown. Here we analyzed the gene expression profiles of more than 10,000 individual microglia cells isolated from cortex and hippocampus of male and female AppNL-G-F at 4 different stages of Aβ deposition and in age-matched control mice. We demonstrate that microglia adopt two major activated states during normal aging and after exposure to amyloid plaques. One of the responses (activated response microglia, ARM) is enhanced in particular by amyloid plaques and is strongly enriched with AD risk genes. The ARM response is not homogeneous, as subgroups of microglia overexpressing MHC type II and tissue repair genes (Dkk2, Gpnmb, Spp1) are induced upon prolonged Aβ exposure. Microglia in female mice advance faster in the activation trajectories. Similar activated states were also found in a second AD model and in human brain. We demonstrate that abolishing the expression of Apoe, the major genetic risk factor for AD, impairs the establishment of ARMs, while the second microglia response type, enriched for interferon response genes, remains unaffected. Our data indicate that ARMs are the converging point of multiple AD risk factors.