Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer's disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA738456 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR14827400.fastq.gz | Fastqsanger.gz | |||
| SRR14827401.fastq.gz | Fastqsanger.gz | |||
| SRR14827402.fastq.gz | Fastqsanger.gz | |||
| SRR14827403.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 17 |
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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.
2023-03-20 | GSE208683 | GEO
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.
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Project description:Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting memory and cognition. The disease is accompanied by an abnormal deposition of ß-amyloid plaques in the brain that contributes to neurodegeneration and is known to induce glial inflammation. Studies in the APP/PS1 mouse model of ß-amyloid-induced neuropathology have suggested a role for inflammasome activation in ß-amyloid-induced neuroinflammation and neuropathology. Here, we evaluated the in vivo role of microglia-selective and full body inflammasome signalling in several mouse models of ß-amyloid-induced AD neuropathology. Unexpectedly, microglia-specific deletion of the inflammasome regulator A20 and inflammasome effector protease caspase-1 in the AppNL-G-F and APP/PS1 models failed to identify a prominent role for microglial inflammasome signalling in ß-amyloid-induced neuropathology. Moreover, global inflammasome inactivation through respectively full body deletion of caspases 1 and 11 in AppNL-G-F mice and Nlrp3 deletion in APP/PS1 mice, also failed to modulate amyloid pathology and disease progression. In agreement, single-cell RNA sequencing did not reveal an important role for Nlrp3 signalling in driving microglial activation and the transition into disease-associated states, both during homeostasis and upon amyloid pathology. Collectively, these results question a generalizable role for inflammasome activation in pre-clinical amyloid-only models of neuroinflammation.
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Project description:The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths1, the latter of which is associated with secondary neuroinflammation2,3. As oligodendrocytes support axonal energy metabolism and neuronal health4-7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.
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Project description:Rapid nerve conduction in the CNS is facilitated by the insulation of axons with myelin, a specialized oligodendroglial compartment distant from the cell body. Myelin is turned over and adapted throughout life; however, the molecular and cellular basis of myelin dynamics is not well understood. Hypothesizing that only a fraction of all myelin-related mRNAs has been identified so far, we subjected myelin biochemically purified from mouse brains at various ages to RNA sequencing. We find a surprisingly large pool of transcripts abundant and/or enriched in myelin. Furthermore, a comprehensive analysis showed that the myelin transcriptome is closely related to the myelin proteome but clearly distinct from the transcriptomes of oligodendrocytes and brain tissues, suggesting that the incorporation of mRNAs into the myelin compartment is highly selective. The mRNA-pool in myelin displays maturation-dependent dynamic changes of composition, abundance, and functional associations; however ageing-dependent changes after 6 months of age were minor. We suggest that this transcript pool provides a basis for the local modulation of myelin turnover and adaptation, i.e. in the individual internode. A light-weight membrane fraction enriched for myelin was purified from mouse brains as described previously (Jahn et al., Neuromethods, 2013). For RNA-Seq, RNA was isolated from myelin of mice from indicated ages.
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