FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4212984944> ?p ?o ?g. }

• W4212984944 abstract "Alzheimer’s disease (AD) is the most common neurodegenerative disease with increasing prevalence due to longer lifespans in the human population. AD manifests as various age-associated cognitive impairments summarised under the syndrome of dementia. Why ageing constitutes the greatest risk factor for the development of AD, however, remains poorly understood. Ageing markedly affects the integrity of myelin at the ultrastructural level, with myelin splitting, outfoldings and secondary low-grade inflammation. In addition to the well-established role of oligodendroglia in producing insulating myelin, these glia cells also provide throphic support to ensheathed axons. Structural breakdown of myelin during ageing likely effects both insulation and metabolic support function of oligodendrocytes. This puts ensheathed axons and their neurons at risk for starvation and malfunction which could contribute to the development of neurodegenerative diseases upon ageing. Intriguingly, age-related myelin breakdown coincides with the beginning of amyloid build-up in the brain, the primary neuropathological hallmark of AD. I propose a mechanistic link between ageing-associated myelin dysfunction and the deposition of amyloid-β (Aβ) and hypothesised that breakdown of myelin - especially in cortical regions – is an upstream driver of amyloid deposition in AD. In my doctorate, I examined this possible link in proof of principle experiments in vivo by combining mouse models of myelin dysfunction with AD mouse models. I here show that in mouse models of AD (5xFAD, APPNLGF) genetically induced myelin defects (knockout of CNP or PLP1) as well as direct demyelinating injuries (experimental autoimmune encephalomyelitis, Cuprizone feeding) are potent drivers of amyloid deposition as shown by quantitative 3D light sheet microscopy. Conversely, lack of compact myelin in forebrain specific MBP knockout animals (“shiverer”) ameliorates plaque deposition. Behavioural analysis revealed synergistic effects of myelin defects and amyloid pathology on the manifestation of impairments. Mechanistically, I show that myelin dysfunction leads to the accumulation of the Aβ producing machinery (APP, β- and ɣ-secretase) in axonal spheroids and enhanced cortical APP cleavage. Additionally, I observed a profound loss of plaque-corralling microglia in AD mice with defective myelin. Transcriptomic analysis of isolated microglia revealed, however, that the disease-associated microglia (DAM) signature found in plaque-corralling microglia in 5xFADs is preserved in microglia additionally challenged with myelin. Indeed, myelin dysfunction alone is sufficient to induce a DAM-like state as shown by single nuclei RNA sequencing. I conclude that upon myelin damage in the brain microglia become primarily engaged in myelin clearance which renders them unresponsive to amyloid and prevents the protective reactions of microglia to Aβ plaques. The work presented in this thesis identifies myelin ageing as a previously overlooked risk factor for AD and makes the case for myelin health-directed therapies to combat AD." @default.
• W4212984944 created "2022-02-24" @default.
• W4212984944 creator A5028331847 @default.
• W4212984944 creator A9999999999 @default.
• W4212984944 date "2022-02-21" @default.
• W4212984944 modified "2023-09-27" @default.
• W4212984944 title "Ageing-associated myelin dysfunction as a driver of amyloid deposition in Alzheimer’s disease" @default.
• W4212984944 doi "https://doi.org/10.53846/goediss-9040" @default.
• W4212984944 hasPublicationYear "2022" @default.
• W4212984944 type Work @default.
• W4212984944 citedByCount "0" @default.
• W4212984944 crossrefType "dissertation" @default.
• W4212984944 hasAuthorship W4212984944A5028331847 @default.
• W4212984944 hasAuthorship W4212984944A9999999999 @default.
• W4212984944 hasBestOaLocation W42129849441 @default.
• W4212984944 hasConcept C142724271 @default.
• W4212984944 hasConcept C169760540 @default.
• W4212984944 hasConcept C2777633098 @default.
• W4212984944 hasConcept C2778609137 @default.
• W4212984944 hasConcept C2779134260 @default.
• W4212984944 hasConcept C2779483572 @default.
• W4212984944 hasConcept C2908647359 @default.
• W4212984944 hasConcept C2984863031 @default.
• W4212984944 hasConcept C500499127 @default.
• W4212984944 hasConcept C529278444 @default.
• W4212984944 hasConcept C54355233 @default.
• W4212984944 hasConcept C71924100 @default.
• W4212984944 hasConcept C86803240 @default.
• W4212984944 hasConcept C99454951 @default.
• W4212984944 hasConceptScore W4212984944C142724271 @default.
• W4212984944 hasConceptScore W4212984944C169760540 @default.
• W4212984944 hasConceptScore W4212984944C2777633098 @default.
• W4212984944 hasConceptScore W4212984944C2778609137 @default.
• W4212984944 hasConceptScore W4212984944C2779134260 @default.
• W4212984944 hasConceptScore W4212984944C2779483572 @default.
• W4212984944 hasConceptScore W4212984944C2908647359 @default.
• W4212984944 hasConceptScore W4212984944C2984863031 @default.
• W4212984944 hasConceptScore W4212984944C500499127 @default.
• W4212984944 hasConceptScore W4212984944C529278444 @default.
• W4212984944 hasConceptScore W4212984944C54355233 @default.
• W4212984944 hasConceptScore W4212984944C71924100 @default.
• W4212984944 hasConceptScore W4212984944C86803240 @default.
• W4212984944 hasConceptScore W4212984944C99454951 @default.
• W4212984944 hasLocation W42129849441 @default.
• W4212984944 hasLocation W42129849442 @default.
• W4212984944 hasOpenAccess W4212984944 @default.
• W4212984944 hasPrimaryLocation W42129849441 @default.
• W4212984944 hasRelatedWork W2038774177 @default.
• W4212984944 hasRelatedWork W2070165017 @default.
• W4212984944 hasRelatedWork W2108804212 @default.
• W4212984944 hasRelatedWork W2160269994 @default.
• W4212984944 hasRelatedWork W2280637608 @default.
• W4212984944 hasRelatedWork W2766474056 @default.
• W4212984944 hasRelatedWork W3031311213 @default.
• W4212984944 hasRelatedWork W3092930784 @default.
• W4212984944 hasRelatedWork W3113292642 @default.
• W4212984944 hasRelatedWork W4312389194 @default.
• W4212984944 isParatext "false" @default.
• W4212984944 isRetracted "false" @default.
• W4212984944 workType "dissertation" @default.