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Interplay Between Autophagy and Amyloid Beta Metabolism in Alzheimer's Disease.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Interplay Between Autophagy and Amyloid Beta Metabolism in Alzheimer's Disease./
作者:	Jiang, Richeng.
面頁冊數:	1 online resource (75 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-02, Section: B.
Contained By:	Dissertations Abstracts International84-02B.
標題:	Neurodegeneration. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29273699click for full text (PQDT)
ISBN:	9798841564607

Interplay Between Autophagy and Amyloid Beta Metabolism in Alzheimer's Disease.
Jiang, Richeng.

Interplay Between Autophagy and Amyloid Beta Metabolism in Alzheimer's Disease. - 1 online resource (75 pages)

Source: Dissertations Abstracts International, Volume: 84-02, Section: B.

Thesis (Ph.D.)--Karolinska Institutet (Sweden), 2022.

Includes bibliographical references

Alzheimer's disease (AD), the most common neurodegenerative disease, is characterized bytwo pathological hallmarks: extracellular amyloid-beta peptide (Aβ) plaque depositions andneurofibrillary tangles (NFTs) composed of intracellular hyperphosphorylated tauaggregations. A cellular degradation system, autophagy is additionally dysfunctional in ADand plays a key role in Aβ and tau metabolisms.Paper I and II. To investigate the molecular mechanisms of autophagy alterations inducedby Aβ amyloidosis, we characterized the autophagy status in amyloid precursor protein (App)knock-in mouse models exhibiting robust Aβ pathology. Interestingly, impaired autophagywas a general phenomenon in the brains which was specifically pronounced in thesurrounding regions of Aβ plaques, especially in neurites and pre-synapses in App knock-inmice. The region-specific autophagy impairment was substantiated by electron microscopyimaging showing autophagic vacuole accumulation in dystrophic neurites around Aβ plaques.Time course bulk RNA sequencing from hippocampi of App knock-in mouse brains furtherrevealed alterations of autophagy-associated gene expression.Paper III. Cerebrospinal fluid (CSF) is an important body fluid source to study brain-derivedbiomarkers for AD diagnosis. Comparing the CSF proteomes from App knock-in mice andAD human subjects revealed an extracellular matrix protein, decorin, as significantlyincreased in preclinical AD subjects having abnormal CSF-Aβ42 but normal CSF-total-tau(a+t-) levels and in AppNL-F mice exhibiting mild Aβ pathology. In a+t- preclinical ADsubjects, CSF-decorin levels positively correlated with CSF-Aβ42 levels and negativelycorrelated with CSF phosphorylated and total tau levels. Increase of CSF-decorin couldpredict an AD subtype having innate immune activation and potential choroid plexusdysfunction in the brain with high sensitivity and specificity. Consistently, increased CSFdecorinin AppNL-F mice correlated with the decorin levels in choroid plexus and Aβ plaqueload.Paper IV. To directly investigate the role of autophagy in Aβ metabolism, we generatedautophagy-deficient AD mouse models by crossing App knock-in mice with autophagyrelatedgene 7 (Atg7) conditional knockout mice. Loss of autophagy in excitatory neuronslowered Aβ plaque load but raised intracellular Aβ levels. Severe Aβ pathology together withlack of autophagy led to an autistic-like behavior, decreased anxiety and memory deficitswhich potentially was related to activated programmed cell death, synaptic impairment, anddegraded gamma oscillation power. However, a mild Aβ amyloidosis in autophagy-deficientAppNL-F mice ameliorated the autistic-like behavior driven by loss of autophagy. Notably,proteomic analysis of CA1 pyramidal cell layer in hippocampus unveiled that loss ofautophagy upregulated cell transport but downregulated protein translation which can bealleviated by a mild Aβ amyloidosis.Paper V. Limitations of App knock-in mice include a less pronounced tau pathology and lackof neurodegeneration. Generation of an App knock-in rat model, AppNL-G-F, circumventedabove mentioned shortages by inducing phosphorylated tau aggregations and neuronal loss.AppNL-G-F rats additionally exhibited enhanced gliosis, impaired spatial learning, and memorydeficits including episodic-like memory.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798841564607Subjects--Topical Terms:

3685376
Neurodegeneration.
Index Terms--Genre/Form:

542853
Electronic books.

Interplay Between Autophagy and Amyloid Beta Metabolism in Alzheimer's Disease.
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504 $a Includes bibliographical references
520 $a Alzheimer's disease (AD), the most common neurodegenerative disease, is characterized bytwo pathological hallmarks: extracellular amyloid-beta peptide (Aβ) plaque depositions andneurofibrillary tangles (NFTs) composed of intracellular hyperphosphorylated tauaggregations. A cellular degradation system, autophagy is additionally dysfunctional in ADand plays a key role in Aβ and tau metabolisms.Paper I and II. To investigate the molecular mechanisms of autophagy alterations inducedby Aβ amyloidosis, we characterized the autophagy status in amyloid precursor protein (App)knock-in mouse models exhibiting robust Aβ pathology. Interestingly, impaired autophagywas a general phenomenon in the brains which was specifically pronounced in thesurrounding regions of Aβ plaques, especially in neurites and pre-synapses in App knock-inmice. The region-specific autophagy impairment was substantiated by electron microscopyimaging showing autophagic vacuole accumulation in dystrophic neurites around Aβ plaques.Time course bulk RNA sequencing from hippocampi of App knock-in mouse brains furtherrevealed alterations of autophagy-associated gene expression.Paper III. Cerebrospinal fluid (CSF) is an important body fluid source to study brain-derivedbiomarkers for AD diagnosis. Comparing the CSF proteomes from App knock-in mice andAD human subjects revealed an extracellular matrix protein, decorin, as significantlyincreased in preclinical AD subjects having abnormal CSF-Aβ42 but normal CSF-total-tau(a+t-) levels and in AppNL-F mice exhibiting mild Aβ pathology. In a+t- preclinical ADsubjects, CSF-decorin levels positively correlated with CSF-Aβ42 levels and negativelycorrelated with CSF phosphorylated and total tau levels. Increase of CSF-decorin couldpredict an AD subtype having innate immune activation and potential choroid plexusdysfunction in the brain with high sensitivity and specificity. Consistently, increased CSFdecorinin AppNL-F mice correlated with the decorin levels in choroid plexus and Aβ plaqueload.Paper IV. To directly investigate the role of autophagy in Aβ metabolism, we generatedautophagy-deficient AD mouse models by crossing App knock-in mice with autophagyrelatedgene 7 (Atg7) conditional knockout mice. Loss of autophagy in excitatory neuronslowered Aβ plaque load but raised intracellular Aβ levels. Severe Aβ pathology together withlack of autophagy led to an autistic-like behavior, decreased anxiety and memory deficitswhich potentially was related to activated programmed cell death, synaptic impairment, anddegraded gamma oscillation power. However, a mild Aβ amyloidosis in autophagy-deficientAppNL-F mice ameliorated the autistic-like behavior driven by loss of autophagy. Notably,proteomic analysis of CA1 pyramidal cell layer in hippocampus unveiled that loss ofautophagy upregulated cell transport but downregulated protein translation which can bealleviated by a mild Aβ amyloidosis.Paper V. Limitations of App knock-in mice include a less pronounced tau pathology and lackof neurodegeneration. Generation of an App knock-in rat model, AppNL-G-F, circumventedabove mentioned shortages by inducing phosphorylated tau aggregations and neuronal loss.AppNL-G-F rats additionally exhibited enhanced gliosis, impaired spatial learning, and memorydeficits including episodic-like memory.
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