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000275846 0247_ $$2doi$$a10.1016/j.immuni.2024.09.014
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000275846 1001_ $$0P:(DE-2719)9000601$$aKaji, Seiji$$b0$$udzne
000275846 245__ $$aApolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis.
000275846 260__ $$a[Cambridge, Mass.]$$bCell Press$$c2024
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000275846 520__ $$aThe seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer's disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (APOE) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.
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000275846 650_7 $$2Other$$aAlzheimer’s disease
000275846 650_7 $$2Other$$aApoE
000275846 650_7 $$2Other$$ainflammation
000275846 650_7 $$2Other$$alipids
000275846 650_7 $$2Other$$amicroglia
000275846 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000275846 650_7 $$2NLM Chemicals$$aApolipoproteins E
000275846 650_7 $$2NLM Chemicals$$aSTAT Transcription Factors
000275846 650_7 $$0EC 2.7.10.2$$2NLM Chemicals$$aJanus Kinases
000275846 650_2 $$2MeSH$$aAnimals
000275846 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000275846 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000275846 650_2 $$2MeSH$$aMicroglia: metabolism
000275846 650_2 $$2MeSH$$aMice
000275846 650_2 $$2MeSH$$aHumans
000275846 650_2 $$2MeSH$$aMice, Transgenic
000275846 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000275846 650_2 $$2MeSH$$aAmyloidosis: metabolism
000275846 650_2 $$2MeSH$$aAmyloidosis: pathology
000275846 650_2 $$2MeSH$$aAmyloidosis: genetics
000275846 650_2 $$2MeSH$$aApolipoproteins E: metabolism
000275846 650_2 $$2MeSH$$aApolipoproteins E: genetics
000275846 650_2 $$2MeSH$$aSignal Transduction
000275846 650_2 $$2MeSH$$aPlaque, Amyloid: metabolism
000275846 650_2 $$2MeSH$$aPlaque, Amyloid: pathology
000275846 650_2 $$2MeSH$$aBrain: metabolism
000275846 650_2 $$2MeSH$$aBrain: pathology
000275846 650_2 $$2MeSH$$aDisease Models, Animal
000275846 650_2 $$2MeSH$$aLipid Metabolism
000275846 650_2 $$2MeSH$$aProtein Aggregation, Pathological
000275846 650_2 $$2MeSH$$aSTAT Transcription Factors: metabolism
000275846 650_2 $$2MeSH$$aJanus Kinases: metabolism
000275846 7001_ $$0P:(DE-2719)9001700$$aBerghoff, Stefan A$$b1$$udzne
000275846 7001_ $$0P:(DE-2719)9002306$$aSpieth, Lena$$b2$$udzne
000275846 7001_ $$0P:(DE-2719)9001719$$aSchlaphoff, Lennart$$b3$$udzne
000275846 7001_ $$0P:(DE-HGF)0$$aSasmita, Andrew O$$b4
000275846 7001_ $$0P:(DE-2719)9002093$$aVitale, Simona$$b5$$udzne
000275846 7001_ $$0P:(DE-HGF)0$$aBüschgens, Luca$$b6
000275846 7001_ $$0P:(DE-2719)9001803$$aKedia, Shreeya$$b7$$udzne
000275846 7001_ $$0P:(DE-2719)9002098$$aZirngibl, Martin$$b8$$udzne
000275846 7001_ $$0P:(DE-2719)9002494$$aNazarenko, Taisiia$$b9$$udzne
000275846 7001_ $$0P:(DE-2719)2813094$$aDamkou, Alkmini$$b10$$udzne
000275846 7001_ $$0P:(DE-HGF)0$$aHosang, Leon$$b11
000275846 7001_ $$0P:(DE-HGF)0$$aDepp, Constanze$$b12
000275846 7001_ $$0P:(DE-2719)2812549$$aKamp, Frits$$b13
000275846 7001_ $$0P:(DE-HGF)0$$aScholz, Patricia$$b14
000275846 7001_ $$0P:(DE-HGF)0$$aEwers, David$$b15
000275846 7001_ $$0P:(DE-HGF)0$$aGiera, Martin$$b16
000275846 7001_ $$0P:(DE-HGF)0$$aIschebeck, Till$$b17
000275846 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b18$$udzne
000275846 7001_ $$0P:(DE-2719)2810988$$aWefers, Benedikt$$b19$$udzne
000275846 7001_ $$0P:(DE-2719)2812260$$aSchifferer, Martina$$b20$$udzne
000275846 7001_ $$0P:(DE-2719)9000433$$aWillem, Michael$$b21
000275846 7001_ $$0P:(DE-HGF)0$$aNave, Klaus-Armin$$b22
000275846 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b23$$udzne
000275846 7001_ $$0P:(DE-2719)2811333$$aArzberger, Thomas$$b24$$udzne
000275846 7001_ $$0P:(DE-HGF)0$$aJäkel, Sarah$$b25
000275846 7001_ $$0P:(DE-HGF)0$$aWirths, Oliver$$b26
000275846 7001_ $$0P:(DE-HGF)0$$aSaher, Gesine$$b27
000275846 7001_ $$0P:(DE-2719)2811642$$aSimons, Mikael$$b28$$eLast author$$udzne
000275846 773__ $$0PERI:(DE-600)2001966-X$$a10.1016/j.immuni.2024.09.014$$gVol. 57, no. 11, p. 2651 - 2668.e12$$n11$$p2651 - 2668.e12$$tImmunity$$v57$$x1074-7613$$y2024
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