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001     275846
005     20250119000359.0
024 7 _ |a 10.1016/j.immuni.2024.09.014
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024 7 _ |a pmid:39419029
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024 7 _ |a 1074-7613
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024 7 _ |a 1097-4180
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024 7 _ |a altmetric:169360708
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037 _ _ |a DZNE-2025-00081
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Kaji, Seiji
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245 _ _ |a Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis.
260 _ _ |a [Cambridge, Mass.]
|c 2024
|b Cell Press
336 7 _ |a article
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336 7 _ |a ARTICLE
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520 _ _ |a The 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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650 _ 7 |a Alzheimer’s disease
|2 Other
650 _ 7 |a ApoE
|2 Other
650 _ 7 |a inflammation
|2 Other
650 _ 7 |a lipids
|2 Other
650 _ 7 |a microglia
|2 Other
650 _ 7 |a Amyloid beta-Peptides
|2 NLM Chemicals
650 _ 7 |a Apolipoproteins E
|2 NLM Chemicals
650 _ 7 |a STAT Transcription Factors
|2 NLM Chemicals
650 _ 7 |a Janus Kinases
|0 EC 2.7.10.2
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Alzheimer Disease: metabolism
|2 MeSH
650 _ 2 |a Alzheimer Disease: pathology
|2 MeSH
650 _ 2 |a Microglia: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Mice, Transgenic
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: metabolism
|2 MeSH
650 _ 2 |a Amyloidosis: metabolism
|2 MeSH
650 _ 2 |a Amyloidosis: pathology
|2 MeSH
650 _ 2 |a Amyloidosis: genetics
|2 MeSH
650 _ 2 |a Apolipoproteins E: metabolism
|2 MeSH
650 _ 2 |a Apolipoproteins E: genetics
|2 MeSH
650 _ 2 |a Signal Transduction
|2 MeSH
650 _ 2 |a Plaque, Amyloid: metabolism
|2 MeSH
650 _ 2 |a Plaque, Amyloid: pathology
|2 MeSH
650 _ 2 |a Brain: metabolism
|2 MeSH
650 _ 2 |a Brain: pathology
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Lipid Metabolism
|2 MeSH
650 _ 2 |a Protein Aggregation, Pathological
|2 MeSH
650 _ 2 |a STAT Transcription Factors: metabolism
|2 MeSH
650 _ 2 |a Janus Kinases: metabolism
|2 MeSH
700 1 _ |a Berghoff, Stefan A
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700 1 _ |a Spieth, Lena
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700 1 _ |a Schlaphoff, Lennart
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700 1 _ |a Sasmita, Andrew O
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700 1 _ |a Vitale, Simona
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700 1 _ |a Büschgens, Luca
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700 1 _ |a Kedia, Shreeya
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700 1 _ |a Zirngibl, Martin
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700 1 _ |a Nazarenko, Taisiia
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700 1 _ |a Damkou, Alkmini
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700 1 _ |a Hosang, Leon
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700 1 _ |a Depp, Constanze
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700 1 _ |a Kamp, Frits
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700 1 _ |a Scholz, Patricia
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700 1 _ |a Ewers, David
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700 1 _ |a Giera, Martin
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700 1 _ |a Ischebeck, Till
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700 1 _ |a Wurst, Wolfgang
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700 1 _ |a Wefers, Benedikt
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700 1 _ |a Schifferer, Martina
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700 1 _ |a Willem, Michael
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700 1 _ |a Nave, Klaus-Armin
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700 1 _ |a Haass, Christian
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700 1 _ |a Arzberger, Thomas
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700 1 _ |a Jäkel, Sarah
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700 1 _ |a Wirths, Oliver
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700 1 _ |a Saher, Gesine
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700 1 _ |a Simons, Mikael
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773 _ _ |a 10.1016/j.immuni.2024.09.014
|g Vol. 57, no. 11, p. 2651 - 2668.e12
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