title: Intracellular amyloid-β accumulation in calcium-binding protein-deficient neurons leads to amyloid-β plaque formation in animal model of Alzheimer's disease.
abstract: One of the major hallmarks of Alzheimer's disease (AD) is the extracellular deposition of amyloid-β (Aβ) as senile plaques in specific brain regions. Clearly, an understanding of the cellular processes underlying Aβ deposition is a crucial issue in the field of AD research. Recent studies have found that accumulation of intraneuronal Aβ (iAβ) is associated with synaptic deficits, neuronal death, and cognitive dysfunction in AD patients. In this study, we found that Aβ deposits had several shapes and sizes, and that iAβ occurred before the formation of extracellular amyloid plaques in the subiculum of 5XFAD mice, an animal model of AD. We also observed pyroglutamate-modified Aβ (N3pE-Aβ), which has been suggested to be a seeding molecule for senile plaques, inside the Aβ plaques only after iAβ accumulation, which argues against its seeding role. In addition, we found that iAβ accumulates in calcium-binding protein (CBP)-free neurons, induces neuronal death, and then develops into senile plaques in 2-4-month-old 5XFAD mice. These findings suggest that N3pE-Aβ-independent accumulation of Aβ in CBP-free neurons might be an early process that triggers neuronal damage and senile plaque formation in AD patients. Our results provide new insights into several long-standing gaps in AD research, namely how Aβ plaques are formed, what happens to iAβ and how Aβ causes selective neuronal loss in AD patients.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Moon
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Hong
authors.forename: Dong Woo
authors.initials: DW
authors.lastname: Nam
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Baik
authors.forename: Hyundong
authors.initials: H
authors.lastname: Song
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Kook
authors.forename: Yong Soo
authors.initials: YS
authors.lastname: Kim
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D002135:Calcium-Binding Proteins / Q000172:deficiency*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D009419:Nerve Tissue Proteins; C043697:calcium-binding protein (brain); D011761:Pyrrolidonecarboxylic Acid