title: Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.
abstract: A central question in Alzheimer's disease concerns the mechanism by which beta-amyloid contributes to neuropathology, and in particular whether intracellular versus extracellular beta-amyloid plays a critical role. Alzheimer transgenic mouse studies demonstrate brain dysfunction, as beta-amyloid levels rise, months before the appearance of beta-amyloid plaques. We have now used immunoelectron microscopy to determine the subcellular site of neuronal beta-amyloid in normal and Alzheimer brains, and in brains from Alzheimer transgenic mice. We report that beta-amyloid 42 localized predominantly to multivesicular bodies of neurons in normal mouse, rat, and human brain. In transgenic mice and human Alzheimer brain, intraneuronal beta-amyloid 42 increased with aging and beta-amyloid 42 accumulated in multivesicular bodies within presynaptic and especially postsynaptic compartments. This accumulation was associated with abnormal synaptic morphology, before beta-amyloid plaque pathology, suggesting that intracellular accumulation of beta-amyloid plays a crucial role in Alzheimer's disease.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Reisuke H
authors.initials: RH
authors.lastname: Takahashi
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Milner
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Nam
authors.forename: Mark A
authors.initials: MA
authors.lastname: Edgar
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Gunnar K
authors.initials: GK
authors.lastname: Gouras
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000276:immunology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000166:cytology / Q000648:ultrastructure; D022162:Cytoplasmic Vesicles / Q000737:chemistry* / Q000648:ultrastructure; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009474:Neurons / Q000737:chemistry* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000032:analysis* / Q000276:immunology; D051381:Rats; D013569:Synapses / Q000737:chemistry / Q000648:ultrastructure*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)