Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.
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.
Takahashi
Reisuke H
RH
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.
Milner
Teresa A
TA
Li
Feng
F
Nam
Ellen E
EE
Edgar
Mark A
MA
Yamaguchi
Haruyasu
H
Beal
M Flint
MF
Xu
Huaxi
H
Greengard
Paul
P
Gouras
Gunnar K
GK
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*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)