Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain.
Multiple lines of evidence implicate beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD), but the mechanisms whereby Abeta is involved remain unclear. Addition of Abeta to the extracellular space can be neurotoxic. Intraneuronal Abeta42 accumulation is also associated with neurodegeneration. We reported previously that in Tg2576 amyloid precursor protein mutant transgenic mice, brain Abeta42 localized by immunoelectron microscopy to, and accumulated with aging in, the outer membranes of multivesicular bodies, especially in neuronal processes and synaptic compartments. We now demonstrate that primary neurons from Tg2576 mice recapitulate the in vivo localization and accumulation of Abeta42 with time in culture. Furthermore, we demonstrate that Abeta42 aggregates into oligomers within endosomal vesicles and along microtubules of neuronal processes, both in Tg2576 neurons with time in culture and in Tg2576 and human AD brain. These Abeta42 oligomer accumulations are associated with pathological alterations within processes and synaptic compartments in Tg2576 mouse and human AD brains.
Takahashi
Reisuke H
RH
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.
Almeida
Claudia G
CG
Kearney
Patrick F
PF
Yu
Fangmin
F
Lin
Michael T
MT
Milner
Teresa A
TA
Gouras
Gunnar K
GK
D000328:Adult; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D011992:Endosomes / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D015388:Organelles / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
D016229:Amyloid beta-Peptides; D046911:Macromolecular Substances; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)