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The Journal of Neuroscience, April 7, 2004, 24(14):3592-3599; doi:10.1523/JNEUROSCI.5167-03.2004
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Neurobiology of Disease
Oligomerization of Alzheimer's  -Amyloid within Processes and Synapses of Cultured Neurons and Brain
Reisuke H. Takahashi,
Claudia G. Almeida,
Patrick F. Kearney,
Fangmin Yu,
Michael T. Lin,
Teresa A. Milner, and
Gunnar K. Gouras
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021
Multiple lines of evidence implicate  -amyloid (A) in the pathogenesis of Alzheimer's disease (AD), but the mechanisms whereby A is involved remain unclear. Addition of A to the extracellular space can be neurotoxic. Intraneuronal A42 accumulation is also associated with neurodegeneration. We reported previously that in Tg2576 amyloid precursor protein mutant transgenic mice, brain A42 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 A42 with time in culture. Furthermore, we demonstrate that A42 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 A42 oligomer accumulations are associated with pathological alterations within processes and synaptic compartments in Tg2576 mouse and human AD brains.
Key words: Alzheimer; amyloid; synapse; oligomer; transgenic; pathology
Received Nov 21, 2003;
revised February 23, 2004;
accepted February 28, 2004.
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