. Mechanism of amyloid plaque formation suggests an intracellular basis of Abeta pathogenicity. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1942-7. PubMed.


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  1. This is a very intriguing study by Fändrich, Friedrich, and colleagues modeling plaque formation in cultured cells following addition of exogenous Aβ. The methods used, including their EM, are excellent. Work such as this is important, while the continued reluctance to even consider the intracellular aspect of Aβ pathology is holding back the field. Leakage of Aβ from multivesicular bodies (MVBs) certainly is also consistent with what we observed by EM in brain. At the same time, the long trails of this Aβ are surprising. Cell culture model systems like the ones used in this paper have many advantages in studying the biological mechanisms of disease.

    I would add a few points to their discussion. Light and electron microscopy evidence supports that Aβ42 accumulation begins in neurons and particularly their distal neurites and synapses. The latter can help explain why one can have many plaques with little cell death. At the same time, our studies, as well as very nice work by D’Andrea and colleagues in human brain, and work by Vassar, Bayer, and others in AD transgenic mice, support that plaques also develop from neuron cell bodies. The current work additionally highlights the potential importance of glia in plaque formation. This study emphasizes Aβ internalization in plaque formation, although it is possible that not much Aβ internalization may be needed to upregulate an intracellular pool of Aβ that already is present in MVBs.