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Mechanisms of amyloid plaque pathogenesis

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Abstract

The first ultrastructural investigations of Alzheimer’s disease noted the prominence of degenerating mitochondria in the dystrophic neurites of amyloid plaques, and speculated that this degeneration might be a major contributor to plaque pathogenesis. However, the fate of these organelles has received scant consideration in the intervening decades. A number of hypotheses for the formation and progression of amyloid plaques have since been suggested, including glial secretion of amyloid, somal and synaptic secretion of amyloid-beta protein from neurons, and endosomal–lysosomal aggregation of amyloid-beta protein in the cell bodies of neurons, but none of these hypotheses fully account for the focal accumulation of amyloid in plaques. In addition to Alzheimer’s disease, amyloid plaques occur in a variety of conditions, and these conditions are all accompanied by dystrophic neurites characteristic of disrupted axonal transport. The disruption of axonal transport results in the autophagocytosis of mitochondria without normal lysosomal degradation, and recent evidence from aging, traumatic injury, Alzheimer’s disease and transgenic mice models of Alzheimer’s disease, suggests that the degeneration of these autophagosomes may lead to amyloid production within dystrophic neurites. The theory of amyloid plaque pathogenesis has thus come full circle, back to the intuitions of the very first researchers in the field.

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Acknowledgments

Thanks to Alan Peters for providing the aged monkey tissue used for Figs. 1 and 3, and to Marcia Feinberg for electron microscopy. Thanks also to Helen Barbas, Alan Peters, and the reviewers for many helpful suggestions on earlier versions of the manuscript.

This work was supported by grants from National Institute of Mental Health (RO1 MH057414) and National Institute of Neurological Disorders and Stroke (RO1 NS024760), from the National Institute on Aging (P01 AG00001), and from the Dudley Allen Sargent Research Fund, Boston University.

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    John C. Fiala

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Fiala, J.C. Mechanisms of amyloid plaque pathogenesis. Acta Neuropathol 114, 551–571 (2007). https://doi.org/10.1007/s00401-007-0284-8

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