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American Journal of Pathology, Vol 141, 1151-1159, Copyright © 1992 by American Society for Investigative Pathology

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The genesis of the senile plaque. Further evidence in support of its neuronal origin

MA Pappolla, RA Omar, K Sambamurti, JP Anderson and NK Robakis
Department of Pathology, Mount Sinai School of Medicine, New York, New York 10029-6574.

Senile plaques are among the most conspicuous neuropathologic changes found in the brains of elderly individuals and patients with Alzheimer's disease (AD). The origin of the amyloid beta protein (A beta P) that accumulates in senile plaques continues to be highly controversial. Recently, using quantitative immunohistochemistry and computerized image analysis, we obtained evidence that at least a subset of early ("diffuse") senile plaques originate from neurons. In the current investigation, we employed monoclonal antibodies to A beta P and the same computerized methodology to examine in further detail the quantitative patterns of A beta P deposition in diffuse plaques in a population of intellectually intact elderly individuals. The presence of neurocentric concentration gradients of A beta P accumulation was confirmed in this study. Most significantly, this was the most predominant pattern of early amyloid deposition in the population studied. The highest concentration of A beta P was centered around neuronal cell bodies or their processes, and occasionally along neuronal plasma membranes. Computerized images showed patterns that can be interpreted as a pathogenetic sequence ranging from initial neurogenic concentration gradients centered around one single neuron to larger deposits (diffuse plaques) composed of several "anastomosing" gradients involving several adjacent neurons. It is proposed that the described very early deposits constitute the initial stage in the development of the senile plaque. Although this study does not fully prove that the accumulated A beta P is synthesized in the neuron or neuronal process it surrounds, the images herein presented suggest that neurons are the initial nidus of plaque formation.

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