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(American Journal of Pathology. 2003;162:1623-1627.)
© 2003 American Society for Investigative Pathology

Microtubule Reduction in Alzheimer’s Disease and Aging Is Independent of Filament Formation

Adam D. Cash^*, Gjumrakch Aliev, Sandra L. Siedlak^*, Akihiko Nunomura, Hisashi Fujioka^*, Xiongwei Zhu^*, Arun K. Raina^*, Harry V. Vinters, Massimo Tabaton^¶, Anne B. Johnson^||, Manuel Paula-Barbosa^**, Jesus Avíla, Paul K. Jones, Rudy J. Castellani^*, Mark A. Smith^* and George Perry^*

From the Institute of Pathology^* and the Departments of Anatomy and Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; the Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa, Japan; the Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California; the Department of Neuroscience,^¶ University of Genoa, Genoa, Italy; the Department of Pathology,|| Albert Einstein College of Medicine, Bronx, New York; the Department of Anatomy,^** Porto Medical School, Porto, Portugal; the Centro de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain; and the Clinical Center, Michigan State University, East Lansing, Michigan

Biochemical studies show that phosphorylated , like that found in paired helical filaments (PHFs), does not promote microtubule assembly leading to the view that PHF formation leads to microtubule deficiency in Alzheimer’s disease (AD). However, although this issue is one of the most important aspects to further understanding the cell biology of AD, no quantitative examination of microtubule diminution in AD and its relationship with PHFs has been performed. To examine this issue directly, we undertook a morphometric study of brain biopsy specimens from AD and control cases. Ultrastructural analysis of neurons was performed to compare the microtubule assembly state in neurons of diseased and control cases and to examine the effect of PHF accumulation. We found that both number and total length of microtubules were significantly and selectively reduced in pyramidal neurons from AD in comparison to control cases (P = 0.000004) but that this decrement in microtubule density was surprisingly unrelated to PHFs (P = 0.8). Further, we found a significant age-dependent decrease in microtubule density with aging in the control cases (P = 0.016). These findings suggest that reduction in microtubule assembly is not dependent on abnormalities of AD and aging.

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