Published online before print May 8, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070829

Accepted for publication February 27, 2008.

Article

Co-Localization of Amyloid Beta and Tau Pathology in Alzheimer's Disease Synaptosomes

Jeffrey A. Fein, Sophie Sokolow, Carol A. Miller^||, Harry V. Vinters^¶, Fusheng Yang^¶, Gregory M. Cole^¶, and Karen Hoppens Gylys^*@

From the Brain Research Institute,* School of Nursing, Department of Pathology and Laboratory Medicine, and Departments of Medicine and Neurology,^¶ University of California at Los Angeles School of Medicine and Sepulveda Veterans Administration Medical Center and Geriatric Research, Education, and Clinical Care Program, Los Angeles, California; and Departments of Pathology, Neurology, and Program in Neuroscience^|| Keck University of Southern California School of Medicine, Los Angeles, California

^@ To whom correspondence should be addressed. E-mail: kgylys{at}sonnet.ucla.edu.

	Abstract

The amyloid cascade hypothesis proposes that amyloid (A) pathology precedes and induces tau pathology, but the neuropathological connection between these two lesions has not been demonstrated. We examined the regional distribution and co-localization of A and phosphorylated tau (p-tau) in synaptic terminals of Alzheimer's disease brains. To quantitatively examine large populations of individual synaptic terminals, flow cytometry was used to analyze synaptosomes prepared from cryopreserved Alzheimer's disease tissue. An average 68.4% of synaptic terminals in the Alzheimer's disease cohort (n = 11) were positive for A, and 32.3% were positive for p-tau; A and p-tau fluorescence was lowest in cerebellum. In contrast to synaptic p-tau, which was highest in the entorhinal cortex and hippocampus (P = 0.004), synaptic A fluorescence was significantly lower in the entorhinal cortex and hippocampus relative to neocortical regions (P = 0.0003). Synaptic A and p-tau fluorescence was significantly correlated (r = 0.683, P < 0.004), and dual-labeling experiments demonstrated that 24.1% of A-positive terminals were also positive for p-tau, with the highest fraction of dual labeling (39.3%) in the earliest affected region, the entorhinal cortex. Western blotting experiments show a significant correlation between synaptic A levels measured by flow cytometry and oligomeric A species (P < 0.0001). These results showing overlapping A and tau pathology are consistent with a model in which both synaptic loss and dysfunction are linked to a synaptic amyloid cascade within the synaptic compartment.