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(American Journal of Pathology. 2004;165:1809-1817.)
© 2004 American Society for Investigative Pathology

Synaptic Changes in Alzheimer’s Disease

Increased Amyloid-ß and Gliosis in Surviving Terminals Is Accompanied by Decreased PSD-95 Fluorescence

Karen Hoppens Gylys*{dagger}, Jeffrey A. Fein*, Fusheng Yang{ddagger}, Dorothy J. Wiley*, Carol A. Miller§ and Gregory M. Cole{ddagger}

From the University of California at Los Angeles School of Nursing* and Brain Research Institute,{dagger} UCLA School of Medicine, Los Angeles; the Departments of Pathology, Neurology, and Program in Neuroscience,§ the Keck USC School of Medicine, Los Angeles, California; and the Department of Medicine and Neurology, UCLA School of Medicine and Sepulveda Veteran’s Administration Medical Center,{ddagger} Sepulveda, California

In an effort to examine changes that precede synapse loss, we have measured amyloid-ß and a series of damage markers in the synaptic compartment of Alzheimer’s disease (AD) cases. Because localization of events to the terminal region in neurons is problematic with conventional methods, we prepared synaptosomes from samples of cryopreserved human association cortex, and immunolabeled terminals with a procedure for intracellular antigens. Fluorescence was quantified using flow cytometry. The viability dye calcein AM was unchanged in AD terminals compared to controls, and the fraction of large synaptosome particles did not change, although a striking loss of large terminals was observed in some AD cases. The percent positive fraction for a series of pre- and postsynaptic markers was not affected by AD in this cohort. However, the amyloid-ß-positive fraction increased from 16 to 27% (P < 0.02) in terminals from AD cortex. The expression level on a per-terminal basis is indicated in this assay by fluorescence (relative fluorescence units). The fluorescence of presynaptic markers did not change in AD terminals, but PSD-95 fluorescence was decreased by 19% (P < 0.03). Amyloid-ß fluorescence was increased by 132% (P < 0.01), and glial fibrillary acidic protein labeling by 31% (P < 0.01). These results suggest that synapse-associated amyloid-ß is prominent in regions relatively unaffected by AD lesions, and that amyloid accumulation in surviving terminals is accompanied by gliosis and alteration in the postsynaptic structure.




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