The Synaptic Accumulation of Hyperphosphorylated Tau Oligomers in Alzheimer Disease Is Associated With Dysfunction of the Ubiquitin-Proteasome System

Male Proteasome Endopeptidase Complex Presynaptic Terminals tau Proteins Pathology and Forensic Medicine Mice 03 medical and health sciences Alzheimer Disease Centrifugation, Density Gradient Animals Humans Phosphorylation Protein Structure, Quaternary Aged Aged, 80 and over Cerebral Cortex 0303 health sciences Amyloid beta-Peptides Ubiquitin Ubiquitination Middle Aged 3. Good health Protein Transport Synapses Biological Markers Female Biomarkers Protein Binding
DOI: 10.1016/j.ajpath.2012.06.033 Publication Date: 2012-08-04T06:31:04Z
ABSTRACT
In Alzheimer disease (AD), deposition of neurofibrillary tangles and loss of synapses in the neocortex and limbic system each correlate strongly with cognitive impairment. Tangles are composed of misfolded hyperphosphorylated tau proteins; however, the link between tau abnormalities and synaptic dysfunction remains unclear. We examined the location of tau in control and AD cortices using biochemical and morphologic methods. We found that, in addition to its well-described axonal localization, normal tau is present at both presynaptic and postsynaptic terminals in control human brains. In AD, tau becomes hyperphosphorylated and misfolded at both presynaptic and postsynaptic terminals, and this abnormally posttranslationally modified tau is enriched in synaptoneurosomal fractions. Synaptic tau seems to be hyperphosphorylated and ubiquitinated, and forms stable oligomers resistant to SDS denaturation. The accumulation of hyperphosphorylated tau oligomers at human AD synapses is associated with increased ubiquitinated substrates and increased proteasome components, consistent with dysfunction of the ubiquitin-proteasome system. Our findings suggest that synaptic hyperphosphorylated tau oligomers may be an important mediator of the proteotoxicity that disrupts synapses in AD.
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