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
AUTHORS (6)
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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