Interaction of 14-3-3ζ with Microtubule-Associated
Protein Tau within Alzheimer’s Disease Neurofibrillary Tangles
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Abstract
Alzheimer’s
disease (AD) is characterized by the presence
of abnormal, straight filaments and paired helical filaments (PHFs)
that are coated with amorphous aggregates. When PHFs are treated with
alkali, they untwist and form filaments with a ribbonlike morphology.
Tau protein is the major component of all of these ultrastructures.
14-3-3ζ is present in NFTs and is significantly upregulated
in AD brain. The molecular basis of the association of 14-3-3ζ
within NFTs and the pathological significance of its association are
not known. In this study, we have found that 14-3-3ζ is copurified
and co-immunoprecipitates with tau from NFTs of AD brain extract. <i>In vitro</i>, tau binds to both phosphorylated and nonphosphorylated
tau. When incubated with 14-3-3ζ, tau forms amorphous aggregates,
single-stranded, straight filaments, ribbonlike filaments, and PHF-like
filaments, all of which resemble the corresponding ultrastructures
found in AD brain. Immuno-electron microscopy determined that both
tau and 14-3-3ζ are present in these ultrastructures and that
they are formed in an incubation time-dependent manner. Amorphous
aggregates are formed first. As the incubation time increases, the
size of amorphous aggregates increases and they are incorporated into
single-stranded filaments. Single-stranded filaments laterally associate
to form double-stranded, ribbonlike, and PHF-like filaments. Both
tau and phosphorylated tau aggregate in a similar manner when they
are incubated with 14-3-3ζ. Our data suggest that 14-3-3ζ
has a role in the fibrillization of tau in AD brain, and that tau
phosphorylation does not affect 14-3-3ζ-induced tau aggregation