Abstract
In Alzheimer disease (AD) and frontotemporal dementia the microtubule-associated protein Tau becomes progressively hyperphosphorylated, eventually forming aggregates. However, how Tau dysfunction is associated with functional impairment is only partly understood, especially at early stages when Tau is mislocalized but has not yet formed aggregates. Impaired axonal transport has been proposed as a potential pathomechanism, based on cellular Tau models and Tau transgenic mice. We recently reported K369I mutant Tau transgenic K3 mice with axonal transport defects that suggested a cargo-selective impairment of kinesin-driven anterograde transport by Tau. Here, we show that kinesin motor complex formation is disturbed in the K3 mice. We show that under pathological conditions hyperphosphorylated Tau interacts with c-Jun N-terminal kinase- interacting protein 1 (JIP1), which is associated with the kinesin motor protein complex. As a result, transport of JIP1 into the axon is impaired, causing JIP1 to accumulate in the cell body. Because we found trapping of JIP1 and a pathological Tau/JIP1 interaction also in AD brain, this may have pathomechanistic implications in diseases with a Tau pathology. This is supported by JIP1 sequestration in the cell body of Tau-transfected primary neuronal cultures. The pathological Tau/JIP1 interaction requires phosphorylation of Tau, and Tau competes with the physiological binding of JIP1 to kinesin light chain. Because JIP1 is involved in regulating cargo binding to kinesin motors, our findings may, at least in part, explain how hyperphosphorylated Tau mediates impaired axonal transport in AD and frontotemporal dementia.
Highlights
The microtubule-associated protein Tau is predominantly found in the axonal compartment of neurons, where it binds to microtubules [1]
Primary cultures, and in vitro experiments, we found that hyperphosphorylated Tau disrupts the functional binding of Jun N-terminal kinase- interacting protein 1 (JIP1) to the kinesin-I motor complex
We found that Tau pathologically interacts with JIP1 both in our K3 mouse model and in Alzheimer disease (AD) brain, causing a re-localization of JIP1 from axons to cell bodies
Summary
Mice—The generation of K3 mice expressing K369I mutant human Tau has been described [17]. Western Blotting and Immunoprecipitation—Proteins were extracted from brain tissues in radioimmunoprecipitation assay buffer (50 mM Tris, pH 8.0, 150 mM sodium chloride, 1% Nonidet P-40, 5 mM EDTA, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulfate (all Sigma)) containing Complete protease inhibitors (Roche Applied Science). After a 1-h preincubation with bovine serum albumin (Sigma)-saturated protein G-coupled beats (Pierce), extracts were incubated with antibodies overnight at 4 °C. Antibodies were subsequently precipitated with bovine serum albumin-saturated protein G-coupled beads that were washed with buffers of increasing sodium chloride concentration (150 – 400 mM). A, immunohistochemistry of sagittal brain sections reveals a predominantly axonal staining of JIP1 (green) in wild-type mice, with little staining of neuronal cell bodies. JIP1 accumulates in the cell body of cortical neurons of K3 mice, whereas axons hardly contain JIP1.
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