Pathogenic Forms of Tau Inhibit Kinesin-Dependent Axonal Transport through a Mechanism Involving Activation of Axonal Phosphotransferases

Abstract

Aggregated filamentous forms of hyperphosphorylated tau (a microtubule-associated protein) represent pathological hallmarks of Alzheimer’s disease (AD) and other tauopathies. While axonal transport dysfunction is thought to represent a primary pathogenic factor in AD and other neurodegenerative diseases, the direct molecular link between pathogenic forms of tau and deficits in axonal transport remain unclear. Recently, we demonstrated that filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Here, we demonstrate that amino acids 2–18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway in axoplasms isolated from squid giant axons. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Importantly, immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity, an early marker of pathological tau. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT. Results from these studies reveal a novel role for tau in modulating axonal phosphotransferases and provide a molecular basis for a toxic gain-of-function associated with pathogenic forms of tau.

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…Alternatively, Tau could inactivate selected motor complexes, by direct binding to kinesin (Utton et al 2005), by sequestering the kinesin-associated protein JIP1 (in case of the K369I mutation; Ittner et al 2009), or by activating phosphatase PP1 and kinase GSK3b through Tau's amino-terminal 18-residues, leading to the release of cargo vesicles from kinesin light chains (Kanaan et al 2011). Similarly, the amino-terminal domain of Tau binds to the p150 subunit of dynactin and thereby supports transport by dynein, which can be disrupted by the R5L mutation in Tau (Magnani et al 2007).…”

Deciphering the mechanism underlying late-onset Alzheimer disease

“…23 Chronic inflammation and cellular stress to neurons during ageing-owing to infection, disease, or agerelated changes-induce hyperphosphorylation and mis sorting of tau, 17 which in turn is expected to destabilize the microtubule-actin networks and impair axonal trans port. 24 Such changes might cause the protein extrusion mechanism to decline or fail completely, thereby inducing focal axonal swellings and concomitant accumulation of mitochondria and other organelles ( Figure 1, step 3). 25,26 Disturbed energy metabolism in the axon could induce further tau phosphorylation, 27 an additional neuropathological event that probably facilitates the formation of paired helical filaments (PHFs; precursor elements of neurofibrillary tangles), as seen in doubleimmune-challenged mice.…”

Levels of kinesin light chain and dynein intermediate chain are reduced in the frontal cortex in Alzheimer’s disease: implications for axoplasmic transport

“…In contrast, aggregated filamentous forms of tau inhibited anterograde fast axonal transport in vivo [25] by a mechanism involving activation of GSK-3! [23,25].…”