Tau 45-230 association with the cytoskeleton and membrane-bound organelles: Functional implications in neurodegeneration

Abstract

The dysregulation of posttranslational modifications of the microtubule-associated protein (MAP) tau plays a key role in Alzheimer’s disease (AD) and related disorders. Thus, we have previously shown that beta amyloid (Aβ)-induced neurotoxicity was mediated, at least in part, by tau cleavage into the tau45-230 fragment. However, the mechanisms underlying the toxicity of tau45-230 remain unknown. To get insights into such mechanisms, we first determined the subcellular localization of this tau fragment in hippocampal neurons. Tau45-230 was easily detectable in cell bodies and processes extended by these neurons. In addition, cell extraction experiments performed using Triton X-100 and saponin showed that a pool of tau45-230 was associated with the cytoskeleton and the cytoskeleton plus membrane-bound organelles, respectively, in cultured hippocampal neurons. Furthermore, they suggested that these associations were independent of the presence of full-length tau. We also assessed whether this tau fragment could alter axonal transport. Our results indicated that tau45-230 significantly reduced the number of organelles transported along hippocampal axons. This altered axonal transport did not correlate with changes in the total number of organelles present in these cells or in motor protein levels. Together these results suggested that tau45-230 could exert its toxic effects by partially blocking axonal transport along microtubules thus contributing to the early pathology of AD.

Tau Oligomers Neurotoxicity

“…Toxic tau species can interfere with microtubule stability, thus affecting the transport and distribution of organelles and signaling proteins (enzymes, receptors) in cell compartments [118]. An intracellular accumulation of tau was often accompanied by an increase in transport time and the instantaneous velocity of the vesicular cargos [119].…”

Human Tau Isoforms and Proteolysis for Production of Toxic Tau Fragments in Neurodegeneration

“…Tau proteolytic fragments have not been studied to precipitate in up-regulated concentrations from 3R- or 4R-isoforms, and it is unclear whether 3R- or 4R-isoforms more toxic fragments. Reference numbers in parentheses refer to cited articles as follows: (1) Zhang et al (2014) ; (2) Matsumoto et al (2015) ; (3) Ozcelik et al (2016) ; (4) Horowitz et al (2004) ; (5) Horowitz et al (2004) ; (6) Gamblin et al (2003) ; (7) Quintanilla et al (2009) ; (8) Foveau et al (2016) ; (9) Guo et al (2004) ; (10) Zhao et al (2016) ; (11) Amadoro et al (2006) ; (12) Amadoro et al (2012) ; (13) Lang et al (2014) ; (14) Afreen et al (2017) ; (15) Park and Ferreira (2005) ; (16) Garg et al (2010) ; (17) Matthews-Roberson et al (2008) ; (18) Yang and Ksiezak-Reding (1995) ; (19) Arai et al (2005) ; (20) Corsetti et al (2008) ; and (21) Florenzano et al (2017) .…”

Tau Proteolysis in the Pathogenesis of Tauopathies: Neurotoxic Fragments and Novel Biomarkers

“…Alongside the cellular phenotypes, behavioural abnormalities were noted with significantly increased freezing response in the fear conditioning test [ 35 ]. Tau 45 - 230 was also shown to impair both anterograde and retrograde organelle transport, which could help to explain how it exerts its neurotoxic effects [ 36 ]. Which calpain cleaves at R230-T231 in vivo is still unclear, since both calpain-1 and –2 [ 34 ] have been shown to cleave this peptide bond in vitro .…”