Truncated tau deregulates synaptic markers in rat model for human tauopathy

Abstract

Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer’s disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre- and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology.

Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment

“…ab11068 RRID:AB_2230303). The antibody recognized drebrin E isoforms of ∼95–120 kDa on Western blot, as previously reported (Xiao et al, ; Jadhav et al, ). HeLa cell line (ab7898) or rat (E16) spinal cord serves as a positive control.…”

“…A β‐tubulin monoclonal antibody (DC126) raised against porcine tubulin in mouse recognizes a single band of ∼55 kDa on Western blots of rat cortical synaptosomes or total extract (Jadhav et al, ). Recombinant porcine β‐tubulin protein or human tubulin extract or rat brain extracts (Jadhav et al, ) acts as a positive control.…”

Tau pathology-mediated presynaptic dysfunction

“…Synaptic dysfunction and abnormalities in axonal transport are early pathogenic events in tauopathies that precede the formation of neurofibrillary tangles (NFTs) and neuronal cell death (Majid et al, 2014, Polydoro et al, 2014, Jadhav et al, 2015). Normally, a substantial amount of cellular tau is sorted into axons (Rao et al, 2014, Jadhav et al, 2015), and there is compelling evidence to suggest that the missorting of tau into the somatodendritic compartment plays a pathological role in tauopathies (Zempel and Mandelkow, 2014). Nevertheless, pathological axonal tau localizations are also prominent (Rao et al, 2014, Tai et al, 2014, Jadhav et al, 2015).…”

“…Normally, a substantial amount of cellular tau is sorted into axons (Rao et al, 2014, Jadhav et al, 2015), and there is compelling evidence to suggest that the missorting of tau into the somatodendritic compartment plays a pathological role in tauopathies (Zempel and Mandelkow, 2014). Nevertheless, pathological axonal tau localizations are also prominent (Rao et al, 2014, Tai et al, 2014, Jadhav et al, 2015). Furthermore, it has been recently proposed that pathological-tau spreading may occur trans-synaptically from pre- to the post-synaptic sites (de Calignon et al, 2012).…”

A comparative study on pathological features of transgenic rat lines expressing either three or four repeat misfolded tau

“…Anti‐pan tau antibody DC25 (AXON Neuroscience, Bratislava, Slovak Republic) was raised against human tau isoform 0N3R and recognize epitope aa 347–353 of protein tau. The antibody recognizes soluble and insoluble tau fraction from human and rodent models (Jadhav et al, ). Recombinant human or rodent tau isoforms or human brain extract serve as positive controls.…”