Signal during exposition with a quantitative imaging system, as these systems are often calibrated to stop the exposure process before the strongest signal on the membrane is outside the linear range of detection. We, therefore, recommend to mask the non-specific signal at 25 kDa, or to cut the membrane prior to incubation with secondary anti-LC antibodies, or to do incremental exposure to improve signal detection. We also tested all of the monoclonal antibodies within a heat stable fraction. This method is routinely used by many groups for Western blotting or to measure total tau after passive immunization, as this procedure very effectively removes any mouse Igs. The heat-stable procedure is based on the fact that tau is an extremely heat stable protein. Here, the non-specific signal seen in TKO mice was completely absent in the heat stable fraction, as expected. However, this technique also seems to decrease the overall tau signal and resolution on a Western blot, as evidenced by the observation that some antibodies failed to reveal all the bands of murine tau in the HS fraction. Furthermore, our results show that there is a significant fraction of tau lost into the pellet, and that this technique is not for studying proteins other than tau, such as kinases, as they were absent from the HS fraction. We further tested two others techniques to clear Igs. We took advantages of the capacity of protein G and Dynabeads to bind the fragment crystallizable region of mouse Igs in order to clear the samples of endogenous Igs. Results with cleared samples showed that the non-specific band in TKO mice was completely eliminated, further confirming that the non-specificity is due to mouse Igs. Both methods can be used to remove the nonspecificity but they involve significant modification of Western blot procedures and are more time-consuming than the simple replacement of secondary antibodies. Furthermore, it is possible that some proteins of interest could form a complex with protein G or Dynabeads and be discarded in the pellet. Finally, we tested some polyclonal antibodies and, as expected, our results indicate that these antibodies were not associated with specificity-related problems secondary to endogenous Igs. Nevertheless, in our study, some polyclonal antibodies, particularly the pS262 and pS409 antibodies, led to high non-specificity that obscured the tau signal detection. These antibodies displayed high non-specificity mainly due to their cross-reactivity with others proteins in the samples. While the HS treatment improved the phospho-tau signal of pS262, it did not for pS409. Indeed some studies have shown that pS409 is not phosphorylated in the human and rat adult brain, which could explain this problem with detection. In conclusion, this study provides evidence that both monoclonal and polyclonal antibodies can display non-specificity in mouse samples during Western blot analysis for tau protein.