Gene Knockout of tau Expression Does Not Contribute to the Pathogenesis of Prion Disease

Abstract

Prion diseases or transmissible spongiform encephalopathies are a group of fatal and transmissible disorders affecting the central nervous system of humans and animals. The principal agent of prion disease transmission and pathogenesis is proposed to be an abnormal protease-resistant isoform of the normal cellular prion protein. The microtubule-associated protein tau is elevated in patients with Creutzfeldt-Jakob disease. To determine whether tau expression contributes to prion disease pathogenesis, tau knockout and control wild-type mice were infected with the M1000 strain of mouse-adapted human prions. Immunohistochemical analysis for total tau expression in prion-infected wild-type mice indicated tau aggregation in the cytoplasm of a subpopulation of neurons in regions associated with spongiform change. Western immunoblot analysis of brain homogenates revealed a decrease in total tau immunoreactivity and epitope-specific changes in tau phosphorylation. No significant difference in incubation period or other disease features were observed between tau knockout and wild-type mice with clinical prion disease. These results demonstrate that, in this model of prion disease, tau does not contribute to the pathogenesis of prion disease and that changes in the tau protein profile observed in mice with clinical prion disease occurs as a consequence of the prion-induced pathogenesis.

Subtype and regional regulation of prion biomarkers in sporadic Creutzfeldt–Jakob disease

“…Tau phosphorylation in prion models seems to be site‐specific regardless of total Tau expression. In prion‐infected mice p‐Tau is increased at S396 but decreased at S404 [40] in addition to a concomitant decrease of total Tau levels. In contrast, in scrapie‐infected hamsters Tau levels are elevated, p‐Tau at S396 while S404 is decreased but increased at S202/T205.…”

Could Intracrine Biology Play a Role in the Pathogenesis of Transmissable Spongiform Encephalopathies Alzheimer’s Disease and Other Neurodegenerative Diseases?

“…In some cases, it trafficks between cells via exosomes. 36,48,[53][54][55][56][57][58]98,99 Therefore, it presumably could act in a fashion similar to the one we have proposed for PrP c /PrP sc . In addition, if it were to lower nuclear zinc concentration, it could downregulate p73, upregulate p53 and thereby increase tau phosphorylation.…”

“…4 However, PrP sc can produce pathology in cultured tau 2/2 cells. 55 Collectively, these observations suggest a synergistic pathogenic relationship between PrP sc and tau. Finally, disordered autophagy appears to play a complex and poorly defined role in intracellular tau accumulation.…”

“…AB Re increases phosphorylated tau. [47][48][49][50][51][52][53][54][55][56][57][58][59][60] Of note, PrP sc also appears to upregulate tau phosphorylation and result in the accumulation of intracellular tau and tau filaments. 4 However, PrP sc can produce pathology in cultured tau 2/2 cells.…”

Is tau ready for admission to the prion club?

“…96,97 Signs of neurofibrillary degeneration were only CSF-tau levels are even higher in CJD than they are in AD, raising the possibility that PrP Sc in at least some TSEs may induce tau misprocessing, especially since tau has recently been shown to bind to PrP on a disease-associated basis. 109 However, the implications of such interactions are unclear, as a recent mouse model study suggests that knockout of endogenous tau does not modulate conversion of PrP c to the toxic PrP Sc form, 110 while another study in a cellular overexpression model demonstrated a tau-mediated depletion of endogenous PrP at the plasma membrane that was correlated with PrP toxicity. 111 That said, there are numerous similarities between tau and PrP misprocessing pathways that would seem to present ample opportunity for these proteins to interact in ways that would favor their mislocation, aberrant phosphorylation, oligomerization and secretion (see Fig.…”