| First Author | Davis SA | Year | 2017 |
| Journal | Neurobiol Dis | Volume | 103 |
| Pages | 154-162 | PubMed ID | 28416393 |
| Mgi Jnum | J:259472 | Mgi Id | MGI:6142850 |
| Doi | 10.1016/j.nbd.2017.04.012 | Citation | Davis SA, et al. (2017) TDP-43 expression influences amyloidbeta plaque deposition and tau aggregation. Neurobiol Dis 103:154-162 |
| abstractText | Although the main focus in Alzheimer''s disease (AD) has been an investigation of mechanisms causing Abeta plaque deposition and tau tangle formation, recent studies have shown that phosphorylated TDP-43 pathology is present in up to 50% of sporadic cases. Furthermore, elevated phosphorylated TDP-43 has been associated with more severe AD pathology. Therefore, we hypothesized that TDP-43 may regulate amyloid-beta precursor protein (APP) trafficking and tau phosphorylation/aggregation. In order to examine the role of TDP-43 in AD, we developed a transgenic mouse that overexpresses hippocampal and cortical neuronal TDP-43 in a mouse expressing familial mutations (K595N and M596L) in APP and presenilin 1 (PSEN1DeltaE9). In our model, increased TDP-43 was related to increased tau aggregation as evidenced by thioflavin S-positive phosphorylated tau, which may implicate TDP-43 expression in pre-tangle formation. In addition, there was increased endosomal/lysosomal localization of APP and reduced Abeta plaque formation with increased TDP-43. Furthermore, there was decreased calcineurin with elevated TDP-43 expression. Since calcineurin is a phosphatase for TDP-43, the decreased calcineurin expression may be one mechanism leading to an increase in accumulation of diffuse phosphorylated TDP-43 in the hippocampus and cortex. We further show that when TDP-43 is knocked down there is an increase in calcineurin. In our model of selective TDP-43 overexpression in an APP/PSEN1 background, we show that TDP-43 decreases Abeta plaque deposition while increasing abnormal tau aggregation. These observations indicate that TDP-43 may play a role in regulating APP trafficking and tau aggregation. Our data suggest that TDP-43 could be a putative target for therapeutic intervention in AD affecting both Abeta plaque formation and tauopathy. |
