TDP-43 expression influences amyloidβ plaque deposition and tau aggregation

NEUROBIOLOGY OF DISEASE

卷:103

Article

Davis, Stephani A.¹  Gan, Kok Ann¹  Dowell, James A.²  Cairns, Nigel J.³  Gitcho, Michael A.¹ 

[1] Delaware State Univ, Delaware Ctr Neurosci Res, Dept Biol Sci, Dover, DE 19901 USA

[2] Wisconsin Inst Discovery, Madison, WI 53705 USA

[3] Washington Univ, Sch Med, Dept Neurol, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA

关键词: TDP-43;    TARDBP;    APP;    Calcineurin;    Alzheimer's disease;    APP/PS1;    Tau;   

DOI  :  10.1016/j.nbd.2017.04.012

来源: Elsevier

【 摘 要 】

Although the main focus in Alzheimer's disease (AD) has been an investigation of mechanisms causing A beta 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 (PSEN1 Delta E9). 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 A beta 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 Ala 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 A beta plaque formation and tauopathy. (C) 2017 Elsevier Inc. All rights reserved.

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