English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the zaia usage as premium feature

ZAIA

Presents the pdf analysis as premium feature

PDF Analysis

Insights

Presents the summarisation as premium feature

Summarisation

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the access of premium content as premium feature

Premium Content

Zendy Tools

Zendy Open

Accumulation of amyloid β (Aβ) and tau represent the two major pathological hallmarks of Alzheimer’s disease (AD). Despite the critical importance of Aβ accumulation as an early event in AD pathogenesis, multiple lines of evidence indicate that tau is required to mediate Aβ-induced neurotoxic signals in neurons. We have previously shown that the scaffolding protein Ran-binding protein 9 (RanBP9), which is highly elevated in brains of AD and AD mouse models, both enhances Aβ production and mediates Aβ-induced neurotoxicity. However, it is unknown whether and how RanBP9 transmits Aβ-induced neurotoxic signals to tau. Here we show for the first time that overexpression or knockdown of RanBP9 directly enhances and reduces tau levels, respectively,  in vitro  and  in vivo . Such changes in tau levels are associated with the ability of RanBP9 to physically interact with tau and heat shock protein 90/heat shock cognate 70 (Hsp90/Hsc70) complexes. Meanwhile, both RanBP9 and tau levels are simultaneously reduced by Hsp90 or Hsc70 inhibitors, whereas overexpression or knockdown of RanBP9 significantly diminishes the anti-tau potency of Hsp90/Hsc70 inhibitors as well as Hsc70 variants (WT &amp; E175S). Further, RanBP9 increases the capacity for Hsp90 and Hsc70 complexes to bind ATP and enhances their ATPase activities  in vitro . These observations  in vitro  and cell lines are recapitulated in primary neurons and  in vivo , as genetic reduction in  RanBP9  not only ameliorates tauopathy in Tau-P301S mice but also rescues the deficits in synaptic integrity and plasticity.

Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes