# Targeting Tau for TBI

> **NIH VA I01** · JAMES A. HALEY VA MEDICAL CENTER · 2020 · —

## Abstract

   
DESCRIPTION (provided by applicant):   
   
Here, we will determine if improved small molecules can protect the microtubule associated  protein tau from a pathogenic cascade caused by the molecular chaperone Hsc70. Tau accumulates  in  traumatic  brain  injury  (TBI),  leading  to  neurodegeneration  and  cognitive  deficits.  Active  Hsc70  binds  to  tau  just  after  microtubule  disruption  precipitated  by  bast-­induced  axonal  injury  and  then  directs tau along one of two paths: It either preserves tau, even when it is hyper-­phosphorylated, in  an effort to recycle it to microtubules, or it triages au for a specialized degradation system called  chaperone mediated autophagy (CMA).  While this seems appropriate in principle, tau is actually a problem for CMA.  It  gets  trapped  in  the  channel  called  LAMP2a,  and  then  it  is  cleaved  into  an  aggregation-­prone form that can seed further aggregation. So the mechanisms used by Hsc70 to triage tau are ineffective, and the overall outcome is its abnormal accumulation. We have shown that  just by inhibiting Hsc70 with small molecules, tau is sent for proteasomal clearance, which is more  effective  for  clearing  tau  than  CMA.  Therefore  we  predict  that  subverting  tau  away  from  CMA  processing  with  Hsc70  inhibitors  will  reduce  the  pathogenic  tau  burden,  and  could  possibly  be  a  therapeutic strategy for TBI, especially immediately following blast TBI when tau fate is determined.  We also predict that we will be able to use these small molecules to define the mechanism through  which  Hsc70  makes  "decisions"  about  tau  fate.  Our  team  has  developed  an  extensive  suite  of  compounds  that  reduce  tau  levels  in  cells  through  this mechanism  and  a  number  of  tools  to  investigate  mechanism  of  action.  Therefore,  we  will  be  able  to  evaluate  both  the  efficacy  of  this  approach for in vivo application whilealso dissecting the mechanisms involved in Hsc70 triage of  tau. We have recently shown that Hsc70 inhibition by rhodacyanines can effectively lower tau in cells  and  in  brain  tissue.  This  scaffold  has  been  modified  to  improve  anti-­tau  potency  and  pharmacokinetics, even permitting BBB permeability. Thus, this compound family could hold promise  as a viable drug candidate for tauopathies. We used this information to create a library of structurally  diverse  derivatives  of  the  rhodacyanine  backbone.  But  we  do  not  know  if  they  have  improved  neuronal anti-­tau potency or pharmacokinetic profiles. We hypothesize that these properties can be  improved. We propose a step-­wise advancement process to test the potency, toxicity, efficacy and  ADME/pharmacokinetic profiles of these derivatives. In addition to their potential therapeutic utility,  the rhodacyanines provide excellent tool molecules to examine mechanisms of Hsc70-­directed tau  trafficking and turnover. We will also employ innovative cell-­bas...

## Key facts

- **NIH application ID:** 9814679
- **Project number:** 5I01BX002947-04
- **Recipient organization:** JAMES A. HALEY VA MEDICAL CENTER
- **Principal Investigator:** David E Kang
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814679

## Citation

> US National Institutes of Health, RePORTER application 9814679, Targeting Tau for TBI (5I01BX002947-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9814679. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*