title: Targeting Alzheimer's Disease Neuro-Metabolic Dysfunction with a Small Molecule Nuclear Receptor Agonist (T3D-959) Reverses Disease Pathologies.
abstract: BACKGROUND
  Alzheimer's disease (AD) could be regarded as a brain form of diabetes since insulin resistance and deficiency develop early and progress with severity of neurodegeneration. Preserving insulin's actions in the brain restores function and reduces neurodegeneration. T3D-959 is a dual nuclear receptor agonist currently in a Phase 2a trial in mild-to-moderate AD patients (ClinicalTrials.gov identifier NCT02560753). Herein, we show that T3D-959 improves motor function and reverses neurodegeneration in a sporadic model of AD.
  
  
  METHODS
  Long Evans rats were administered intracerebral (i.c.) streptozotocin (STZ) or normal saline (control) and dosed orally with T3D-959 (1.0 mg/kg/day) or saline for 21 or 28 days. Rotarod tests evaluated motor function. Histopathology with image analysis was used to assess neurodegeneration.
  
  
  RESULTS
  T3D-959 significantly improved motor performance, and preserved both cortical and normalized white matter structure in i.c STZ-treated rats. T3D-959 treatments were effective when dosed therapeutically, whether initiated 1 day or 7 days after i.c. STZ.
  
  
  CONCLUSIONS
  T3D-959's targeting neuro-metabolic dysfunctions via agonism of PPAR delta and PPAR gamma nuclear receptors provides potential disease modification in AD.
authors.affiliation: Liver Research Center, Warren Alpert Medical School of Brown University, Providence, RI, USA; Divisions of Gastroenterology, Warren Alpert Medical School of Brown University, Providence, RI, USA; Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.affiliation: Williams College, Williams, MA, USA.
authors.forename: Cesar
authors.initials: C
authors.lastname: Dominguez
authors.affiliation: T3D Pharmaceuticals, Raleigh Durham, NC, USA5Australian School of Advanced Medicine, Macquarie University, Sydney, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Didsbury
authors.affiliation: Liver Research Center, Warren Alpert Medical School of Brown University, Providence, RI, USA; Divisions of Gastroenterology, Warren Alpert Medical School of Brown University, Providence, RI, USA; Department of Neuropathology, Warren Alpert Medical School of Brown University, Providence, RI, USA; Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA; Department of Pathology, Warren Alpert Medical School of Brown University, Providence, RI, USA; Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA; Department of Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
keywords: Alzheimer; Cerebellum; Motor function; Neurodegeneration; PPAR agonist; Streptozotocin; T3D-959; Type 3 diabetes