title: Improved Brain Insulin/IGF Signaling and Reduced Neuroinflammation with T3D-959 in an Experimental Model of Sporadic Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is associated with progressive impairments in brain insulin, insulin-like growth factor (IGF), and insulin receptor substrate (IRS) signaling through Akt pathways that regulate neuronal growth, survival, metabolism, and plasticity. The intracerebral streptozotocin (i.c. STZ) model replicates the full range of abnormalities in sporadic AD. T3D-959, an orally active PPAR-delta/gamma agonist remediates neurocognitive deficits and AD neuropathology in the i.c. STZ model.
  
  
  
  This study characterizes the effects of T3D-959 on AD biomarkers, insulin/IGF/IRS signaling through Akt pathways, and neuroinflammation in an i.c. STZ model.
  
  
  
  Long Evans rats were treated with i.c. STZ or saline, followed by daily oral doses of T3D-959 (1 mg/kg) or saline initiated 1 day (T3D-959-E) or 7 days (T3D-959-L) later through Experimental Day 28. Protein and phospho-protein expression and pro-inflammatory cytokine activation were measured in temporal lobe homogenates by duplex or multiplex bead-based ELISAs.
  
  
  
  i.c. STZ treatments caused neurodegeneration with increased pTau, AβPP, Aβ42, ubiquitin, and SNAP-25, and reduced levels of synaptophysin, IGF-1 receptor (R), IRS-1, Akt, p70S6K, mTOR, and S9-GSK-3β. i.c. STZ also broadly increased neuroinflammation. T3D-959 abrogated or reduced most of the AD neuropathological and biomarker abnormalities, increased/normalized IGF-1R, IRS-1, Akt, p70S6K, and S9-GSK-3β, and decreased expression of multiple pro-inflammatory cytokines. T3D-959-E or -L effectively restored insulin/IGF signaling, whereas T3D-959-L more broadly resolved neuroinflammation.
  
  
  
  AD remediating effects of T3D-959 are potentially due to enhanced expression of key insulin/IGF signaling proteins and inhibition of GSK-3β and neuroinflammation. These effects lead to reduced neurodegeneration, cognitive impairment, and AD biomarker levels in the brain.
authors: Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Division of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Division of Neuropathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Department of Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Department of Neurology, Rhode Island Hospital and the 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, USA.
authors: Suzanne M
authors: SM
authors: de la Monte
authors: Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Division of Gastroenterology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.|Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors: Ming
authors: M
authors: Tong
authors: Quinnipiac University, Biomedical Sciences Department in Hamden, CT, USA.
authors: Irio
authors: I
authors: Schiano
authors: T3D Therapeutics, Inc., Research Triangle Park, NC, USA.
authors: John
authors: J
authors: Didsbury
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000150:complications*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008297:Male; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D051381:Rats; D020318:Rats, Long-Evans; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013311:Streptozocin / Q000633:toxicity; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000903:Antibiotics, Antineoplastic; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D050825:Synaptosomal-Associated Protein 25; D016875:tau Proteins; D013311:Streptozocin; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer’s disease; PPAR delta; T3D-959; cytokines; insulin resistance; neurodegeneration; rat model