{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T15:58:18Z","timestamp":1791043098630,"version":"4.1.0"},"reference-count":38,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2016,10,14]],"date-time":"2016-10-14T00:00:00Z","timestamp":1476403200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2016,11,19]]},"abstract":"<jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    Alzheimer\u2019s 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.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Objective:<\/jats:bold>\n                    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.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    Long Evans rats were treated with i.c. STZ or saline, followed by daily oral doses of T3D-959 (1\u200amg\/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.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    i.c. STZ treatments caused neurodegeneration with increased pTau, A\u03b2PP, A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    , ubiquitin, and SNAP-25, and reduced levels of synaptophysin, IGF-1 receptor (R), IRS-1, Akt, p70S6K, mTOR, and\n                    <jats:sup>S9<\/jats:sup>\n                    -GSK-3\u03b2. 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\n                    <jats:sup>S9<\/jats:sup>\n                    -GSK-3\u03b2, 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.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusion:<\/jats:bold>\n                    AD remediating effects of T3D-959 are potentially due to enhanced expression of key insulin\/IGF signaling proteins and inhibition of GSK-3\u03b2 and neuroinflammation. These effects lead to reduced neurodegeneration, cognitive impairment, and AD biomarker levels in the brain.\n                  <\/jats:p>","DOI":"10.3233\/jad-160656","type":"journal-article","created":{"date-parts":[[2016,10,14]],"date-time":"2016-10-14T10:38:37Z","timestamp":1476441517000},"page":"849-864","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":64,"title":["Improved Brain Insulin\/IGF Signaling and\u00a0Reduced Neuroinflammation with\u00a0T3D-959 in an Experimental Model\u00a0of\u00a0Sporadic Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"55","author":[{"given":"Suzanne M.","family":"de la Monte","sequence":"first","affiliation":[{"name":"Rhode Island Hospital and the Warren Alpert Medical School of Brown University","place":["USA"]},{"name":"Rhode Island Hospital and the Warren Alpert Medical School of Brown University","place":["USA"]},{"name":"Rhode Island Hospital and the Warren Alpert Medical School of Brown University","place":["USA"]},{"name":"Rhode Island Hospital and the Warren Alpert Medical School of Brown University","place":["USA"]},{"name":"Rhode Island Hospital and the Warren Alpert Medical School of Brown University","place":["USA"]},{"name":"Department of Neurology","place":["USA"]},{"name":"Rhode Island Hospital and the Warren Alpert Medical School of Brown University","place":["USA"]},{"name":"Rhode Island Hospital and the Warren Alpert Medical School of Brown University","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Tong","sequence":"additional","affiliation":[{"name":"Rhode Island Hospital and the Warren Alpert Medical School of Brown University","place":["USA"]},{"name":"Rhode Island Hospital and the Warren Alpert Medical School of Brown University","place":["USA"]},{"name":"Rhode Island Hospital and the Warren Alpert Medical School of Brown University","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irio","family":"Schiano","sequence":"additional","affiliation":[{"name":"Quinnipiac University","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Didsbury","sequence":"additional","affiliation":[{"name":"Research Triangle Park","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2016,10,14]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2009-1070"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.2174\/156720512799015037"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.2741\/e482"},{"key":"e_1_3_3_5_2","first-page":"1049","article-title":"Insulin resistance and neurodegeneration: Roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis","volume":"10","author":"de la Monte SM","year":"2009","unstructured":"de la MonteSM, LongatoL, TongM, WandsJR (2009) Insulin resistance and neurodegeneration: Roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis. 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