PMID- 27412291 OWN - NLM STAT- MEDLINE DCOM- 20171109 LR - 20190111 IS - 1750-1326 (Electronic) IS - 1750-1326 (Linking) VI - 11 IP - 1 DP - 2016 Jul 13 TI - Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease. PG - 52 LID - 10.1186/s13024-016-0118-z [doi] LID - 52 AB - BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Clinically, AD is characterized by impairments of memory and cognitive functions. Accumulation of amyloid-beta (Abeta) and neurofibrillary tangles are the prominent neuropathologies in patients with AD. Strong evidence indicates that an imbalance between production and degradation of key proteins contributes to the pathogenesis of AD. The mammalian target of rapamycin (mTOR) plays a key role in maintaining protein homeostasis as it regulates both protein synthesis and degradation. A key regulator of mTOR activity is the proline-rich AKT substrate 40 kDa (PRAS40), which directly binds to mTOR and reduces its activity. Notably, AD patients have elevated levels of phosphorylated PRAS40, which correlate with Abeta and tau pathologies as well as cognitive deficits. Physiologically, PRAS40 phosphorylation is regulated by Pim1, a protein kinase of the protoconcogene family. Here, we tested the effects of a selective Pim1 inhibitor (Pim1i), on spatial reference and working memory and AD-like pathology in 3xTg-AD mice. RESULTS: We have identified a Pim1i that crosses the blood brain barrier and reduces PRAS40 phosphorylation. Pim1i-treated 3xTg-AD mice performed significantly better than their vehicle treated counterparts as well as non-transgenic mice. Additionally, 3xTg-AD Pim1i-treated mice showed a reduction in soluble and insoluble Abeta40 and Abeta42 levels, as well as a 45.2 % reduction in Abeta42 plaques within the hippocampus. Furthermore, phosphorylated tau immunoreactivity was reduced in the hippocampus of Pim1i-treated 3xTg-AD mice by 38 %. Mechanistically, these changes were linked to a significant increase in proteasome activity. CONCLUSION: These results suggest that reductions in phosphorylated PRAS40 levels via Pim1 inhibition reduce Abeta and Tau pathology and rescue cognitive deficits by increasing proteasome function. Given that Pim1 inhibitors are already being tested in ongoing human clinical trials for cancer, the results presented here may open a new venue of drug discovery for AD by developing more Pim1 inhibitors. FAU - Velazquez, Ramon AU - Velazquez R AD - Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, 727 E. Tyler Street, Tempe, AZ, 85287-5001, USA. FAU - Shaw, Darren M AU - Shaw DM AD - Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, 727 E. Tyler Street, Tempe, AZ, 85287-5001, USA. AD - School of Life Sciences, Arizona State University, Tempe, AZ, 85287, USA. FAU - Caccamo, Antonella AU - Caccamo A AD - Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, 727 E. Tyler Street, Tempe, AZ, 85287-5001, USA. FAU - Oddo, Salvatore AU - Oddo S AUID- ORCID: 0000-0001-7304-7430 AD - Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, 727 E. Tyler Street, Tempe, AZ, 85287-5001, USA. oddo@asu.edu. AD - School of Life Sciences, Arizona State University, Tempe, AZ, 85287, USA. oddo@asu.edu. LA - eng GR - R01 AG037637/AG/NIA NIH HHS/United States GR - RF1 AG037637/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160713 PL - England TA - Mol Neurodegener JT - Molecular neurodegeneration JID - 101266600 RN - 0 (Amyloid beta-Protein Precursor) RN - EC 2.7.11.1 (PIM1 protein, human) RN - EC 2.7.11.1 (Pim1 protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-pim-1) SB - IM MH - Alzheimer Disease/drug therapy/*metabolism MH - Amyloid beta-Protein Precursor/metabolism MH - Animals MH - Cognition/*physiology MH - Cognition Disorders/metabolism MH - Disease Models, Animal MH - Hippocampus/*metabolism MH - Humans MH - Memory/physiology MH - Mice MH - Neurofibrillary Tangles/*metabolism MH - Proto-Oncogene Proteins c-pim-1/*antagonists & inhibitors/metabolism PMC - PMC4944476 OTO - NOTNLM OT - 3xTg-AD OT - AD OT - Aging OT - Abeta OT - PRAS40 OT - Pim1 inhibitor OT - Proteasome OT - Working memory OT - mTOR OT - tau EDAT- 2016/07/15 06:00 MHDA- 2017/11/10 06:00 PMCR- 2016/07/13 CRDT- 2016/07/15 06:00 PHST- 2016/02/18 00:00 [received] PHST- 2016/07/02 00:00 [accepted] PHST- 2016/07/15 06:00 [entrez] PHST- 2016/07/15 06:00 [pubmed] PHST- 2017/11/10 06:00 [medline] PHST- 2016/07/13 00:00 [pmc-release] AID - 10.1186/s13024-016-0118-z [pii] AID - 118 [pii] AID - 10.1186/s13024-016-0118-z [doi] PST - epublish SO - Mol Neurodegener. 2016 Jul 13;11(1):52. doi: 10.1186/s13024-016-0118-z.