PMID- 31527120 OWN - NLM STAT- MEDLINE DCOM- 20200630 LR - 20240214 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 39 IP - 43 DP - 2019 Oct 23 TI - Depletion of Caveolin-1 in Type 2 Diabetes Model Induces Alzheimer's Disease Pathology Precursors. PG - 8576-8583 LID - 10.1523/JNEUROSCI.0730-19.2019 [doi] AB - Type 2 diabetes mellitus (T2DM) is a risk factor for the development of late-onset Alzheimer's disease (AD). However, the mechanism underlying the development of late-onset AD is largely unknown. Here we show that levels of the endothelial-enriched protein caveolin-1 (Cav-1) are reduced in the brains of T2DM patients compared with healthy aging, and inversely correlated with levels of beta-amyloid (Abeta). Depletion of Cav-1 is recapitulated in the brains of db/db (Lepr(db) ) diabetic mice and corresponds with recognition memory deficits as well as the upregulation of amyloid precursor protein (APP), BACE-1, a trending increase in beta-amyloid Abeta(42/40) ratio and hyperphosphorylated tau (p-tau) species. Importantly, we show that restoration of Cav-1 levels in the brains of male db/db mice using adenovirus overexpressing Cav-1 (AAV-Cav-1) rescues learning and memory deficits and reduces pathology (i.e., APP, BACE-1 and p-tau levels). Knocking down Cav-1 using shRNA in HEK cells expressing the familial AD-linked APPswe mutant variant upregulates APP, APP carboxyl terminal fragments, and Abeta levels. In turn, rescue of Cav-1 levels restores APP metabolism. Together, these results suggest that Cav-1 regulates APP metabolism, and that depletion of Cav-1 in T2DM promotes the amyloidogenic processing of APP and hyperphosphorylation of tau. This may suggest that depletion of Cav-1 in T2DM underlies, at least in part, the development of AD and imply that restoration of Cav-1 may be a therapeutic target for diabetic-associated sporadic AD.SIGNIFICANCE STATEMENT More than 95% of the Alzheimer's patients have the sporadic late-onset form (LOAD). The cause for late-onset Alzheimer's disease is unknown. Patients with Type 2 diabetes mellitus have considerably higher incidence of cognitive decline and AD compared with the general population, suggesting a common mechanism. Here we show that the expression of caveolin-1 (Cav-1) is reduced in the brain in Type 2 diabetes mellitus. In turn, reduced Cav-1 levels induce AD-associated neuropathology and learning and memory deficits. Restoration of Cav-1 levels rescues these deficits. This study unravels signals underlying LOAD and suggests that restoration of Cav-1 may be an effective therapeutic target. CI - Copyright (c) 2019 the authors. FAU - Bonds, Jacqueline A AU - Bonds JA AUID- ORCID: 0000-0001-7929-3499 AD - Departments of Anatomy and Cell Biology. FAU - Shetti, Aashutosh AU - Shetti A AD - Departments of Anatomy and Cell Biology. FAU - Bheri, Abdullah AU - Bheri A AUID- ORCID: 0000-0002-1759-682X AD - Departments of Anatomy and Cell Biology. FAU - Chen, Zhenlong AU - Chen Z AD - Anesthesiology. FAU - Disouky, Ahmed AU - Disouky A AD - Departments of Anatomy and Cell Biology. FAU - Tai, Leon AU - Tai L AD - Departments of Anatomy and Cell Biology. FAU - Mao, Mao AU - Mao M AD - Medicine. FAU - Head, Brian P AU - Head BP AD - Veteran Affairs San Diego Healthcare System, San Diego, California 92161. AD - Department of Anesthesiology, University of California at San Diego, San Diego, California 92103. FAU - Bonini, Marcelo G AU - Bonini MG AD - Departments of Medicine and Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226. FAU - Haus, Jacob M AU - Haus JM AUID- ORCID: 0000-0002-8048-2470 AD - School of Kinesiology, University of Michigan, Ann Arbor, Michigan 48109. FAU - Minshall, Richard D AU - Minshall RD AUID- ORCID: 0000-0003-3164-475X AD - Anesthesiology, olazarov@uic.edu rminsh@uic.edu. AD - Pharmacology, University of Illinois at Chicago, Chicago, Illinois 60612. FAU - Lazarov, Orly AU - Lazarov O AUID- ORCID: 0000-0002-5887-948X AD - Departments of Anatomy and Cell Biology, olazarov@uic.edu rminsh@uic.edu. LA - eng GR - I01 BX003671/BX/BLRD VA/United States GR - R01 HL125356/HL/NHLBI NIH HHS/United States GR - P50 AG005136/AG/NIA NIH HHS/United States GR - R01 AG062251/AG/NIA NIH HHS/United States GR - UL1 TR002003/TR/NCATS NIH HHS/United States GR - R01 AG033570/AG/NIA NIH HHS/United States GR - R01 AG060238/AG/NIA NIH HHS/United States GR - RF1 AG033570/AG/NIA NIH HHS/United States GR - R21 AG061628/AG/NIA NIH HHS/United States GR - R01 AI131267/AI/NIAID NIH HHS/United States GR - T32 AG057468/AG/NIA NIH HHS/United States GR - P30 DK020572/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190916 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Amyloid beta-Peptides) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Caveolin 1) SB - IM MH - Alzheimer Disease/genetics/*metabolism/pathology MH - Amyloid beta-Peptides/genetics/metabolism MH - Amyloid beta-Protein Precursor/genetics/metabolism MH - Animals MH - Brain/metabolism/*pathology MH - Caveolin 1/*genetics/metabolism MH - Diabetes Mellitus, Type 2/genetics/*metabolism/pathology MH - Disease Models, Animal MH - Male MH - Mice MH - Phosphorylation PMC - PMC6807274 OTO - NOTNLM OT - Alzheimer's disease OT - Type 2 diabetes OT - amyloid OT - caveolin-1 OT - cognition OT - tau EDAT- 2019/09/19 06:00 MHDA- 2020/07/01 06:00 PMCR- 2020/04/23 CRDT- 2019/09/19 06:00 PHST- 2019/04/01 00:00 [received] PHST- 2019/08/27 00:00 [revised] PHST- 2019/08/29 00:00 [accepted] PHST- 2019/09/19 06:00 [pubmed] PHST- 2020/07/01 06:00 [medline] PHST- 2019/09/19 06:00 [entrez] PHST- 2020/04/23 00:00 [pmc-release] AID - JNEUROSCI.0730-19.2019 [pii] AID - 0730-19 [pii] AID - 10.1523/JNEUROSCI.0730-19.2019 [doi] PST - ppublish SO - J Neurosci. 2019 Oct 23;39(43):8576-8583. doi: 10.1523/JNEUROSCI.0730-19.2019. Epub 2019 Sep 16.