Atypical PKC, PKCŒª/Œπ, activates Œ≤-secretase and increases AŒ≤1‚Ä?0/42 and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimer's disease
Authors: Margaret G Higgs
David M Diamond
Ursula Braun
C Ron Kahn
Mini P Sajan
Barbara C Hansen
Robert V Farese
Collin R Park
Michael Leitges
Journal: Neurobiology of Aging (2018)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Akt; Alzheimer's; Atypical PKC; AŒ≤; Beta-secretase
Affiliations: Internal Medicine and Research Services, James A. Haley Veterans Medical Center, Tampa, Florida, USA; Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida, USA., Internal Medicine and Research Services, James A. Haley Veterans Medical Center, Tampa, Florida, USA., Joslin Research Foundation, Harvard Medical School, Boston, MA, USA., Biotechnology Centre of Oslo, Oslo, Norway., Departments of Psychology, Molecular Pharmacology and Physiology, Center for Preclinical and Clinical Research on PTSD, University of South Florida, Tampa, Florida, USA., Internal Medicine and Research Services, James A. Haley Veterans Medical Center, Tampa, Florida, USA; Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida, USA. Electronic address: .

Abstract:  Hyperinsulinemia activates brain Akt and PKC-Œª/Œπ and increases AŒ≤1-40/42 and phospho-tau in insulin-resistant animals. Here, we examined underlying mechanisms in mice, neuronal cells, and mouse hippocampal slices. Like AŒ≤1-40/42, Œ≤-secretase activity was increased in insulin-resistant mice and monkeys. In insulin-resistant mice, inhibition of hepatic PKC-Œª/Œπ sufficient to correct hepatic abnormalities and hyperinsulinemia simultaneously reversed increases in Akt, atypical protein kinase C (aPKC), Œ≤-secretase, and AŒ≤1-40/42, and restored acute Akt activation. However, 2 aPKC inhibitors additionally blocked insulin's ability to activate brain PKC-Œª/Œπ and thereby increase Œ≤-secretase and AŒ≤1-40/42. Furthermore, direct blockade of brain aPKC simultaneously corrected an impairment in novel object recognition in high-fat-fed insulin-resistant mice. In neuronal cells and/or mouse hippocampal slices, PKC-Œπ/Œª activation by insulin, metformin, or expression of constitutive PKC-Œπ provoked increases in Œ≤-secretase, AŒ≤1-40/42, and phospho-thr-231-tau that were blocked by various PKC-Œª/Œπ inhibitors, but not by an Akt inhibitor. PKC-Œª/Œπ provokes increases in brain Œ≤-secretase, AŒ≤1-40/42, and phospho-thr-231-tau. Excessive signaling via PKC-Œª/Œπ may link hyperinsulinemia and other PKC-Œª/Œπ activators to pathological and functional abnormalities in Alzheimer's disease. 

Retracted: No

PubPeer comments:
 Wrong number of lanes. Should be 7 lanes throughout Fig 7.  CA in Fig 7B shows 8 lanes , 
 Figure 7 C : significant at 25 and 100, but not at 50 MOI ? , 
 #1 The lane lane is now deleted. Please see attached file. , 
 Figure 7 C : Where are the SEM at 50 and 100 MOI ? The easier are obtained results the simpler is the correction - deletion of band ! Is there any reason as to why the last band though ? , 
 #4 The last (8th) band in original Fig 7B was inadvertently included, and should have been cropped off, as it is from another series of samples that were simultaneously being examined in the same immunoblot (it is in fact a sample comparable to that shown in lane 7). In the new replacement Figure, the extra band has been removed and there are now only 7 bands. The SEMs at 50 and 100 MOI in Fig 7C are smaller than the square symbols and therefore not visible, as portrayed. For MOI50. Mean + or - SEM values are 1.17+ or - 0.02 For 100MOI, values are 1.36 + or - 0.03 , 
 #5 Are the authors intending to correct the paper? ,