Home LiteratureArticle Details
PMID: 10377346 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Mutant presenilin-1 induces apoptosis and downregulates Akt/PKB.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 19 ·No. 13 ·1999-07-01 ·Pages 5360-9

Weihl CC, Ghadge GD, Kennedy SG, Hay N, Miller RJ, Roos RP

Abstract

Most early onset cases of familial Alzheimer's disease (AD) are caused by mutations in presenilin-1 (PS1) and presenilin-2 (PS2). These mutations lead to increased beta-amyloid formation and may induce apoptosis in some model systems. Using primary cultured hippocampal neurons (HNs) and rat pheochromocytoma (PC12) cells transiently transfected with replication-defective recombinant adenoviral vectors expressing wild-type or mutant PS1, we demonstrate that mutant PS1s induce apoptosis, downregulate the survival factor Akt/PKB, and affect several Akt/PKB downstream targets, including glycogen synthase kinase-3beta and beta-catenin. Expression of a constitutively active Akt/PKB rescues HNs from mutant PS1-induced neuronal cell death, suggesting a potential therapeutic target for AD. Downregulation of Akt/PKB may be a mechanism by which mutant PS1 induces apoptosis and may play a role in the pathogenesis of familial AD.

MeSH Terms
Adenoviridae/genetics Alzheimer Disease/genetics Animals Apoptosis Calcium-Calmodulin-Dependent Protein Kinases/metabolism Carrier Proteins/metabolism Cells, Cultured Cytoskeletal Proteins/metabolism Down-Regulation Enzyme Activation/drug effects Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Hippocampus/cytology JNK Mitogen-Activated Protein Kinases Membrane Proteins/genetics,metabolism,physiology Mitogen-Activated Protein Kinases Mutation Nerve Growth Factors/pharmacology Neurons/cytology,drug effects,enzymology,metabolism PC12 Cells Phosphatidylinositol 3-Kinases/metabolism Phosphoinositide-3 Kinase Inhibitors Presenilin-1 Protein Serine-Threonine Kinases/genetics,metabolism Proto-Oncogene Proteins/physiology Proto-Oncogene Proteins c-akt Rats Receptor, trkA Ribosomal Protein S6 Kinases/metabolism Signal Transduction/drug effects Trans-Activators Transfection Wnt Proteins Zebrafish Proteins beta Catenin
Chemicals
Carrier Proteins Ctnnb1 protein, rat Cytoskeletal Proteins Membrane Proteins Nerve Growth Factors Phosphoinositide-3 Kinase Inhibitors Presenilin-1 Proto-Oncogene Proteins Trans-Activators Wnt Proteins Zebrafish Proteins beta Catenin Receptor, trkA Glycogen Synthase Kinases Akt1 protein, rat Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinases Calcium-Calmodulin-Dependent Protein Kinases JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases Glycogen Synthase Kinase 3
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Weihl C C
Committee on Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.
Ghadge G D
Kennedy S G
Hay N
Miller R J
Roos R P
References (39)
39 references, click to expand
  1. Mechanism of activation and function of protein kinase B.
    Curr Opin Genet Dev. 1998 Feb;8(1):55-62 PMID: 9529606
  2. Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis.
    J Biol Chem. 1998 Jun 26;273(26):16568-75 PMID: 9632728
  3. Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation.
    Science. 1996 Dec 6;274(5293):1710-3 PMID: 8939861
  4. Presenilins are processed by caspase-type proteases.
    J Biol Chem. 1997 Aug 15;272(33):20655-9 PMID: 9252383
  5. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans.
    Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14940-4 PMID: 8962160
  6. Phosphorylation and activation of p70s6k by PDK1.
    Science. 1998 Jan 30;279(5351):707-10 PMID: 9445476
  7. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin.
    J Biol Chem. 1998 Jun 26;273(26):16470-5 PMID: 9632714
  8. Light and electron microscopic localization of presenilin-1 in primate brain.
    J Neurosci. 1997 Mar 15;17(6):1971-80 PMID: 9045726
  9. Expression and analysis of presenilin 1 in a human neuronal system: localization in cell bodies and dendrites.
    Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9223-8 PMID: 8799182
  10. Direct association of presenilin-1 with beta-catenin.
    FEBS Lett. 1998 Aug 14;433(1-2):73-7 PMID: 9738936
  11. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway.
    J Biol Chem. 1998 Aug 7;273(32):19929-32 PMID: 9685326
  12. Mutant genes in familial Alzheimer's disease and transgenic models.
    Annu Rev Neurosci. 1998;21:479-505 PMID: 9530504
  13. Presenilin 1 interaction in the brain with a novel member of the Armadillo family.
    Neuroreport. 1997 May 27;8(8):2085-90 PMID: 9223106
  14. Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of beta-catenin, a component of the presenilin protein complex.
    Nat Med. 1999 Feb;5(2):164-9 PMID: 9930863
  15. Requirement of the familial Alzheimer's disease gene PS2 for apoptosis. Opposing effect of ALG-3.
    J Biol Chem. 1996 Dec 6;271(49):31025-8 PMID: 8940094
  16. Overexpression in neurons of human presenilin-1 or a presenilin-1 familial Alzheimer disease mutant does not enhance apoptosis.
    J Neurosci. 1998 Dec 1;18(23):9790-9 PMID: 9822738
  17. Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3.
    J Biol Chem. 1997 Oct 3;272(40):25326-32 PMID: 9312151
  18. Processing of wild-type and mutant familial Alzheimer's disease-associated presenilin-1 in cultured neurons.
    J Neurochem. 1999 Jul;73(1):31-40 PMID: 10386952
  19. Inactivation and dephosphorylation of protein kinase Balpha (PKBalpha) promoted by hyperosmotic stress.
    EMBO J. 1998 Dec 15;17(24):7294-303 PMID: 9857186
  20. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.
    Nat Med. 1996 Aug;2(8):864-70 PMID: 8705854
  21. Glycogen synthase kinase-3: functions in oncogenesis and development.
    Biochim Biophys Acta. 1992 Dec 16;1114(2-3):147-62 PMID: 1333807
  22. Regulation of neuronal survival by the serine-threonine protein kinase Akt.
    Science. 1997 Jan 31;275(5300):661-5 PMID: 9005851
  23. Regulation of apoptosis by presenilin 1.
    Neurobiol Aging. 1998 Jan-Feb;19(1 Suppl):S23-7 PMID: 9562463
  24. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro.
    Curr Biol. 1998 Jan 15;8(2):69-81 PMID: 9427642
  25. Mutant superoxide dismutase-1-linked familial amyotrophic lateral sclerosis: molecular mechanisms of neuronal death and protection.
    J Neurosci. 1997 Nov 15;17(22):8756-66 PMID: 9348345
  26. Adenovirus E1B 19,000-molecular-weight protein activates c-Jun N-terminal kinase and c-Jun-mediated transcription.
    Mol Cell Biol. 1998 Jul;18(7):4012-22 PMID: 9632786
  27. Wnt signaling: a common theme in animal development.
    Genes Dev. 1997 Dec 15;11(24):3286-305 PMID: 9407023
  28. Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau.
    Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9637-41 PMID: 9689133
  29. The activation of p38 and apoptosis by the inhibition of Erk is antagonized by the phosphoinositide 3-kinase/Akt pathway.
    J Biol Chem. 1998 Apr 24;273(17):10792-7 PMID: 9553146
  30. Destabilization of beta-catenin by mutations in presenilin-1 potentiates neuronal apoptosis.
    Nature. 1998 Oct 15;395(6703):698-702 PMID: 9790190
  31. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation.
    Biochem J. 1998 Oct 1;335 ( Pt 1):1-13 PMID: 9742206
  32. Distribution, levels, and activity of glycogen synthase kinase-3 in the Alzheimer disease brain.
    J Neuropathol Exp Neurol. 1997 Jan;56(1):70-8 PMID: 8990130
  33. Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress.
    Genes Dev. 1998 Jul 1;12(13):1941-6 PMID: 9649498
  34. Essential role for protein kinase B (PKB) in insulin-induced glycogen synthase kinase 3 inactivation. Characterization of dominant-negative mutant of PKB.
    J Biol Chem. 1998 May 22;273(21):13150-6 PMID: 9582355
  35. Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide.
    Neuroreport. 1996 Dec 20;8(1):379-83 PMID: 9051814
  36. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal.
    Genes Dev. 1997 Mar 15;11(6):701-13 PMID: 9087425
  37. Alzheimer's disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells.
    Curr Biol. 1994 Dec 1;4(12):1077-86 PMID: 7704571
  38. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.
    Nature. 1995 Dec 21-28;378(6559):785-9 PMID: 8524413
  39. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo.
    Neuron. 1996 Jul;17(1):181-90 PMID: 8755489
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
0270-6474
Published
1999-07-01
Pages
5360-9
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6782321
Subset
IM
Grants
NIMH NIH HHS · F30MH11697 · United States
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2