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PMID: 16203860 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease.

The Journal of cell biology ·Vol. 171 ·No. 1 ·2005-10-10 ·Pages 87-98

Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Näslund J, Mathews PM, Cataldo AM, Nixon RA

Abstract

Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before beta-amyloid (Abeta) deposits extracellularly in the presenilin (PS) 1/Abeta precursor protein (APP) mouse model of beta-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Abeta. Purified AVs contain APP and beta-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent gamma-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Abeta production. Our results, therefore, link beta-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

MeSH Terms
Adult Aged Aged, 80 and over Alzheimer Disease/metabolism,pathology Amyloid Precursor Protein Secretases Amyloid beta-Peptides/genetics,metabolism Amyloid beta-Protein Precursor/genetics,metabolism Animals Aspartic Acid Endopeptidases Autophagy/physiology Brain/pathology Endopeptidases/analysis,metabolism,physiology Female Humans Male Membrane Proteins/genetics,metabolism Mice Microscopy, Immunoelectron Middle Aged Models, Molecular Mutation Presenilin-1 Signal Transduction Vacuoles/chemistry,metabolism
Chemicals
Amyloid beta-Peptides Amyloid beta-Protein Precursor Membrane Proteins PSEN1 protein, human Presenilin-1 Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Yu W Haung
Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA.
Cuervo Ana Maria
Kumar Asok
Peterhoff Corrinne M
Schmidt Stephen D
Lee Ju-Hyun
Mohan Panaiyur S
Mercken Marc
Farmery Mark R
Tjernberg Lars O
Jiang Ying
Duff Karen
Uchiyama Yasuo
Näslund Jan
Mathews Paul M
Cataldo Anne M
Nixon Ralph A
References (71)
71 references, click to expand
  1. The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis.
    Eur J Biochem. 2002 Apr;269(8):1996-2002 PMID: 11985575
  2. The endosomal-lysosomal system of neurons in Alzheimer's disease pathogenesis: a review.
    Neurochem Res. 2000 Oct;25(9-10):1161-72 PMID: 11059790
  3. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice.
    Neuron. 2005 Mar 3;45(5):675-88 PMID: 15748844
  4. Neuronal and nonneuronal quantitative BACE immunocytochemical expression in the entorhinohippocampal and frontal regions in Alzheimer's disease.
    Dement Geriatr Cogn Disord. 2005;19(4):171-83 PMID: 15677864
  5. Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and Down syndrome.
    Neurobiol Aging. 2004 Nov-Dec;25(10):1263-72 PMID: 15465622
  6. Age-related decline in chaperone-mediated autophagy.
    J Biol Chem. 2000 Oct 6;275(40):31505-13 PMID: 10806201
  7. Amino acids and insulin control autophagic proteolysis through different signaling pathways in relation to mTOR in isolated rat hepatocytes.
    J Biol Chem. 2004 Feb 27;279(9):8452-9 PMID: 14610086
  8. Reconstitution of gamma-secretase activity.
    Nat Cell Biol. 2003 May;5(5):486-8 PMID: 12679784
  9. Induction of autophagy by amino-acid deprivation in perfused rat liver.
    Nature. 1977 Nov 10;270(5633):174-6 PMID: 927529
  10. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease.
    Nat Genet. 2004 Jun;36(6):585-95 PMID: 15146184
  11. Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells.
    Cell Death Differ. 2004 Apr;11(4):448-57 PMID: 14713959
  12. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.
    Nat Med. 1998 Jan;4(1):97-100 PMID: 9427614
  13. Amino acids as regulators of proteolysis.
    J Nutr. 2003 Jun;133(6 Suppl 1):2052S-2056S PMID: 12771364
  14. Inhibition of macroautophagy triggers apoptosis.
    Mol Cell Biol. 2005 Feb;25(3):1025-40 PMID: 15657430
  15. Changes in the proteolytic activities of proteasomes and lysosomes in human fibroblasts produced by serum withdrawal, amino-acid deprivation and confluent conditions.
    Biochem J. 2003 Oct 1;375(Pt 1):75-86 PMID: 12841850
  16. Structural aspects of autophagy.
    Adv Exp Med Biol. 1996;389:103-11 PMID: 8860999
  17. Fibrillar beta-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer's disease.
    Neuroscience. 2001;104(3):609-13 PMID: 11440793
  18. Re-evaluation of the structural organization of neuritic plaques in Alzheimer's disease.
    J Neuropathol Exp Neurol. 1993 Nov;52(6):619-32 PMID: 8229081
  19. Studies on the mechanisms of autophagy: formation of the autophagic vacuole.
    J Cell Biol. 1990 Jun;110(6):1923-33 PMID: 2351689
  20. Regulation of translational effectors by amino acid and mammalian target of rapamycin signaling pathways. Possible involvement of autophagy in cultured hepatoma cells.
    J Biol Chem. 1999 Jan 8;274(2):1058-65 PMID: 9873051
  21. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.
    Nature. 1996 Oct 24;383(6602):710-3 PMID: 8878479
  22. Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology.
    J Neuropathol Exp Neurol. 2004 Aug;63(8):821-30 PMID: 15330337
  23. Exosomes: a bubble ride for prions?
    Traffic. 2005 Jan;6(1):10-7 PMID: 15569241
  24. Calpain activity regulates the cell surface distribution of amyloid precursor protein. Inhibition of calpains enhances endosomal generation of beta-cleaved C-terminal APP fragments.
    J Biol Chem. 2002 Sep 27;277(39):36415-24 PMID: 12087104
  25. Regulation and role of autophagy in mammalian cells.
    Int J Biochem Cell Biol. 2004 Dec;36(12):2445-62 PMID: 15325584
  26. Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome.
    Arch Pathol Lab Med. 2001 Apr;125(4):489-92 PMID: 11260621
  27. Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology.
    Am J Pathol. 2002 Nov;161(5):1869-79 PMID: 12414533
  28. Presenilin-1, nicastrin, amyloid precursor protein, and gamma-secretase activity are co-localized in the lysosomal membrane.
    J Biol Chem. 2003 Jul 18;278(29):26687-94 PMID: 12736250
  29. Prelysosomal convergence of autophagic and endocytic pathways.
    Biochem Biophys Res Commun. 1988 Feb 29;151(1):40-7 PMID: 3126737
  30. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation.
    J Cell Sci. 2004 Jun 1;117(Pt 13):2805-12 PMID: 15169837
  31. Induction of autophagy causes dramatic changes in the subcellular distribution of GFP-Rab24.
    Traffic. 2002 Jul;3(7):472-82 PMID: 12047555
  32. Lysosomal activation is a compensatory response against protein accumulation and associated synaptopathogenesis--an approach for slowing Alzheimer disease?
    J Neuropathol Exp Neurol. 2003 May;62(5):451-63 PMID: 12769185
  33. Abeta-generating enzymes: recent advances in beta- and gamma-secretase research.
    Neuron. 2000 Sep;27(3):419-22 PMID: 11055423
  34. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast.
    J Biol Chem. 1998 Feb 13;273(7):3963-6 PMID: 9461583
  35. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
    EMBO J. 2000 Nov 1;19(21):5720-8 PMID: 11060023
  36. Rab5-stimulated up-regulation of the endocytic pathway increases intracellular beta-cleaved amyloid precursor protein carboxyl-terminal fragment levels and Abeta production.
    J Biol Chem. 2003 Aug 15;278(33):31261-8 PMID: 12761223
  37. Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease.
    J Neuropathol Exp Neurol. 1999 Nov;58(11):1147-55 PMID: 10560657
  38. Neuropathological stageing of Alzheimer-related changes.
    Acta Neuropathol. 1991;82(4):239-59 PMID: 1759558
  39. Dynamic organization of endocytic pathways in axons of cultured sympathetic neurons.
    J Neurosci. 1996 Oct 1;16(19):6056-64 PMID: 8815888
  40. Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells.
    J Biol Chem. 2000 Jan 14;275(2):992-8 PMID: 10625637
  41. Autophagy as a cell death and tumor suppressor mechanism.
    Oncogene. 2004 Apr 12;23(16):2891-906 PMID: 15077152
  42. Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities.
    J Biol Chem. 2003 Jun 20;278(25):22475-81 PMID: 12684521
  43. Autophagy genes are essential for dauer development and life-span extension in C. elegans.
    Science. 2003 Sep 5;301(5638):1387-91 PMID: 12958363
  44. Monodansylcadaverine (MDC) is a specific in vivo marker for autophagic vacuoles.
    Eur J Cell Biol. 1995 Jan;66(1):3-14 PMID: 7750517
  45. Amino acid control of autophagic sequestration and protein degradation in isolated rat hepatocytes.
    J Cell Biol. 1984 Aug;99(2):435-44 PMID: 6746735
  46. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease.
    Neurology. 1991 Apr;41(4):479-86 PMID: 2011243
  47. The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein.
    J Cell Biol. 2001 Aug 20;154(4):731-40 PMID: 11502763
  48. The autophagosomal-lysosomal compartment in programmed cell death.
    Cell Death Differ. 2001 Jun;8(6):569-81 PMID: 11536007
  49. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy.
    Science. 2004 Aug 27;305(5688):1292-5 PMID: 15333840
  50. Isolation of autophagic vacuoles from rat liver: morphological and biochemical characterization.
    J Cell Biol. 1982 Apr;93(1):144-54 PMID: 7068752
  51. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study.
    J Neuropathol Exp Neurol. 2005 Feb;64(2):113-22 PMID: 15751225
  52. Colocalization of lysosomal hydrolase and beta-amyloid in diffuse plaques of the cerebellum and striatum in Alzheimer's disease and Down's syndrome.
    J Neuropathol Exp Neurol. 1996 Jun;55(6):704-15 PMID: 8642396
  53. Mutant presenilin 1 increases the levels of Alzheimer amyloid beta-peptide Abeta42 in late compartments of the constitutive secretory pathway.
    J Neurochem. 2000 May;74(5):1878-84 PMID: 10800930
  54. Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport.
    J Cell Biol. 1993 Apr;121(2):305-15 PMID: 7682217
  55. Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease.
    Int J Biochem Cell Biol. 2004 Dec;36(12):2531-40 PMID: 15325590
  56. Membrane traffic to and from lysosomes.
    Biochem Soc Symp. 2005;(72):77-86 PMID: 15649132
  57. Microglia cells are the driving force in fibrillar plaque formation, whereas astrocytes are a leading factor in plague degradation.
    Acta Neuropathol. 2000 Oct;100(4):356-64 PMID: 10985692
  58. Fine structural localization of acid phosphatase in senile plaques in Alzheimer's presenile dementia.
    Acta Neuropathol. 1967 May 5;8(3):276-84 PMID: 6039977
  59. Developmental cell death: morphological diversity and multiple mechanisms.
    Anat Embryol (Berl). 1990;181(3):195-213 PMID: 2186664
  60. The neuronal endosomal-lysosomal system in Alzheimer's disease.
    J Alzheimers Dis. 2001 Feb;3(1):97-107 PMID: 12214078
  61. Alzheimer's disease-associated presenilin 1 in neuronal cells: evidence for localization to the endoplasmic reticulum-Golgi intermediate compartment.
    J Neurosci Res. 1997 Sep 15;49(6):719-31 PMID: 9335259
  62. Partial purification and characterization of gamma-secretase from post-mortem human brain.
    J Biol Chem. 2003 Jul 4;278(27):24277-84 PMID: 12697771
  63. Protein accumulation in traumatic brain injury.
    Neuromolecular Med. 2003;4(1-2):59-72 PMID: 14528053
  64. Subversion of cellular autophagosomal machinery by RNA viruses.
    PLoS Biol. 2005 May;3(5):e156 PMID: 15884975
  65. Autophagy and its possible roles in nervous system diseases, damage and repair.
    Autophagy. 2005 Apr;1(1):11-22 PMID: 16874045
  66. Use of [3H]raffinose as a specific probe of autophagic sequestration.
    Exp Cell Res. 1986 Jan;162(1):273-7 PMID: 3940229
  67. Light and electron microscopic immunolocalization of presenilin 1 in abnormal muscle fibers of patients with sporadic inclusion-body myositis and autosomal-recessive inclusion-body myopathy.
    Am J Pathol. 1998 Apr;152(4):889-95 PMID: 9546349
  68. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker.
    Mol Biol Cell. 2004 Mar;15(3):1101-11 PMID: 14699058
  69. Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists.
    Arch Pathol Lab Med. 1993 Feb;117(2):132-44 PMID: 8427562
  70. Studies on the mechanisms of autophagy: maturation of the autophagic vacuole.
    J Cell Biol. 1990 Jun;110(6):1935-45 PMID: 2161853
  71. MAP-LC3, a promising autophagosomal marker, is processed during the differentiation and recovery of podocytes from PAN nephrosis.
    FASEB J. 2003 Jun;17(9):1165-7 PMID: 12709412
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200505082
Published
2005-10-10
Epub
2005-00-03
Pages
87-98
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2171227
Subset
IM
Grants
NIA NIH HHS · R01 AG021904 · United States
NIA NIH HHS · R37 AG021904 · United States
NIA NIH HHS · AG17617-05 · United States
NIA NIH HHS · P01 AG017617 · United States
NIA NIH HHS · AG021904 · United States
Corrections
CommentIn
PMID: 16216920
External Links
PubMed source DOI: 10.1083/jcb.200505082 PMC Full Text View journal details
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