Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease

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 β-amyloid (Aβ) deposits extracellularly in the presenilin (PS) 1/Aβ precursor protein (APP) mouse model of β-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 Aβ. Purified AVs contain APP and β-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent γ-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 Aβ production. Our results, therefore, link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

[1]  N. Heintz,et al.  Autophagy and Its Possible Roles in Nervous System Diseases, Damage and Repair , 2005, Autophagy.

[2]  K. Kirkegaard,et al.  Subversion of Cellular Autophagosomal Machinery by RNA Viruses , 2005, PLoS biology.

[3]  J. D. McGaugh,et al.  Intraneuronal Aβ Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice , 2005, Neuron.

[4]  G. Leuba,et al.  Neuronal and Nonneuronal Quantitative BACE Immunocytochemical Expression in the Entorhinohippocampal and Frontal Regions in Alzheimer’s Disease , 2005, Dementia and Geriatric Cognitive Disorders.

[5]  Ralph A. Nixon,et al.  Extensive Involvement of Autophagy in Alzheimer Disease: An Immuno-Electron Microscopy Study , 2005, Journal of neuropathology and experimental neurology.

[6]  Philippe Dessen,et al.  Inhibition of Macroautophagy Triggers Apoptosis , 2005, Molecular and Cellular Biology.

[7]  G. Raposo,et al.  Exosomes: A Bubble Ride for Prions? , 2005, Traffic.

[8]  P. Codogno,et al.  Regulation and role of autophagy in mammalian cells. , 2004, The international journal of biochemistry & cell biology.

[9]  B. Lamb,et al.  Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease. , 2004, The international journal of biochemistry & cell biology.

[10]  J. Buxbaum,et al.  Aβ localization in abnormal endosomes: association with earliest Aβ elevations in AD and Down syndrome , 2004, Neurobiology of Aging.

[11]  Peter T. Lansbury,et al.  Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy , 2004, Science.

[12]  S. Schmidt,et al.  Presenilin Mutations in Familial Alzheimer Disease and Transgenic Mouse Models Accelerate Neuronal Lysosomal Pathology , 2004, Journal of neuropathology and experimental neurology.

[13]  A. Yamamoto,et al.  LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation , 2004, Journal of Cell Science.

[14]  Francesco Scaravilli,et al.  Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease , 2004, Nature Genetics.

[15]  A. Kimchi,et al.  Autophagy as a cell death and tumor suppressor mechanism , 2004, Oncogene.

[16]  I. Germano,et al.  Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells , 2004, Cell Death and Differentiation.

[17]  F. Yoshizawa,et al.  Amino Acids and Insulin Control Autophagic Proteolysis through Different Signaling Pathways in Relation to mTOR in Isolated Rat Hepatocytes* , 2004, Journal of Biological Chemistry.

[18]  M. Matsui,et al.  In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. , 2003, Molecular biology of the cell.

[19]  A. Rivett,et al.  Changes in the proteolytic activities of proteasomes and lysosomes in human fibroblasts produced by serum withdrawal, amino-acid deprivation and confluent conditions. , 2003, The Biochemical journal.

[20]  D. Hall,et al.  Autophagy Genes Are Essential for Dauer Development and Life-Span Extension in C. elegans , 2003, Science.

[21]  S. Schmidt,et al.  Rab5-stimulated Up-regulation of the Endocytic Pathway Increases Intracellular β-Cleaved Amyloid Precursor Protein Carboxyl-terminal Fragment Levels and Aβ Production* , 2003, Journal of Biological Chemistry.

[22]  C. Ackerley,et al.  Presenilin-1, Nicastrin, Amyloid Precursor Protein, and γ-Secretase Activity Are Co-localized in the Lysosomal Membrane* , 2003, Journal of Biological Chemistry.

[23]  B. Winblad,et al.  Partial Purification and Characterization of γ-Secretase from Post-mortem Human Brain* , 2003, Journal of Biological Chemistry.

[24]  Min Xu,et al.  Presenilin-1 and Presenilin-2 Exhibit Distinct yet Overlapping γ-Secretase Activities* , 2003, Journal of Biological Chemistry.

[25]  Y. Tomino,et al.  MAP‐LC3, a promising autophagosomal marker, is processed during the differentiation and recovery of podocytes from PAN nephrosis , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  M. Kadowaki,et al.  Amino acids as regulators of proteolysis. , 2003, The Journal of nutrition.

[27]  B. Bahr,et al.  Lysosomal Activation Is a Compensatory Response Against Protein Accumulation and Associated Synaptopathogenesis—An Approach for Slowing Alzheimer Disease? , 2003, Journal of neuropathology and experimental neurology.

[28]  J. Regula,et al.  Reconstitution of γ-secretase activity , 2003, Nature Cell Biology.

[29]  P. Greengard,et al.  Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. , 2002, The American journal of pathology.

[30]  M. Mercken,et al.  Calpain Activity Regulates the Cell Surface Distribution of Amyloid Precursor Protein , 2002, The Journal of Biological Chemistry.

[31]  M. Colombo,et al.  Induction of Autophagy Causes Dramatic Changes in the Subcellular Distribution of GFP‐Rab24 , 2002, Traffic.

[32]  R. Mohs,et al.  Consortium to establish a registry for Alzheimer's disease (CERAD) clinical and neuropsychological assessment of Alzheimer's disease. , 2002, Psychopharmacology bulletin.

[33]  U. Brunk,et al.  The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. , 2002, European journal of biochemistry.

[34]  H. Vanderstichele,et al.  The discrepancy between presenilin subcellular localization and γ-secretase processing of amyloid precursor protein , 2001, The Journal of cell biology.

[35]  J. L. François,et al.  Fibrillar β-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer’s disease , 2001, Neuroscience.

[36]  W. Bursch.  The autophagosomal–lysosomal compartment in programmed cell death , 2001, Cell Death and Differentiation.

[37]  J. Troncoso,et al.  Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. , 2001, Archives of pathology & laboratory medicine.

[38]  Takeshi Noda,et al.  LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing , 2000, The EMBO journal.

[39]  A. Cuervo,et al.  Age-related Decline in Chaperone-mediated Autophagy* , 2000, The Journal of Biological Chemistry.

[40]  P. Mathews,et al.  The Endosomal-Lysosomal System of Neurons in Alzheimer's Disease Pathogenesis: A Review , 2000, Neurochemical Research.

[41]  J. Wegiel,et al.  Microglial cells are the driving force in fibrillar plaque formation, whereas astrocytes are a leading factor in plaque degradation , 2000, Acta Neuropathologica.

[42]  M. Citron,et al.  Aβ-Generating Enzymes Recent Advances in β- and γ-Secretase Research , 2000, Neuron.

[43]  S. Gandy,et al.  Mutant Presenilin 1 Increases the Levels of Alzheimer Amyloid β‐Peptide Aβ42 in Late Compartments of the Constitutive Secretory Pathway , 2000 .

[44]  P. Codogno,et al.  Distinct Classes of Phosphatidylinositol 3′-Kinases Are Involved in Signaling Pathways That Control Macroautophagy in HT-29 Cells* , 2000, The Journal of Biological Chemistry.

[45]  J. Growdon,et al.  Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease. , 1999, Journal of neuropathology and experimental neurology.

[46]  J. Avruch,et al.  Regulation of Translational Effectors by Amino Acid and Mammalian Target of Rapamycin Signaling Pathways , 1999, The Journal of Biological Chemistry.

[47]  W. Engel,et al.  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. , 1998, The American journal of pathology.

[48]  Takeshi Noda,et al.  Tor, a Phosphatidylinositol Kinase Homologue, Controls Autophagy in Yeast* , 1998, The Journal of Biological Chemistry.

[49]  C. Masters,et al.  Alzheimer's disease‐associated presenilin 1 in neuronal cells: Evidence for localization to the endoplasmic reticulum‐Golgi intermediate compartment , 1997, Journal of neuroscience research.

[50]  J. Hardy,et al.  Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1 , 1996, Nature.

[51]  C. Overly,et al.  Dynamic Organization of Endocytic Pathways in Axons of Cultured Sympathetic Neurons , 1996, The Journal of Neuroscience.

[52]  D. Mann,et al.  Colocalization of Lysosomal Hydrolase and β-Amyloid in Diffuse Plaques of the Cerebellum and Striatum in Alzheimer's Disease and Down's Syndrome , 1996, Journal of neuropathology and experimental neurology.

[53]  C. Clark,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1994, Neurology.

[54]  T. Deerinck,et al.  Re‐Evaluation of the Structural Organization of Neuritic Plaques in Alzheimer's Disease , 1993 .

[55]  P. Hollenbeck.  Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport , 1993, The Journal of cell biology.

[56]  S. Mirra,et al.  Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists. , 1993, Archives of pathology & laboratory medicine.

[57]  S. M. Sumi,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1991, Neurology.

[58]  W. Dunn.  Studies on the mechanisms of autophagy: maturation of the autophagic vacuole , 1990, The Journal of cell biology.

[59]  W. Dunn,et al.  Studies on the mechanisms of autophagy: formation of the autophagic vacuole , 1990, The Journal of cell biology.

[60]  P. Seglen,et al.  Prelysosomal convergence of autophagic and endocytic pathways. , 1988, Biochemical and biophysical research communications.

[61]  P. Seglen,et al.  Amino acid control of autophagic sequestration and protein degradation in isolated rat hepatocytes , 1984, The Journal of cell biology.

[62]  H. Glaumann,et al.  Isolation of autophagic vacuoles from rat liver: morphological and biochemical characterization , 1982, The Journal of cell biology.

[63]  C. Schworer,et al.  Induction of autophagy by amino-acid deprivation in perfused rat liver , 1977, Nature.

[64]  R. Terry,et al.  Fine structural localization of acid phosphatase in senile plaques in Alzheimer's presenile dementia , 1967, Acta Neuropathologica.

[65]  J. Trojanowski,et al.  Protein accumulation in traumatic brain injury , 2007, NeuroMolecular Medicine.

[66]  J. Luzio,et al.  Membrane traffic to and from lysosomes. , 2005, Biochemical Society symposium.

[67]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[68]  P. Clarke,et al.  Developmental cell death: morphological diversity and multiple mechanisms , 2004, Anatomy and Embryology.

[69]  J. Regula,et al.  Reconstitution of gamma-secretase activity. , 2003, Nature cell biology.

[70]  B. Winblad,et al.  Partial purification and characterization of gamma-secretase from post-mortem human brain. , 2003, The Journal of biological chemistry.

[71]  P. Mathews,et al.  The neuronal endosomal-lysosomal system in Alzheimer's disease. , 2001, Journal of Alzheimer's disease : JAD.

[72]  J. Wegiel,et al.  Microglia cells are the driving force in fibrillar plaque formation, whereas astrocytes are a leading factor in plague degradation. , 2000, Acta neuropathologica.

[73]  S. Gandy,et al.  Mutant presenilin 1 increases the levels of Alzheimer amyloid beta-peptide Abeta42 in late compartments of the constitutive secretory pathway. , 2000, Journal of neurochemistry.

[74]  John X. Morris,et al.  The diagnosis of Alzheimer's disease. , 1999, Journal of Alzheimer's disease : JAD.

[75]  J. Hardy,et al.  Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes , 1998, Nature Medicine.

[76]  P. Seglen,et al.  Structural aspects of autophagy. , 1996, Advances in experimental medicine and biology.

[77]  H. Elsässer,et al.  Monodansylcadaverine (MDC) is a specific in vivo marker for autophagic vacuoles. , 1995, European journal of cell biology.

[78]  P. Seglen,et al.  Use of [3H]raffinose as a specific probe of autophagic sequestration. , 1986, Experimental cell research.