Dysregulation of Hypoxia-Inducible Factor by Presenilin/γ-Secretase Loss-of-Function Mutations

Presenilin (PSEN) 1 and 2 are the catalytic components of the γ-secretase complex, which cleaves a variety of proteins, including the amyloid precursor protein (APP). Proteolysis of APP leads to the formation of the APP intracellular domain (AICD) and amyloid β that is crucially involved in the pathogenesis of Alzheimer's disease. Prolyl-4-hydroxylase-domain (PHD) proteins regulate the hypoxia-inducible factors (HIFs), the master regulators of the hypoxic response. We previously identified the FK506 binding protein 38 (FKBP38) as a negative regulator of PHD2. Genetic ablation of PSEN1/2 has been shown to increase FKBP38 protein levels. Therefore, we investigated the role of PSEN1/2 in the oxygen sensing pathway using a variety of genetically modified cell and mouse lines. Increased FKBP38 protein levels and decreased PHD2 protein levels were found in PSEN1/2-deficient mouse embryonic fibroblasts and in the cortex of forebrain-specific PSEN1/2 conditional double knock-out mice. Hypoxic HIF-1α protein accumulation and transcriptional activity were decreased, despite reduced PHD2 protein levels. Proteolytic γ-secretase function of PSEN1/2 was needed for proper HIF activation. Intriguingly, PSEN1/2 mutations identified in Alzheimer patients differentially affected the hypoxic response, involving the generation of AICD. Together, our results suggest a direct role for PSEN in the regulation of the oxygen sensing pathway via the APP/AICD cleavage cascade.

[1]  B. de Strooper,et al.  The mechanism of γ-Secretase dysfunction in familial Alzheimer disease , 2012, The EMBO journal.

[2]  G. Kristiansen,et al.  Synthetic transactivation screening reveals ETV4 as broad coactivator of hypoxia-inducible factor signaling , 2011, Nucleic acids research.

[3]  K. Akassoglou,et al.  Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1α. , 2011, Molecular cell.

[4]  P. Grammas,et al.  Brain microvasculature and hypoxia-related proteins in Alzheimer's disease. , 2011, International journal of clinical and experimental pathology.

[5]  K. Nave,et al.  Expression of constitutively active erythropoietin receptor in pyramidal neurons of cortex and hippocampus boosts higher cognitive functions in mice , 2011, BMC Biology.

[6]  G. Elder,et al.  Presenilin-1 regulates induction of hypoxia inducible factor-1α: altered activation by a mutation associated with familial Alzheimer's disease , 2010, Molecular Neurodegeneration.

[7]  W. Le,et al.  Pathological role of hypoxia in Alzheimer's disease , 2010, Experimental Neurology.

[8]  M. Youdim,et al.  Up-regulation of hypoxia-inducible factor (HIF)-1α and HIF-target genes in cortical neurons by the novel multifunctional iron chelator anti-Alzheimer drug, M30. , 2010, Current Alzheimer research.

[9]  J. Mallm,et al.  Generation of conditional null alleles for APP and APLP2 , 2010, Genesis.

[10]  R. Nitsch,et al.  Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway , 2009, Journal of Cell Science.

[11]  C. Joe,et al.  Notch Signal Activates Hypoxia Pathway through HES1-Dependent SRC/Signal Transducers and Activators of Transcription 3 Pathway , 2009, Molecular Cancer Research.

[12]  M. Dallas,et al.  Hypoxia and Neurodegeneration , 2009, Annals of the New York Academy of Sciences.

[13]  O. Ogunshola,et al.  Contribution of hypoxia to Alzheimer’s disease: is HIF-1α a mediator of neurodegeneration? , 2009, Cellular and Molecular Life Sciences.

[14]  W. Le,et al.  Hypoxia increases Aβ generation by altering β- and γ-cleavage of APP , 2009, Neurobiology of Aging.

[15]  P. Hasgall,et al.  Hypoxia-inducible Factor Prolyl-4-hydroxylase PHD2 Protein Abundance Depends on Integral Membrane Anchoring of FKBP38* , 2009, The Journal of Biological Chemistry.

[16]  K. Plaschke,et al.  VEGF overexpression improves mice cognitive abilities after unilateral common carotid artery occlusion , 2008, Experimental Neurology.

[17]  B. de Strooper,et al.  Presenilins: members of the gamma-secretase quartets, but part-time soloists too. , 2008, Physiology.

[18]  W. Kaelin,et al.  Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. , 2008, Molecular cell.

[19]  Ashley I Bush,et al.  Metals in Alzheimer's and Parkinson's diseases. , 2008, Current opinion in chemical biology.

[20]  J. Pouysségur,et al.  PHDs overactivation during chronic hypoxia “desensitizes” HIFα and protects cells from necrosis , 2008, Proceedings of the National Academy of Sciences.

[21]  W. Ladiges,et al.  Fe65 Stimulates Proteolytic Liberation of the β-Amyloid Precursor Protein Intracellular Domain* , 2007, Journal of Biological Chemistry.

[22]  G. Semenza,et al.  Hypoxia-Inducible Factor 1 (HIF-1) Pathway , 2007, Science's STKE.

[23]  Jiankun Cui,et al.  Hypoxia-inducible Factor 1 (HIF-1 )-mediated Hypoxia Increases BACE1 Expression and -Amyloid Generation* , 2007 .

[24]  P. Hasgall,et al.  The Peptidyl Prolyl cis/trans Isomerase FKBP38 Determines Hypoxia-Inducible Transcription Factor Prolyl-4-Hydroxylase PHD2 Protein Stability , 2007, Molecular and Cellular Biology.

[25]  D. Curtis,et al.  Presenilin diversifies its portfolio. , 2007, Trends in genetics : TIG.

[26]  R. J. Kelleher,et al.  The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism , 2007, Proceedings of the National Academy of Sciences.

[27]  Hong Qing,et al.  Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression , 2006, Proceedings of the National Academy of Sciences.

[28]  Roland H Wenger,et al.  Increased Prolyl 4-Hydroxylase Domain Proteins Compensate for Decreased Oxygen Levels , 2006, Journal of Biological Chemistry.

[29]  B. Strooper,et al.  Presenilin clinical mutations can affect γ‐secretase activity by different mechanisms , 2006, Journal of neurochemistry.

[30]  U. Lendahl,et al.  Hypoxia requires notch signaling to maintain the undifferentiated cell state. , 2005, Developmental cell.

[31]  G. Camenisch,et al.  Integration of Oxygen Signaling at the Consensus HRE , 2005, Science's STKE.

[32]  M. Youdim,et al.  Novel multifunctional neuroprotective iron chelator‐monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition , 2005, Journal of neurochemistry.

[33]  W. Gan,et al.  Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2 , 2005, Neuroscience Letters.

[34]  G. Fischer,et al.  Bcl‐2 regulator FKBP38 is activated by Ca2+/calmodulin , 2005, The EMBO journal.

[35]  T. Kudo,et al.  Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2. , 2005, Human molecular genetics.

[36]  G. Camenisch,et al.  Copper-dependent activation of hypoxia-inducible factor ( HIF ) – 1 : implications for ceruloplasmin regulation , 2005 .

[37]  P. S. St George-Hyslop,et al.  Potential roles for presenilin-1 in oxygen sensing and in glial-specific gene expression , 2004, Neuroreport.

[38]  R. Nitsch,et al.  The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor , 2004, Journal of Cell Science.

[39]  P. Doraiswamy,et al.  Metals in our minds: therapeutic implications for neurodegenerative disorders , 2004, The Lancet Neurology.

[40]  D. Bowtell,et al.  Siah2 Regulates Stability of Prolyl-Hydroxylases, Controls HIF1α Abundance, and Modulates Physiological Responses to Hypoxia , 2004, Cell.

[41]  Christopher J. Schofield,et al.  Oxygen sensing by HIF hydroxylases , 2004, Nature Reviews Molecular Cell Biology.

[42]  E. Kandel,et al.  Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration , 2004, Neuron.

[43]  Y. Suh,et al.  C‐terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase‐3β expression , 2003 .

[44]  R. Wenger,et al.  The antimycotic ciclopirox olamine induces HIF‐1α stability, VEGF expression, and angiogenesis , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[45]  B. de Strooper,et al.  γ-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation , 2003, Journal of Cell Science.

[46]  R. Rozmahel,et al.  Differential display analysis of presenilin 1-deficient mouse brains. , 2002, Brain research. Molecular brain research.

[47]  C. Peers,et al.  Altered processing of amyloid precursor protein in the human neuroblastoma SH‐SY5Y by chronic hypoxia , 2002, Journal of neurochemistry.

[48]  R. Rozmahel,et al.  Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[49]  N. Bazan,et al.  Cyclooxygenase-2 and Presenilin-1 Gene Expression Induced by Interleukin-1β and Amyloid β42 Peptide Is Potentiated by Hypoxia in Primary Human Neural Cells* , 2002, The Journal of Biological Chemistry.

[50]  Christopher K. Glass,et al.  Exchange of N-CoR Corepressor and Tip60 Coactivator Complexes Links Gene Expression by NF-κB and β-Amyloid Precursor Protein , 2002, Cell.

[51]  D. Peet,et al.  FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. , 2002, Genes & development.

[52]  G. Semenza,et al.  FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. , 2001 .

[53]  S. McKnight,et al.  A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF , 2001, Science.

[54]  Thomas C. Südhof,et al.  A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60 , 2001, Science.

[55]  Xudong Huang,et al.  Metal Chelation as a Potential Therapy for Alzheimer's Disease , 2000, Annals of the New York Academy of Sciences.

[56]  H. Lipp,et al.  Mice with Combined Gene Knock-Outs Reveal Essential and Partially Redundant Functions of Amyloid Precursor Protein Family Members , 2000, The Journal of Neuroscience.

[57]  M. Gassmann,et al.  Epolones induce erythropoietin expression via hypoxia-inducible factor-1α activation , 2000 .

[58]  H. Vanderstichele,et al.  Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[59]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[60]  D. Selkoe,et al.  Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity , 1999, Nature.

[61]  William J. Ray,et al.  A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain , 1999, Nature.

[62]  M. Gassmann,et al.  Mouse hypoxia-inducible factor-1alpha is encoded by two different mRNA isoforms: expression from a tissue-specific and a housekeeping-type promoter. , 1998, Blood.

[63]  Hugo Vanderstichele,et al.  Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein , 1998, Nature.

[64]  D. Price,et al.  Generation of APLP2 KO Mice and Early Postnatal Lethality in APLP2/APP Double KO Mice , 1997, Neurobiology of Aging.

[65]  G. Perry,et al.  Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[66]  M. Gassmann,et al.  The mouse gene for hypoxia-inducible factor-1alpha--genomic organization, expression and characterization of an alternative first exon and 5' flanking sequence. , 1997, European journal of biochemistry.

[67]  D. Pollen,et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease , 1995, Nature.

[68]  G. Dawson,et al.  β-amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity , 1995, Cell.

[69]  G. Semenza,et al.  Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. , 1993, Blood.

[70]  R. Kalaria,et al.  Accumulation of the beta amyloid precursor protein at sites of ischemic injury in rat brain. , 1993, Neuroreport.

[71]  N. A. Baker.  A galvanic cell suitable for monitoring cortical oxygen in man , 1975, Medical and biological engineering.

[72]  T. Acker,et al.  Prolyl hydroxylases 2 and 3 act in gliomas as protective negative feedback regulators of hypoxia-inducible factors. , 2010, Cancer research.

[73]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[74]  B. Strooper,et al.  Presenilins: members of the gamma-secretase quartets, but part-time soloists too. , 2008, Physiology.