Amyloid-β Triggers the Release of Neuronal Hexokinase 1 from Mitochondria

Brain accumulation of the amyloid-β peptide (Aβ) and oxidative stress underlie neuronal dysfunction and memory loss in Alzheimer's disease (AD). Hexokinase (HK), a key glycolytic enzyme, plays important pro-survival roles, reducing mitochondrial reactive oxygen species (ROS) generation and preventing apoptosis in neurons and other cell types. Brain isozyme HKI is mainly associated with mitochondria and HK release from mitochondria causes a significant decrease in enzyme activity and triggers oxidative damage. We here investigated the relationship between Aβ-induced oxidative stress and HK activity. We found that Aβ triggered HKI detachment from mitochondria decreasing HKI activity in cortical neurons. Aβ oligomers further impair energy metabolism by decreasing neuronal ATP levels. Aβ-induced HKI cellular redistribution was accompanied by excessive ROS generation and neuronal death. 2-deoxyglucose blocked Aβ-induced oxidative stress and neuronal death. Results suggest that Aβ-induced cellular redistribution and inactivation of neuronal HKI play important roles in oxidative stress and neurodegeneration in AD.

[1]  Pierre J. Magistretti,et al.  Neuroenergetics Original Research Article Deciphering Neuron-glia Compartmentalization in Cortical Energy Metabolism , 2022 .

[2]  W. Klein,et al.  Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers , 2009, Proceedings of the National Academy of Sciences.

[3]  J. Díaz-Nido,et al.  Mitochondrial Hexokinase II Promotes Neuronal Survival and Acts Downstream of Glycogen Synthase Kinase-3* , 2009, Journal of Biological Chemistry.

[4]  M. Mattson,et al.  Mitochondria in Neuroplasticity and Neurological Disorders , 2008, Neuron.

[5]  E. Bigio,et al.  Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers , 2008, Neurobiology of Aging.

[6]  N. Inestrosa,et al.  The role of Wnt signaling in neuronal dysfunction in Alzheimer's Disease , 2008, Molecular Neurodegeneration.

[7]  Á. Simonyi,et al.  Amyloid beta peptide and NMDA induce ROS from NADPH oxidase and AA release from cytosolic phospholipase A2 in cortical neurons , 2008, Journal of neurochemistry.

[8]  L. Juliano,et al.  Amyloid-β Binds to the Extracellular Cysteine-rich Domain of Frizzled and Inhibits Wnt/β-Catenin Signaling* , 2008, Journal of Biological Chemistry.

[9]  P. Fernyhough,et al.  Blockade of hexokinase activity and binding to mitochondria inhibits neurite outgrowth in cultured adult rat sensory neurons , 2008, Neuroscience Letters.

[10]  J. Houzel,et al.  Soluble oligomers from a non‐disease related protein mimic Aβ‐induced tau hyperphosphorylation and neurodegeneration , 2007, Journal of neurochemistry.

[11]  W. Klein,et al.  Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine* , 2007, Journal of Biological Chemistry.

[12]  D. Selkoe,et al.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide , 2007, Nature Reviews Molecular Cell Biology.

[13]  S. Ferreira,et al.  Formation of Soluble Oligomers and Amyloid Fibrils with Physical Properties of the Scrapie Isoform of the Prion Protein from the C-terminal Domain of Recombinant Murine Prion Protein mPrP-(121–231)* , 2006, Journal of Biological Chemistry.

[14]  P. Verstreken,et al.  Mitochondria at the Synapse , 2006, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[15]  S. Ferreira,et al.  Activation of GABAA receptors by taurine and muscimol blocks the neurotoxicity of β-amyloid in rat hippocampal and cortical neurons , 2005, Neuropharmacology.

[16]  H. Fromm,et al.  Glucose 6-Phosphate Release of Wild-type and Mutant Human Brain Hexokinases from Mitochondria* , 2005, Journal of Biological Chemistry.

[17]  J. Hoek,et al.  Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. , 2005, Cancer research.

[18]  A. Gliozzi,et al.  β-Amyloid Is Different in Normal Aging and in Alzheimer Disease* , 2005, Journal of Biological Chemistry.

[19]  Benjamin J. Shannon,et al.  Molecular, Structural, and Functional Characterization of Alzheimer's Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory , 2005, The Journal of Neuroscience.

[20]  L. Pellerin.  How astrocytes feed hungry neurons , 2005, Molecular Neurobiology.

[21]  C. Haass,et al.  Shedding and γ-secretase-mediated intramembrane proteolysis of the mucin-type molecule CD43 , 2005 .

[22]  A. Verkhratsky,et al.  Insulin enhances mitochondrial inner membrane potential and increases ATP levels through phosphoinositide 3-kinase in adult sensory neurons , 2005, Molecular and Cellular Neuroscience.

[23]  C. Thompson,et al.  Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. , 2004, Molecular cell.

[24]  Eric Klann,et al.  Reactive oxygen species and synaptic plasticity in the aging hippocampus , 2004, Ageing Research Reviews.

[25]  R. Moreno-Sánchez,et al.  Mitochondrial Bound Hexokinase Activity as a Preventive Antioxidant Defense , 2004, Journal of Biological Chemistry.

[26]  J. D. Figueroa-Villar,et al.  Targeting the neurotoxic species in Alzheimer's disease: inhibitors of Aβ oligomerization , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  M. Mattson.  Pathways towards and away from Alzheimer's disease , 2004, Nature.

[28]  Fahmeed Hyder,et al.  Energetic basis of brain activity: implications for neuroimaging , 2004, Trends in Neurosciences.

[29]  D. Teplow,et al.  Small assemblies of unmodified amyloid β-protein are the proximate neurotoxin in Alzheimer’s disease , 2004, Neurobiology of Aging.

[30]  Thomas Wisniewski,et al.  Amyloid‐β Deposition Is Associated with Decreased Hippocampal Glucose Metabolism and Spatial Memory Impairment in APP/PS1 Mice , 2004 .

[31]  Xi Chen,et al.  Materials and Methods Som Text Figs. S1 and S2 Table S1 References Abad Directly Links A␤ to Mitochondrial Toxicity in Alzheimer's Disease , 2022 .

[32]  V. Shoshan-Barmatz,et al.  In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death. , 2004, The Biochemical journal.

[33]  C. Finch,et al.  Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  John Eric Wilson.  Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function , 2003, Journal of Experimental Biology.

[35]  J. Olzmann,et al.  High glucose‐induced oxidative stress and mitochondrial dysfunction in neurons , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

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

[37]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[38]  David R. Plas,et al.  Growth Factors Can Influence Cell Growth and Survival through Effects on Glucose Metabolism , 2001, Molecular and Cellular Biology.

[39]  R. Lent,et al.  Inhibition of Alzheimer's disease β‐amyloid aggregation, neurotoxicity, and in vivo deposition by nitrophenols: implications for Alzheimer's therapy , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[40]  R. Dringen,et al.  Metabolism and functions of glutathione in brain , 2000, Progress in Neurobiology.

[41]  R. Lent,et al.  Inhibition of Alzheimer's disease beta-amyloid aggregation, neurotoxicity, and in vivo deposition by nitrophenols: implications for Alzheimer's therapy. , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[43]  R J Mark,et al.  Amyloid β-Peptide Impairs Glucose Transport in Hippocampal and Cortical Neurons: Involvement of Membrane Lipid Peroxidation , 1997, The Journal of Neuroscience.

[44]  E. Masliah,et al.  Glycogen synthase kinase 3 alteration in Alzheimer disease is related to neurofibrillary tangle formation. , 1996, Molecular and chemical neuropathology.

[45]  B. Yankner,et al.  Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[46]  M. Mattson,et al.  beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[47]  I. A. Rose,et al.  Mitochondrial hexokinase. Release, rebinding, and location. , 1967, The Journal of biological chemistry.

[48]  Mark A. Smith,et al.  Faculty of 1000 evaluation for Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. , 2012 .

[49]  E. Bigio,et al.  Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. , 2008, Neurobiology of aging.

[50]  S. Ferreira,et al.  Soluble protein oligomers as emerging toxins in alzheimer's and other amyloid diseases , 2007, IUBMB life.

[51]  G. Perry,et al.  Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease. , 2006, Journal of Alzheimer's disease : JAD.

[52]  A. Gliozzi,et al.  beta-amyloid is different in normal aging and in Alzheimer disease. , 2005, The Journal of biological chemistry.

[53]  C. Haass,et al.  Shedding and gamma-secretase-mediated intramembrane proteolysis of the mucin-type molecule CD43. , 2005, The Biochemical journal.

[54]  Thomas Wisniewski,et al.  Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice. , 2004, Journal of neuropathology and experimental neurology.

[55]  Michael D. Abràmoff,et al.  Image processing with ImageJ , 2004 .

[56]  R. Schliebs,et al.  Cortical glucose metabolism is altered in aged transgenic Tg2576 mice that demonstrate Alzheimer plaque pathology , 2003, Journal of Neural Transmission.

[57]  D. Brdiczka,et al.  The Function of Complexes between the Outer Mitochondrial Membrane Pore (vdac) and the Adenine Nucleotide Translocase in Regulation of Energy Metabolism and Apoptosis , 2003 .