1 / 30

Beta Amyloid and Nitric Oxide : Putative Links

Beta Amyloid and Nitric Oxide : Putative Links. Umesh Chaudhary. Contents. Introduction. Nitric oxide and neurological functioning. Molecular basis of Alzheimer’s disease. B-Amyloid stimulation of iNOS : TNF alpha and NF-kB dependent iNOS expression.

onofre
Download Presentation

Beta Amyloid and Nitric Oxide : Putative Links

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Beta Amyloid and Nitric Oxide : Putative Links Umesh Chaudhary

  2. Contents • Introduction • Nitric oxide and neurological functioning • Molecular basis of Alzheimer’s disease • B-Amyloid stimulation of iNOS : • TNF alpha and NF-kB dependent iNOS expression. • Current prospects in Alzheimer therapy

  3. Nitric Oxide A class of inter- and intra-cellular messenger molecules • Small molecular weight, Highly diffusible, Gaseous, Highly reactive stable free radical • Second messenger role requires • low concentrations of NO (<2mM) • occurs usually via guanylate cyclase. • Cytotoxic effects due to a combination of • Elevated concentration (>10mM) • Formation of highly reactive peroxynitrite

  4. Chemistry of Indirect Effects Direct Effects of Nitric Oxide Free Radical Biology & Medicine, Vol. 25, Nos. 4/5, pp. 434–456, 1998

  5. Properties of NOS Isozymes

  6. Nitric Oxide Biosynthesis Overall reaction Catalyzed and cofactors of NOS Biochem. J. (2001) 357, 593-615

  7. Nitric Oxide and Nervous System • Extensive distribution of NOS positive neuron • Role in long term potentiation • Learning and Memory • Pain perception • Neuromodulatory functions • Host defense against pathogens • Neurotoxicity

  8. Alzheimer’s Disease • Epidemiology • Most common Neurodegenerative disorder & dementia • Currently affecting nearly 5 million individuals in USA alone. • Symptoms • Progressive cognitive decline affecting memory, learning, emotions and behaviour • Pathology • Neurofibrillary Tangles, Senile Plaques and Synapse Loss • Mutation in one of the genes that codes for three transmembrane proteins-APP, PS1 and PS2 • APOe4 allele is higher 3

  9. Neuropathological Hallmarks

  10. VARADARAJAN ET AL. Journal of Structural Biology 130, 184–208 (2000) Central Role of Amyloid b in Neurotoxicity

  11. VARADARAJAN ET AL. Journal of Structural Biology 130, 184–208 (2000) Amyloid Precursor Protein Processing • APP is 770AA Transmembrane protein, Gene located on Chromosome 21 • Cleavage by a,b and g Secretase yields Amyloid b ( 1-40, 42) • Conversion of soluble forms to insoluble fibrils accounts for its toxicity • Amyloid b binding to RAGE leads to formation of plaque • Amyloid can directly produce Hydrogen peroxide through metal ion reduction

  12. Mutations in Presenilin genes • Presenilin 1 (PS1) on chromo 14 encodes 467 residue polypeptide & Presenilin 2 (PS2) on chromo 1 encodes for 448 residue polypeptide • PS1 and PS2 are found in nuclear membrane ,ER and Golgi body • Necessary for Neurogenesis and Neuronal survival • 50 mutations of PS1 and 2 mutations of PS2 found in AD families Apolipoprotein E • A plasma protein Involved in transport and metabolism of triglyceride and cholesterol • e2, e3 and e4 allelic variants • ApoE e4 allelic variant is high and linked with Alzheimer All mutations enhances production of Fibrillar A b 42 and Tau Hyper-phosphorylation leading to NFT’s

  13. p p p p p p p p p P sites -C N- Microtubule binding domain (MBD) Neurofibrillary Tangles • Intra neuronal lesions in degenerating neurones • Composed of hyper-phosphorylated tau-protein organised in paired helical filaments Tau is a soluble, microtubule-associated phospho-protein involved in neuronal stabilisation • In AD Tau becomes hyper-phosphorylated

  14. NO Neurotoxicity and Neuroprotection in AD Law et al . / Brain Research Reviews 35 (2001) 73– 96

  15. b -Amyloid Stimulation of Inducible Nitric-oxide Synthase in Astrocytes Is Interleukin-1b- and Tumor Necrosis Factor-a (TNFa)-dependent, and Involves a TNFa Receptor-associated Factor- and NFkB-inducing Kinase-dependent Signaling Mechanism (Keith T. Akama and Linda J. Van Eldik) From the ‡Department of Cell and Molecular Biology and §Northwestern Drug Discovery Program, NorthwesternUniversity Medical School, Chicago, Illinois 60611 The Journal of Biological Chemistry, Vol-275. No. 11, March 17, pp –7918-7924

  16. A- b stimulated Cytokine production occurs before iNOS Production

  17. Protein synthesis inhibitor blocks A b stimulated iNOS mRNA levels

  18. IL-1 b Receptor antagonist Decreases the levels of Amyloid b-stimulated i-NOS and Nitrite Production

  19. Dominant Negative TRAF Proteins can Block NF-kB Activation in Astrocytes

  20. Dominant Negative TRAF6 Inhibits iNOS Promoter Activation by A b 42

  21. IL-1 b Localizes to Microglia and iNOS Localizes to Astrocytes in A b 42 Stimulated Glial Cultures

  22. SUMMARY • Amyloid b activates Microglia to produce Pro-Inflammatory Cytokines such as IL-1 b and TNF- a • These Cytokines in turn activate surrounding Astrocytes, which exacerbate the inflammation with the production of Neurotoxic Mediators such as iNOS. • The resultant NO and Peroxynitrite ultimately damages local neurons and contributes to the Neurodegeneration observed in AD

  23. Evidence for NF-kB and Cytokine dependent iNOS induction

  24. Other Signaling Cascade Activated by Amyloid b

  25. Binding to Neurotrophin receptor leads to Apoptotic cell death • Induction of Transcription of c-JUN mRNA and stimulates JUN Amino Terminal Kinase

  26. Neuroscience Letters 312 (2001) 177–179

  27. Amyloid can Directly activate Caspase 3 and induce Apoptosis in Neurons Science Vol 293, 21 September 2001 P- 2192-94

  28. Potential Novel Therapeutic Approach Focusing on b -Amyloid plaques • Enhance alpha-Secretase activity or inhibit beta or gamma-Secretase activity • Correcting APP or presenilin mutations • Antioxidants such as Vitamin E and Extracts from roots of Ginko biloba • Oestrogen modulate APP processing and reduce Amyloid- b 42 • Vaccination with Amyloid Beta • Focusing on Apolipoprotein E • Replace ApoE e4 alleles with e2/3 alleles • Cholesterol lowering drugs ( Lipitor ) • Tau protein based therapies • Prevent t-protein phosphorylation Gene Therapy - Nerve Growth Factor, Propentophylline 22

  29. Conclusions • Oxidative stress plays a vital role in Alzheimer Pathology • Amyloid-b can initiate a variety of signalling cascades leading to Neuronal cell death in AD • Amyloid-b can stimulate Pro inflammatory cytokines and ultimately contribute to Oxidative and Nitrosative Stress induced cell death and Apoptosis • Further Detailed Studies needed to have a deeper Insight into Signal transduction pathways involved in Alzheimer Disease

  30. Illness in Alzheimer's vaccine study AP [ SUNDAY, FEBRUARY 24, 2002  7:10:41 PM ] TIMES - SUNDAY, FEBRUARY 24, 2002   Twelve Alzheimer's patients injected with an experimental vaccine are suffering serious brain inflammation. The vaccine's manufacturer halted the experiment last month when it discovered that the first four patients, all from France, were suffering the encephalitis-like reaction. Since then, doctors have discovered eight more people with the apparent side effect, which can be hard to distinguish from worsening Alzheimer's.

More Related