Amyloid , Amyloid Precursor Proteins and Alzheimer’s

1. Amyloid, Amyloid Precursor Proteins and Alzheimer’s By: Jessica Sawyer, DaniellaSantaera and Christina Mai November 9, 2012 PHM142 Fall 2012 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. What is an Amyloid Precursor Protein? • Chromosome 21 • Integral protein in tissues • Mostly central nervous system • Concentrated in the synapses of neurons • Function is not known • Accumulation of APP lead to Alzheimer’s

3. Amyloid Precursor Protein Proteolysis • APP metabolized in two pathways: • nonamyloidogenic • amyloidogenic

4. Normal Non-amyloidogenic Pathway • APP cleaved by γ-secretase • releases soluble N terminal fragments and C terminal fragments • APP further cleaved by α secretase • releases C-terminal fragment of 3KDa • α secretase cleavage occurs within Aβ peptide • does not produce full length Aβ peptide

5. Amyloidogenic Pathway • APP gene mutation: β secretase cleaves APP • N-terminal fragment and C-terminal are released • Further cleavage by γ-secretase • Forms full length β-amyloid peptides

6. β-Amyloid Synthesis Pathway

7. β-Amyloid Synthesis Pathway

8. β -Amyloid • Many Aβ peptides • Aβ40 and Aβ42 most abundant in the brain • Aβ42 most toxic • Interacts with neurons and glial cells • Core are resistant to degradation • peptides released as monomers • Monomers eventually aggregate into fibrils • Mature into plaques • Plaques cause neuronal death

9. What is Cholesterol? • GENERAL PROPERTIES • - waxy, fat-like substances • - travels in the blood by carrier proteins: lipoproteins • - 2 main types of lipoproteins: • - LDL (low density lipoproteins) also known as “bad” cholesterol • - HDL (high density lipoproteins) also known as “good” cholesterol • ROLE OF CHOLESTEROL IN THE BODY: • - membrane permeability and fluidity • - synthesis of steroids, hormones, bile and vitamin D • ABNORMAL CHOLESTEROL LEVELS • - can lead to hypercholesterolemia • - recent attention towards cholesterol and Alzheimer’s Disease

10. Cholesterol and Alzheimer’s Disease • GENERAL PROPERTIES • - cholesterol affects APP processing and amyloid protein aggregation in 3 ways: • - genetically (late onset Alzheimer’s Disease) • - biochemically • - metabolically • APOE GENE (Apolipoprotein) • - located on chromosome 19 • - 4 variants: APOEε1, APOEε2, APOEε3, APOEε4 • - 95% of individuals with late onset AD have the 4th variant of the gene • - gene contains instructions for the production of the apoE lipoprotein: major cholesterol carrier • EXPERIMENTAL EVIDENCE?

11. How Does apoE facilitate amyloid protein internalization? apoE FACILITATES AMYLOID PROTEIN BRAIN INTERNALIZATION AND AGGREGATION: - 2 models: - soluble amyloid protein interacts with an apoE associated lipoprotein and undergoes receptor mediated endocytosis - apoE up-regulates the rate of amyloid protein production through increasing intracellular cholesterol

12. What is Alzheimer’s Disease? • Degenerative disorder of the CNS • Dementia characterized by memory dysfunction • Prevalence of AD increases with age • Cognitive symptoms • Memory loss, disorientation • Non cognitive symptoms • Depression, aggression, wandering • Decreases cholinergic receptors • Memory impairment

13. What is the mechanism of AD? • Brain tissue contains amyloid plaques surrounded by dead and dying neurons • Amyloid plaques are amyloid beta protein, a fragment of amyloid beta precursor protein • The amyloid beta protein is cleaved from the APP and accumulates in brain as amyloid plaques

14. Visualization of AD

15. How is AD caused? • A mutation in amyloid precursor protein • Follows the amyloidogenic pathway • Homozygous ε4 for the APO gene • Increase of accumulation of amyloid beta protein • Cholinergic dysfunction • APO transports cholesterol, ε4 VLDL = more cholesterol • ε4, ε4 leads to more cholesterol in brain • Cholesterol accumulates in the plaques

16. Treatment for AD • No treatment • Goal: to treat psychiatric and behavioral symptoms • Anticholinesterases: • Rivastigmine – reversibly inhibits AChE& butylcholinesterases • Donepezil – inhibits AChE reversibly • Galantamine– reversible inhibition of AChE and enhances Ach action • Statins: • May protect against AD by decreasing cholesterol levels

17. Summary • APP metabolized in two pathways: • Nonamyloidogenic – cleaved by α & γsecretase; does not β-amyloid peptide • Amyloidogenic – cleaved by β & γsecretase; produces β-amyloid peptide • gene contains instructions for the production of apoE lipoprotein: major cholesterol carrier • apoE facilitates amyloid protein internalization and aggregation via two possible models: • soluble amyloid protein interacts with an apoE associated lipoprotein and undergoes receptor mediated endocytosis • apoE up-regulates the rate of amyloid protein production through increasing intracellular cholesterol • AD is a degenerative disorder due to accumulation of amyloid beta protein plaques in brain tissue leading to neuronal dysfunction • Caused by a mutation in amyloid precursor protein or homozygous ε4 for the APO gene • Anticholinesterases used include: Galantamine, Rivastigmine, Donepezil • Statins used to decrease cholesterol

18. References • Bales, K.R., Verina, T., Dodel, R.C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnston, E.M., Little, S.P., Cummins, D.J., Piccardo, P., Ghetti, B., & Paul, S.M. (1997) Nature Genetics, 17(3). 263-264. • Ballard, C., Gauthier, S., Corbertt, A., Brayne, C., Aarsland, D., & Jones, E. (2011). Alzheimer’s Disease. Lancet, 377. 1019-1031. • Brunton, L., Chabner, B., & Knollman, B. (2011). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition. Toronto: McGraw Hill. 619-622. • Checler, F. (1995) Short review: processing β-amyloid precursor protein and its regulation in Alzheimer’s disease. Journal of Neurochemistry, 65(4). 1432-1444. • Dipiro, J.T., Talbert, R.L., Yee, G.C., Matzke, G.R., Wells, B.G., & Posey, L.M. (2011). Pharmacotherapy: A pathophysiologic Approach, 8th edition. Toronto: McGraw Hill. • Nelson, T.J., & Alkon, D.L. (2005) Oxidation of cholesterol by amyloid precursor protein and β-amyloid peptide. Journal of Biological Chemistry, 280(8). 7377-7387 • Paula, V.J.R., Guimaraes, F.M., Diniz, B.S., & Forlenza, O.V.(2009) Neurobiological pathways to Alzheimer’s disease amyloid-beta, tau protein or both? Dimentia & Neuropsychologia, 3(3). 188-194 • Priller, C., Bauer, T., Mitteregger, G., Krebs, B., Kretzschmar, H.A., & Herms, J. (2006). Journal of Neuroscience, 26(27). 7212-7221. • Puglielli, L. Tanzi, R., & Kovacs, D. (2003). Alzheimer’s disease: the cholesterol connection. Nature Neuroscience, 6(4). 345-351. • Selkoe, D.J. (1994) Normal and abnormal biology of the β-amyloid precursor protein. Annual Review Neuroscience, 17. 489-517. • Voet, D., Voet, J.D., & Pratt, C.W. (2008). Fundamentals of Biochemistry: Life at the Molecular Level. New Jersey: John Wiley & Sons, Inc. pg. 169.