Existing users Log In New users Sign up

Functional Amyloids in Alzheimer Disease

DISCOVERIES (ISSN 2359-7232), 2017, October-December issue


Lau A, Bourkas M, Lu YQQ, Ostrowski LA, Weber-Adrian D, Figueiredo C, Arshad H, Shoaei SZS, Morrone CD, Matan-Lithwick S, Abraham KJ, Wang H, Schmitt-Ulms G. Functional Amyloids and their Possible Influence on Alzheimer Disease. Discoveries 2017, Oct-Dec; 5(4): e79. DOI: 10.15190/d.2017.9

Submitted: Aug 09, 2017; Revised: Sept. 29th, 2017; Accepted: Oct. 2nd, 2017; Published: Oct. 16th, 2017;

 GO BACK to 2017, October-December issue


Functional Amyloids and their Possible Influence on Alzheimer Disease

Angus Lau (1, 2), Matthew Bourkas (1, 2), Yang Qing Qin Lu (1), Lauren Anne Ostrowski (1), Danielle Weber-Adrian (1), Carlyn Figueiredo (1), Hamza Arshad (1, 2), Seyedeh Zahra Shams Shoaei (1), Christopher Daniel Morrone (1), Stuart Matan-Lithwick (1), Karan Joshua Abraham (1), Hansen Wang (2,*), Gerold Schmitt-Ulms (1, 2,*) 

(1) Department of Laboratory Medicine & Pathobiology, University of Toronto, Medical Sciences Building, 6th Floor, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.

(2) Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada.

*Corresponding author: Dr. Hansen Wang, PhD and Dr. Gerold Schmitt-Ulms, PhD Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Centre, 6th floor, 60 Leonard Ave, Toronto, M5T 2S8 Ontario, Canada. Phone: (416) 507-6864, Fax: (416) 603-6435, Emails: hansen.wang@utoronto.ca, g.schmittulms@utoronto.ca


Amyloids play critical roles in human diseases but have increasingly been recognized to also exist naturally. Shared physicochemical characteristics of amyloids and of their smaller oligomeric building blocks offer the prospect of molecular interactions and crosstalk amongst these assemblies, including the propensity to mutually influence aggregation. A case in point might be the recent discovery of an interaction between the amyloid β peptide (Aβ) and somatostatin (SST). Whereas Aβ is best known for its role in Alzheimer disease (AD) as the main constituent of amyloid plaques, SST is intermittently stored in amyloid-form in dense core granules before its regulated release into the synaptic cleft. This review was written to introduce to readers a large body of literature that surrounds these two peptides. After introducing general concepts and recent progress related to our understanding of amyloids and their aggregation, the review focuses separately on the biogenesis and interactions of Aβ and SST, before attempting to assess the likelihood of encounters of the two peptides in the brain, and summarizing key observations linking SST to the pathobiology of AD. While the review focuses on Aβ and SST, it is to be anticipated that crosstalk amongst functional and disease-associated amyloids will emerge as a general theme with much broader significance in the etiology of dementias and other amyloidosis.

Access full text of the manuscript here: 


1. Knowles TP, Vendruscolo M, Dobson CM. The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol 2014, 15(6): 384-396.

2. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003, 300(5618): 486-489.

3. Bucciantini M, Calloni G, Chiti F, Formigli L, Nosi D, Dobson CM, et al. Prefibrillar amyloid protein aggregates share common features of cytotoxicity. J Biol Chem 2004, 279(30): 31374-31382.

4. Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984, 120(3): 885-890.

5. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO molecular medicine 2016, 8(6): 595-608.

6. Jarosz-Griffiths HH, Noble E, Rushworth JV, Hooper NM. Amyloid-beta Receptors: The Good, the Bad, and the Prion Protein. J Biol Chem 2016, 291(7): 3174-3183.

7. Mucke L, Selkoe DJ. Neurotoxicity of Amyloid beta-Protein: Synaptic and Network Dysfunction. Cold Spring Harbor Perspect Med 2012, 2(7): a006338.

8. Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 2009, 457(7233): 1128-1132.

9. Stohr J, Condello C, Watts JC, Bloch L, Oehler A, Nick M, et al. Distinct synthetic Abeta prion strains producing different amyloid deposits in bigenic mice. Proc Natl Acad Sci U S A 2014, 111(28): 10329-10334.

10. Fowler DM, Koulov AV, Balch WE, Kelly JW. Functional amyloid--from bacteria to humans. Trends in biochemical sciences 2007, 32(5): 217-224.

11. Maji SK, Perrin MH, Sawaya MR, Jessberger S, Vadodaria K, Rissman RA, et al. Functional amyloids as natural storage of peptide hormones in pituitary secretory granules. Science 2009, 325(5938): 328-332.

12. Wang H, Muiznieks LD, Ghosh P, Williams D, Solarski M, Fang A, et al. Somatostatin binds to the human amyloid beta peptide and favors the formation of distinct oligomers. Elife 2017, 6.

13. Roberts GW, Crow TJ, Polak JM. Location of neuronal tangles in somatostatin neurones in Alzheimer's disease. Nature 1985, 314(6006): 92-94.

14. Beal MF, Mazurek MF, Tran VT, Chattha G, Bird ED, Martin JB. Reduced numbers of somatostatin receptors in the cerebral cortex in Alzheimer's disease. Science 1985, 229(4710): 289-291.

15. Saito T, Iwata N, Tsubuki S, Takaki Y, Takano J, Huang SM, et al. Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat Med 2005, 11(4): 434-439.

16. Vepsalainen S, Helisalmi S, Koivisto AM, Tapaninen T, Hiltunen M, Soininen H. Somatostatin genetic variants modify the risk for Alzheimer's disease among Finnish patients. Journal of neurology 2007, 254(11): 1504-1508.

17. Xue S, Jia L, Jia J. Association between somatostatin gene polymorphisms and sporadic Alzheimer's disease in Chinese population. Neuroscience letters 2009, 465(2): 181-183.

18. Virchow R. Neue Beobachtungen über Amyloid Degeneration. Virchows Arch Pathol Anat Physiol 1857, 11: 188-189.

19. Buxbaum JN, Linke RP. A molecular history of the amyloidoses. J Mol Biol 2012, 421(2-3): 142-159.

20. Cohen AS, Calkins E. Electron microscopic observations on a fibrous component in amyloid of diverse origins. Nature 1959, 183(4669): 1202-1203.

21. Glenner GG, Terry W, Harada M, Isersky C, Page D. Amyloid fibril proteins: proof of homology with immunoglobulin light chains by sequence analyses. Science 1971, 172(3988): 1150-1151.

22. Dobson CM. Protein folding and misfolding. Nature 2003, 426(6968): 884-890.

23. Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI, et al. Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature 2007, 447(7143): 453-457.

24. Petkova AT, Ishii Y, Balbach JJ, Antzutkin ON, Leapman RD, Delaglio F, et al. A structural model for Alzheimer's beta-amyloid fibrils based on experimental constraints from solid state NMR. P Natl Acad Sci USA 2002, 99(26): 16742-16747.

25. Salahuddin P, Fatima MT, Abdelhameed AS, Nusrat S, Khan RH. Structure of amyloid oligomers and their mechanisms of toxicities: Targeting amyloid oligomers using novel therapeutic approaches. Eur J Med Chem 2016, 114: 41-58.

26. Josephs KA, Whitwell JL, Ahmed Z, Shiung MM, Weigand SD, Knopman DS, et al. Beta-amyloid burden is not associated with rates of brain atrophy. Ann Neurol 2008, 63(2): 204-212.

27. Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, et al. Imaging beta-amyloid burden in aging and dementia. Neurology 2007, 68(20): 1718-1725.

28. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol 1999, 46(6): 860-866.

29. Nichols MR, Colvin BA, Hood EA, Paranjape GS, Osborn DC, Terrill-Usery SE. Biophysical comparison of soluble amyloid-beta(1-42) protofibrils, oligomers, and protofilaments. Biochemistry 2015, 54(13): 2193-2204.

30. Lorenzen N, Nielsen SB, Buell AK, Kaspersen JD, Arosio P, Vad BS, et al. The role of stable alpha-synuclein oligomers in the molecular events underlying amyloid formation. J Am Chem Soc 2014, 136(10): 3859-3868.

31. Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 2002, 416(6880): 507-511.

32. Giehm L, Svergun DI, Otzen DE, Vestergaard B. Low-resolution structure of a vesicle disrupting α-synuclein oligomer that accumulates during fibrillation. Proc Natl Acad Sci U S A 2011, 108(8): 3246-3251.

33. Bolognesi B, Kumita JR, Barros TP, Esbjorner EK, Luheshi LM, Crowther DC, et al. ANS binding reveals common features of cytotoxic amyloid species. ACS Chem Biol 2010, 5(8): 735-740.

34. Paslawski W, Andreasen M, Nielsen SB, Lorenzen N, Thomsen K, Kaspersen JD, et al. High stability and cooperative unfolding of alpha-synuclein oligomers. Biochemistry 2014, 53(39): 6252-6263.

35. Mannini B, Mulvihill E, Sgromo C, Cascella R, Khodarahmi R, Ramazzotti M, et al. Toxicity of protein oligomers is rationalized by a function combining size and surface hydrophobicity. ACS Chem Biol 2014, 9(10): 2309-2317.

36. Campioni S, Mannini B, Zampagni M, Pensalfini A, Parrini C, Evangelisti E, et al. A causative link between the structure of aberrant protein oligomers and their toxicity. Nat Chem Biol 2010, 6(2): 140-147.

37. Haass C, Kaether C, Thinakaran G, Sisodia S. Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2012, 2(5): a006270.

38. Furukawa K, Sopher BL, Rydel RE, Begley JG, Pham DG, Martin GM, et al. Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J Neurochem 1996, 67(5): 1882-1896.

39. Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, et al. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 2010, 29(17): 3020-3032.

40. Jorissen E, Prox J, Bernreuther C, Weber S, Schwanbeck R, Serneels L, et al. The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. J Neurosci 2010, 30(14): 4833-4844.

41. Vassar R. BACE1: the beta-secretase enzyme in Alzheimer's disease. Journal of molecular neuroscience : MN 2004, 23(1-2): 105-114.

42. Bohm C, Chen F, Sevalle J, Qamar S, Dodd R, Li Y, et al. Current and future implications of basic and translational research on amyloid-beta peptide production and removal pathways. Mol Cell Neurosci 2015, 66(Pt A): 3-11.

43. Cao X, Sudhof TC. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 2001, 293(5527): 115-120.

44. Parvathy S, Hussain I, Karran EH, Turner AJ, Hooper NM. Cleavage of Alzheimer's amyloid precursor protein by alpha-secretase occurs at the surface of neuronal cells. Biochemistry 1999, 38(30): 9728-9734.

45. Lai A, Sisodia SS, Trowbridge IS. Characterization of sorting signals in the beta-amyloid precursor protein cytoplasmic domain. J Biol Chem 1995, 270(8): 3565-3573.

46. Kinoshita A, Fukumoto H, Shah T, Whelan CM, Irizarry MC, Hyman BT. Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes. J Cell Sci 2003, 116(Pt 16): 3339-3346.

47. Dries DR, Yu G. Assembly, maturation, and trafficking of the gamma-secretase complex in Alzheimer's disease. Curr Alzheimer Res 2008, 5(2): 132-146.

48. Toh WH, Gleeson PA. Dysregulation of intracellular trafficking and endosomal sorting in Alzheimer's disease: controversies and unanswered questions. Biochem J 2016, 473(14): 1977-1993.

49. Das U, Wang L, Ganguly A, Saikia JM, Wagner SL, Koo EH, et al. Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway. Nature neuroscience 2016, 19(1): 55-64.

50. Hook VY, Toneff T, Aaron W, Yasothornsrikul S, Bundey R, Reisine T. Beta-amyloid peptide in regulated secretory vesicles of chromaffin cells: evidence for multiple cysteine proteolytic activities in distinct pathways for beta-secretase activity in chromaffin vesicles. J Neurochem 2002, 81(2): 237-256.

51. Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, et al. Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A 2006, 103(30): 11172-11177.

52. Nilsson P, Saido TC. Dual roles for autophagy: degradation and secretion of Alzheimer's disease Abeta peptide. Bioessays 2014, 36(6): 570-578.

53. Bibl M, Gallus M, Welge V, Lehmann S, Sparbier K, Esselmann H, et al. Characterization of cerebrospinal fluid aminoterminally truncated and oxidized amyloid-beta peptides. Proteomics Clin Appl 2012, 6(3-4): 163-169.

54. Pauwels K, Williams TL, Morris KL, Jonckheere W, Vandersteen A, Kelly G, et al. Structural basis for increased toxicity of pathological abeta42:abeta40 ratios in Alzheimer disease. J Biol Chem 2012, 287(8): 5650-5660.

55. Ahmed M, Davis J, Aucoin D, Sato T, Ahuja S, Aimoto S, et al. Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils. Nat Struct Mol Biol 2010, 17(5): 561-567.

56. Acx H, Chavez-Gutierrez L, Serneels L, Lismont S, Benurwar M, Elad N, et al. Signature amyloid beta profiles are produced by different gamma-secretase complexes. J Biol Chem 2014, 289(7): 4346-4355.

57. Kummer MP, Heneka MT. Truncated and modified amyloid-beta species. Alzheimer's research & therapy 2014, 6(3): 28.

58. Kumar S, Rezaei-Ghaleh N, Terwel D, Thal DR, Richard M, Hoch M, et al. Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease. EMBO J 2011, 30(11): 2255-2265.

59. Sullivan CP, Berg EA, Elliott-Bryant R, Fishman JB, McKee AC, Morin PJ, et al. Pyroglutamate-Abeta 3 and 11 colocalize in amyloid plaques in Alzheimer's disease cerebral cortex with pyroglutamate-Abeta 11 forming the central core. Neuroscience letters 2011, 505(2): 109-112.

60. Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science 1992, 256(5054): 184-185.

61. Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 1991, 353(6347): 844-846.

62. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995, 375(6534): 754-760.

63. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 1995, 376(6543): 775-778.

64. Karran E, De Strooper B. The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem 2016, 139 Suppl 2: 237-252.

65. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 2012, 488(7409): 96-99.

66. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011, 7(3): 280-292.

67. Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 2001, 293(5534): 1491-1495.

68. Armstrong RA. A critical analysis of the 'amyloid cascade hypothesis'. Folia neuropathologica 2014, 52(3): 211-225.

69. Bieschke J, Herbst M, Wiglenda T, Friedrich RP, Boeddrich A, Schiele F, et al. Small-molecule conversion of toxic oligomers to nontoxic beta-sheet-rich amyloid fibrils. Nat Chem Biol 2011, 8(1): 93-101.

70. Kayed R, Lasagna-Reeves CA. Molecular mechanisms of amyloid oligomers toxicity. J Alzheimers Dis 2013, 33 Suppl 1: S67-78.

71. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 1998, 95(11): 6448-6453.

72. Drews A, Flint J, Shivji N, Jönsson P, Wirthensohn D, De Genst E, et al. Individual aggregates of amyloid beta induce temporary calcium influx through the cell membrane of neuronal cells. Scientific Reports 2016, 6: 31910.

73. Kayed R, Head E, Sarsoza F, Saing T, Cotman CW, Necula M, et al. Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Molecular Neurodegeneration 2007, 2: 18.

74. Reed MN, Hofmeister JJ, Jungbauer L, Welzel AT, Yu C, Sherman MA, et al. Cognitive effects of cell-derived and synthetically-derived Aβ oligomers. Neurobiology of aging 2011, 32(10): 1784-1794.

75. Benilova I, Karran E, De Strooper B. The toxic Abeta oligomer and Alzheimer's disease: an emperor in need of clothes. Nature neuroscience 2012, 15(3): 349-357.

76. Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A 2011, 108(14): 5819-5824.

77. Glabe CG. Structural classification of toxic amyloid oligomers. J Biol Chem 2008, 283(44): 29639-29643.

78. Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB. Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways. Proc Natl Acad Sci U S A 2003, 100(1): 330-335.

79. Wolff M, Unuchek D, Zhang B, Gordeliy V, Willbold D, Nagel-Steger L. Amyloid β Oligomeric Species Present in the Lag Phase of Amyloid Formation. PLoS One 2015, 10(5).

80. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 2008, 14(8): 837-842.

81. Sandberg A, Luheshi LM, Sollvander S, Pereira de Barros T, Macao B, Knowles TP, et al. Stabilization of neurotoxic Alzheimer amyloid-beta oligomers by protein engineering. Proc Natl Acad Sci U S A 2010, 107(35): 15595-15600.

82. Narayan P, Orte A, Clarke RW, Bolognesi B, Hook S, Ganzinger KA, et al. The extracellular chaperone clusterin sequesters oligomeric forms of the Aβ(1–40) peptide. Nat Struct Mol Biol 2012, 19(1): 79-83.

83. O'Nuallain B, Freir DB, Nicoll AJ, Risse E, Ferguson N, Herron CE, et al. Aβ dimers rapidly form stable synaptotoxic protofibrils. J Neurosci 2010, 30(43): 14411-14419.

84. Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, et al. Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A 2003, 100(18): 10417-10422.

85. Barghorn S, Nimmrich V, Striebinger A, Krantz C, Keller P, Janson B, et al. Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer's disease. J Neurochem 2005, 95(3): 834-847.

86. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006, 440(7082): 352-357.

87. Larson ME, Lesné SE. Soluble Aβ oligomer production and toxicity. J Neurochem 2012, 120(Suppl 1): 125-139.

88. Lesne SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, et al. Brain amyloid-beta oligomers in ageing and Alzheimer's disease. Brain : a journal of neurology 2013, 136(Pt 5): 1383-1398.

89. Kayed R. Annular Protofibrils Are a Structurally and Functionally Distinct Type of. 2009, 284(7): 4230-4237.

90. Serra-Batiste M, Ninot-Pedrosa M, Bayoumi M, Gairí M, Maglia G, Carulla N. Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments. Proceedings of the National Academy of Sciences 2016, 113(39): 10866-10871.

91. Stromer T, Serpell LC. Structure and morphology of the Alzheimer's amyloid fibril. Microsc Res Tech 2005, 67(3-4): 210-217.

92. Xiao Y, Ma B, McElheny D, Parthasarathy S, Long F, Hoshi M, et al. Abeta(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nat Struct Mol Biol 2015, 22(6): 499-505.

93. Bernstein SL, Dupuis NF, Lazo ND, Wyttenbach T, Condron MM, Bitan G, et al. Amyloid-beta protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease. Nat Chem 2009, 1(4): 326-331.

94. Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nature neuroscience 2005, 8(8): 1051-1058.

95. Cisse M, Halabisky B, Harris J, Devidze N, Dubal DB, Sun B, et al. Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 2011, 469(7328): 47-52.

96. Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A, et al. Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nature neuroscience 2012, 15(9): 1227-1235.

97. Chacon MA, Varela-Nallar L, Inestrosa NC. Frizzled-1 is involved in the neuroprotective effect of Wnt3a against Abeta oligomers. Journal of cellular physiology 2008, 217(1): 215-227.

98. Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, et al. Amyloid beta oligomers induce impairment of neuronal insulin receptors. Faseb j 2008, 22(1): 246-260.

99. Chai GS, Duan DX, Ma RH, Shen JY, Li HL, Ma ZW, et al. Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid beta-peptide in rats. Neuroscience bulletin 2014, 30(6): 923-935.

100. Jung SS, Van Nostrand WE. Humanin rescues human cerebrovascular smooth muscle cells from Abeta-induced toxicity. J Neurochem 2003, 84(2): 266-272.

101. Yuan L, Liu XJ, Han WN, Li QS, Wang ZJ, Wu MN, et al. [Gly14]-Humanin Protects Against Amyloid beta Peptide-Induced Impairment of Spatial Learning and Memory in Rats. Neuroscience bulletin 2016, 32(4): 374-382.

102. Soto C, Kindy MS, Baumann M, Frangione B. Inhibition of Alzheimer's amyloidosis by peptides that prevent beta-sheet conformation. Biochem Biophys Res Commun 1996, 226(3): 672-680.

103. Sigurdsson EM, Permanne B, Soto C, Wisniewski T, Frangione B. In vivo reversal of amyloid-beta lesions in rat brain. J Neuropathol Exp Neurol 2000, 59(1): 11-17.

104. Funke SA, Willbold D. Peptides for therapy and diagnosis of Alzheimer's disease. Current pharmaceutical design 2012, 18(6): 755-767.

105. Chacon MA, Barria MI, Soto C, Inestrosa NC. Beta-sheet breaker peptide prevents Abeta-induced spatial memory impairments with partial reduction of amyloid deposits. Molecular psychiatry 2004, 9(10): 953-961.

106. Permanne B, Adessi C, Saborio GP, Fraga S, Frossard MJ, Van Dorpe J, et al. Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a beta-sheet breaker peptide. Faseb j 2002, 16(8): 860-862.

107. Frydman-Marom A, Rechter M, Shefler I, Bram Y, Shalev DE, Gazit E. Cognitive-performance recovery of Alzheimer's disease model mice by modulation of early soluble amyloidal assemblies. Angewandte Chemie (International ed in English) 2009, 48(11): 1981-1986.

108. Perchiacca JM, Ladiwala AR, Bhattacharya M, Tessier PM. Structure-based design of conformation- and sequence-specific antibodies against amyloid beta. Proc Natl Acad Sci U S A 2012, 109(1): 84-89.

109. Mamikonyan G, Necula M, Mkrtichyan M, Ghochikyan A, Petrushina I, Movsesyan N, et al. Anti-A beta 1-11 antibody binds to different beta-amyloid species, inhibits fibril formation, and disaggregates preformed fibrils but not the most toxic oligomers. J Biol Chem 2007, 282(31): 22376-22386.

110. Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016, 537(7618): 50-56.

111. Palhano FL, Lee J, Grimster NP, Kelly JW. Toward the molecular mechanism(s) by which EGCG treatment remodels mature amyloid fibrils. J Am Chem Soc 2013, 135(20): 7503-7510.

112. McLaurin J, Kierstead ME, Brown ME, Hawkes CA, Lambermon MH, Phinney AL, et al. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med 2006, 12(7): 801-808.

113. Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R. Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils. Science 2005, 307(5707): 262-265.

114. Frost B, Diamond MI. Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 2010, 11(3): 155-159.

115. Nilsson KP, Aslund A, Berg I, Nystrom S, Konradsson P, Herland A, et al. Imaging distinct conformational states of amyloid-beta fibrils in Alzheimer's disease using novel luminescent probes. ACS Chem Biol 2007, 2(8): 553-560.

116. Watts JC, Condello C, Stohr J, Oehler A, Lee J, DeArmond SJ, et al. Serial propagation of distinct strains of Abeta prions from Alzheimer's disease patients. Proc Natl Acad Sci U S A 2014, 111(28): 10323-10328.

117. Fandrich M, Meinhardt J, Grigorieff N. Structural polymorphism of Alzheimer Abeta and other amyloid fibrils. Prion 2009, 3(2): 89-93.

118. Liao L, Cheng D, Wang J, Duong DM, Losik TG, Gearing M, et al. Proteomic characterization of postmortem amyloid plaques isolated by laser capture microdissection. J Biol Chem 2004, 279(35): 37061-37068.

119. Portelius E, Bogdanovic N, Gustavsson MK, Volkmann I, Brinkmalm G, Zetterberg H, et al. Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer's disease. Acta Neuropathol 2010, 120(2): 185-193.

120. Morales R, Moreno-Gonzalez I, Soto C. Cross-seeding of misfolded proteins: implications for etiology and pathogenesis of protein misfolding diseases. PLoS Pathog 2013, 9(9): e1003537.

121. Sarell CJ, Stockley PG, Radford SE. Assessing the causes and consequences of co-polymerization in amyloid formation. Prion 2013, 7(5): 359-368.

122. Ono K, Takahashi R, Ikeda T, Yamada M. Cross-seeding effects of amyloid beta-protein and alpha-synuclein. J Neurochem 2012, 122(5): 883-890.

123. Bakou M, Hille K, Kracklauer M, Spanopoulou A, Frost CV, Malideli E, et al. Key aromatic/hydrophobic amino acids controlling a cross-amyloid peptide interaction versus amyloid self-assembly. J Biol Chem 2017.

124. Moreno-Gonzalez I, Edwards Iii G, Salvadores N, Shahnawaz M, Diaz-Espinoza R, Soto C. Molecular interaction between type 2 diabetes and Alzheimer's disease through cross-seeding of protein misfolding. Molecular psychiatry 2017.

125. Morales R, Estrada LD, Diaz-Espinoza R, Morales-Scheihing D, Jara MC, Castilla J, et al. Molecular cross talk between misfolded proteins in animal models of Alzheimer's and prion diseases. J Neurosci 2010, 30(13): 4528-4535.

126. Guo JP, Arai T, Miklossy J, McGeer PL. Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer's disease. Proc Natl Acad Sci U S A 2006, 103(6): 1953-1958.

127. Styren SD, Hamilton RL, Styren GC, Klunk WE. X-34, a fluorescent derivative of Congo red: a novel histochemical stain for Alzheimer's disease pathology. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 2000, 48(9): 1223-1232.

128. Kinghorn KJ, Crowther DC, Sharp LK, Nerelius C, Davis RL, Chang HT, et al. Neuroserpin binds Abeta and is a neuroprotective component of amyloid plaques in Alzheimer disease. J Biol Chem 2006, 281(39): 29268-29277.

129. Tsigelny IF, Crews L, Desplats P, Shaked GM, Sharikov Y, Mizuno H, et al. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PLoS One 2008, 3(9): e3135.

130. Cukalevski R, Yang X, Meisl G, Weininger U, Bernfur K, Frohm B, et al. The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation. Chemical Science 2015, 6: 4215 –4233.

131. Cecchi C, Stefani M. The amyloid-cell membrane system. The interplay between the biophysical features of oligomers/fibrils and cell membrane defines amyloid toxicity. Biophys Chem 2013, 182: 30-43.

132. Chiti F, Dobson CM. Protein misfolding, functional amyloid, and human disease. Annual review of biochemistry 2006, 75: 333-366.

133. Greenwald J, Riek R. Biology of amyloid: structure, function, and regulation. Structure 2010, 18(10): 1244-1260.

134. Smith JF, Knowles TP, Dobson CM, Macphee CE, Welland ME. Characterization of the nanoscale properties of individual amyloid fibrils. Proc Natl Acad Sci U S A 2006, 103(43): 15806-15811.

135. Si K, Choi YB, White-Grindley E, Majumdar A, Kandel ER. Aplysia CPEB can form prion-like multimers in sensory neurons that contribute to long-term facilitation. Cell 2010, 140(3): 421-435.

136. Miniaci MC, Kim JH, Puthanveettil SV, Si K, Zhu H, Kandel ER, et al. Sustained CPEB-dependent local protein synthesis is required to stabilize synaptic growth for persistence of long-term facilitation in Aplysia. Neuron 2008, 59(6): 1024-1036.

137. Szyk A, Wu Z, Tucker K, Yang D, Lu W, Lubkowski J. Crystal structures of human alpha-defensins HNP4, HD5, and HD6. Protein Sci 2006, 15(12): 2749-2760.

138. Chu H, Pazgier M, Jung G, Nuccio SP, Castillo PA, de Jong MF, et al. Human alpha-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science 2012, 337(6093): 477-481.

139. Chairatana P, Nolan EM. Molecular basis for self-assembly of a human host-defense peptide that entraps bacterial pathogens. J Am Chem Soc 2014, 136(38): 13267-13276.

140. Hou F, Sun L, Zheng H, Skaug B, Jiang QX, Chen ZJ. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 2011, 146(3): 448-461.

141. Fowler DM, Koulov AV, Alory-Jost C, Marks MS, Balch WE, Kelly JW. Functional amyloid formation within mammalian tissue. PLoS biology 2006, 4(1): e6.

142. Kelly RB. Pathways of Protein Secretion in Eukaryotes. Science 1985, 230: 25-32.

143. Burgess TL, Craik CS, Kelly RB. The exocrine protein trypsinogen is targeted into the secretory granules of an endocrine cell line: studies by gene transfer. The Journal of cell biology 1985, 101(2): 639-645.

144. Dannies PS. Concentrating hormones into secretory granules: layers of control. Molecular and cellular endocrinology 2001, 177(1-2): 87-93.

145. Moore HP, Walker MD, Lee F, Kelly RB. Expressing a human proinsulin cDNA in a mouse ACTH-secreting cell. Intracellular storage, proteolytic processing, and secretion on stimulation. Cell 1983, 35(2 Pt 1): 531-538.

146. Audas TE, Audas DE, Jacob MD, Ho JJ, Khacho M, Wang M, et al. Adaptation to Stressors by Systemic Protein Amyloidogenesis. Dev Cell 2016, 39(2): 155-168.

147. Maji SK, Schubert D, Rivier C, Lee S, Rivier JE, Riek R. Amyloid as a depot for the formulation of long-acting drugs. PLoS biology 2008, 6(2): e17.

148. Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol 1999, 20(3): 157-198.

149. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973, 179(4068): 77-79.

150. Pradayrol L, Jornvall H, Mutt V, Ribet A. N-terminally extended somatostatin: the primary structure of somatostatin-28. FEBS Lett 1980, 109(1): 55-58.

151. Kumar U, Grant M. Somatostatin and somatostatin receptors. Results and problems in cell differentiation 2010, 50: 137-184.

152. Goodman RH, Aron DC, Roos BA. Rat pre-prosomatostatin. Structure and processing by microsomal membranes. J Biol Chem 1983, 258(9): 5570-5573.

153. Lepage-Lezin A, Joseph-Bravo P, Devilliers G, Benedetti L, Launay JM, Gomez S, et al. Prosomatostatin is processed in the Golgi apparatus of rat neural cells. J Biol Chem 1991, 266(3): 1679-1688.

154. Xu H, Shields D. Prohormone processing in permeabilized cells: endoproteolytic cleavage of prosomatostatin in the trans-Golgi network. Biochimie 1994, 76(3-4): 257-264.

155. Brakch N, Lazar N, Panchal M, Allemandou F, Boileau G, Cohen P, et al. The somatostatin-28(1-12)-NPAMAP sequence: an essential helical-promoting motif governing prosomatostatin processing at mono- and dibasic sites. Biochemistry 2002, 41(5): 1630-1639.

156. Tooze SA. Biogenesis of secretory granules in the trans-Golgi network of neuroendocrine and endocrine cells. Biochim Biophys Acta 1998, 1404(1-2): 231-244.

157. Mouchantaf R, Kumar U, Sulea T, Patel YC. A conserved alpha-helix at the amino terminus of prosomatostatin serves as a sorting signal for the regulated secretory pathway. J Biol Chem 2001, 276(28): 26308-26316.

158. Sevarino KA, Stork P. Multiple preprosomatostatin sorting signals mediate secretion via discrete cAMP- and tetradecanoylphorbolacetate-responsive pathways. J Biol Chem 1991, 266(28): 18507-18513.

159. van Grondelle W, Iglesias CL, Coll E, Artzner F, Paternostre M, Lacombe F, et al. Spontaneous fibrillation of the native neuropeptide hormone Somatostatin-14. J Struct Biol 2007, 160(2): 211-223.

160. Anoop A, Ranganathan S, Das Dhaked B, Jha NN, Pratihar S, Ghosh S, et al. Elucidating the role of disulfide bond on amyloid formation and fibril reversibility of somatostatin-14: relevance to its storage and secretion. J Biol Chem 2014, 289(24): 16884-16903.

161. Anoop A, Ranganathan S, Das Dhaked B, Jacob RS, Kumar A, Padinhateeri R, et al. Understanding the Mechanism of Somatostatin-14 Amyloid Formation In Vitro. Biophysical Journal 2013, 104(2): 50a.

162. Billova S, Galanopoulou AS, Seidah NG, Qiu X, Kumar U. Immunohistochemical expression and colocalization of somatostatin, carboxypeptidase-E and prohormone convertases 1 and 2 in rat brain. Neuroscience 2007, 147(2): 403-418.

163. Drouva SV, Epelbaum J, Hery M, Tapia-Arancibia L, Laplante E, Kordon C. Ionic channels involved in the LHRH and SRIF release from rat mediobasal hypothalamus. Neuroendocrinology 1981, 32(3): 155-162.

164. Gamse R, Vacarro DE, Gamse G, DePace M, Fox TO, Leeman SE. Release of immunoreactive somatostatin from hypothalamic cells in culture: Inhibition by y-aminobutyric acid. Proc Natl Acad Sci U S A 1980, 77(9): 5552-5556.

165. Epelbaum J. Somatostatin in the central nervous system: physiology and pathological modifications. Progress in neurobiology 1986, 27(1): 63-100.

166. Xu Y, Berelowitz M, Bruno JF. Dexamethasone regulates somatostatin receptor subtype messenger ribonucleic acid expression in rat pituitary GH4C1 cells. Endocrinology 1995, 136(11): 5070-5075.

167. Tallent MK. Somatostatin in the dentate gyrus. Progress in brain research 2007, 163: 265-284.

168. Tuboly G, Vecsei L. Somatostatin and cognitive function in neurodegenerative disorders. Mini Rev Med Chem 2013, 13(1): 34-46.

169. Spier AD, de Lecea L. Cortistatin: a member of the somatostatin neuropeptide family with distinct physiological functions. Brain Res Brain Res Rev 2000, 33(2-3): 228-241.

170. de Lecea L. Cortistatin--functions in the central nervous system. Molecular and cellular endocrinology 2008, 286(1-2): 88-95.

171. de Lecea L, Criado JR, Prospero-Garcia O, Gautvik KM, Schweitzer P, Danielson PE, et al. A cortical neuropeptide with neuronal depressant and sleep-modulating properties. Nature 1996, 381(6579): 242-245.

172. Theodoropoulou M, Stalla GK. Somatostatin receptors: from signaling to clinical practice. Front Neuroendocrinol 2013, 34(3): 228-252.

173. Cordoba-Chacon J, Gahete MD, Pozo-Salas AI, Martinez-Fuentes AJ, de Lecea L, Gracia-Navarro F, et al. Cortistatin is not a somatostatin analogue but stimulates prolactin release and inhibits GH and ACTH in a gender-dependent fashion: potential role of ghrelin. Endocrinology 2011, 152(12): 4800-4812.

174. Deghenghi R, Avallone R, Torsello A, Muccioli G, Ghigo E, Locatelli V. Growth hormone-inhibiting activity of cortistatin in the rat. Journal of endocrinological investigation 2001, 24(11): RC31-33.

175. Epelbaum J, Guillou JL, Gastambide F, Hoyer D, Duron E, Viollet C. Somatostatin, Alzheimer's disease and cognition: an old story coming of age? Progress in neurobiology 2009, 89(2): 153-161.

176. Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C. Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nature reviews Drug discovery 2003, 2(12): 999-1017.

177. Chisholm C, Greenberg GR. Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures. American journal of physiology Endocrinology and metabolism 2002, 283(2): E311-317.

178. Vale W, Rivier J, Ling N, Brown M. Biologic and immunologic activities and applications of somatostatin analogs. Metabolism 1978, 27(9 Suppl 1): 1391-1401.

179. Dong SS, Goddard WA, 3rd, Abrol R. Conformational and Thermodynamic Landscape of GPCR Activation from Theory and Computation. Biophys J 2016, 110(12): 2618-2629.

180. Poll F, Lehmann D, Illing S, Ginj M, Jacobs S, Lupp A, et al. Pasireotide and octreotide stimulate distinct patterns of sst2A somatostatin receptor phosphorylation. Molecular endocrinology 2010, 24(2): 436-446.

181. Liu Q, Bee MS, Schonbrunn A. Site specificity of agonist and second messenger-activated kinases for somatostatin receptor subtype 2A (Sst2A) phosphorylation. Mol Pharmacol 2009, 76(1): 68-80.

182. Schulz S, Lehmann A, Kliewer A, Nagel F. Fine-tuning somatostatin receptor signalling by agonist-selective phosphorylation and dephosphorylation: IUPHAR Review 5. Brit J Pharmacol 2014, 171(7): 1591-1599.

183. Petrich A, Mann A, Kliewer A, Nagel F, Strigli A, Martens JC, et al. Phosphorylation of threonine 333 regulates trafficking of the human sst5 somatostatin receptor. Molecular endocrinology 2013, 27(4): 671-682.

184. Poll F, Doll C, Schulz S. Rapid dephosphorylation of G protein-coupled receptors by protein phosphatase 1beta is required for termination of beta-arrestin-dependent signaling. J Biol Chem 2011, 286(38): 32931-32936.

185. Kliewer A, Schulz S. Differential regulation of somatostatin receptor dephosphorylation by beta-arrestin1 and beta-arrestin2. Naunyn-Schmiedebergs Archives of Pharmacology 2014, 387(3): 263-269.

186. Doll C, Poll F, Peuker K, Loktev A, Gluck L, Schulz S. Deciphering micro-opioid receptor phosphorylation and dephosphorylation in HEK293 cells. Br J Pharmacol 2012, 167(6): 1259-1270.

187. Lehmann A, Kliewer A, Martens JC, Nagel F, Schulz S. Carboxyl-terminal receptor domains control the differential dephosphorylation of somatostatin receptors by protein phosphatase 1 isoforms. PLoS One 2014, 9(3): e91526.

188. Seino S, Shibasaki T. PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiological reviews 2005, 85(4): 1303-1342.

189. Szabo S, Reichlin S. Somatostatin in rat tissues is depleted by cysteamine administration. Endocrinology 1981, 109(6): 2255-2257.

190. McIntosh CH, Bakich V, Bokenfohr K, DiScala-Guenot D, Kwok YN, Brown JC. Cysteamine-induced reduction in gastrointestinal somatostatin: evidence for a region-specific loss in immunoreactivity. Regul Pept 1988, 21(3-4): 205-218.

191. Vecsei L, Horvath Z, Tuka B. Old and new neuroendocrine molecules: somatostatin, cysteamine, pantethine and kynurenine. Ideggyogyaszati szemle 2014, 67(3-4): 107-112.

192. Reichlin S, Bollinger-Gruber JA. Pantethine, a cysteamine precursor, depletes immunoreactive somatostatin and prolactin in the rat. Endocrinology 1985, 117(2): 492-495.

193. Vecsei L, Widerlöv E. Preclinical and clinical studies with cysteamine and pantethine related to the central nervous system. 1990, 14: 835-862.

194. De Lecea L, del Rio, J.A., Criado, J.R., Alcantara, A., Morales, M., Danielson, P.E., et al. . Cortistatin Is Expressed in a Distinct Subset of Cortical Interneurons. J Neurosci 1997, 7(15): 13.

195. Miklossy J, McGeer PL. Common mechanisms involved in Alzheimer's disease and type 2 diabetes: a key role of chronic bacterial infection and inflammation. Aging 2016, 8(4): 575-588.

196. Fawver J, Ghiwot Y, Koola C, Carrera W, Rodriguez-Rivera J, Hernandez C, et al. Islet Amyloid Polypeptide (IAPP): A Second Amyloid in Alzheimer's Disease. Current Alzheimer Research 2014, 11(10): 928-940.

197. Baram M, Atsmon-Raz Y, Ma B, Nussinov R, Miller Y. Amylin-Abeta oligomers at atomic resolution using molecular dynamics simulations: a link between Type 2 diabetes and Alzheimer's disease. Phys Chem Chem Phys 2016, 18(4): 2330-2338.

198. Zhu H, Wang X, Wallack M, Li H, Carreras I, Dedeoglu A, et al. Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease. Molecular psychiatry 2015, 20(2): 252-262.

199. Wang E, Zhu H, Wang X, Gower A, Wallack M, Blusztajn JK, et al. Amylin Treatment Reduces Neuroinflammation and Ameliorates Abnormal Patterns of Gene Expression in the Cerebral Cortex of an Alzheimer's Disease Mouse Model. J Alzheimers Dis 2016.

200. Mitsukawa T, Takemura J, Asai J, Nakazato M, Kangawa K, Matsuo H, et al. Islet amyloid polypeptide response to glucose, insulin, and somatostatin analogue administration. Diabetes 1990, 39(5): 639-642.

201. Inoue K, Hisatomi A, Umeda F, Nawata H. Effects of exogenous somatostatin and insulin on islet amyloid polypeptide (amylin) release from perfused rat pancreas. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 1992, 24(6): 251-253.

202. Uhlén M, Fagerberg, L., Hallstrom, B.M., Lindskog, C., Oksvold, P., Mardinoglu, A., et al. . Proteomics. Tissue-based map of the human proteome. Science 2015, 347(6220): 11.

203. LaFerla FM, Green, K.N., and Oddo, S. Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci 2007, 8: 11.

204. Zheng L, Cedazo-Minguez, A., Hallbeck, M., Jerhammar, F., Marcusson, J., and Terman, A. Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system. Translational Neurodegeneration 2012, 1(1): 19.

205. Stroh T, Sarret, P., Tannenbaum, G.S., and Beaudet, A. Immunohistochemical distribution and subcellular localization of the somatostatin receptor subtype 1 (SST1) in the rat hypothalamus. Neurochem Res 2006, 31: 11.

206. Shukla C, and Bridges, L.R. Regional distribution of tau, beta-amyloid and beta-amyloid precursor protein in the Alzheimer's brain: a quantitative immunolabelling study. Neuroreport 1999, 10(18): 5.

207. Schettini G. Brain somatostatin: Receptor-coupled transducing mechanisms and role in cognitive functions. Pharmacol Res 1991, 23(3): 13.

208. Elde R, Hokfelt, T., Johansson, O., Schultzberg, M., Efendic, S., and Luft, R. . Cellular localization of somatostatin. Metabolism 1977, 27(9): 9.

209. Hellstrom-Lindahl E, Viitanen M, Marutle A. Comparison of Abeta levels in the brain of familial and sporadic Alzheimer's disease. Neurochemistry international 2009, 55(4): 243-252.

210. Bibl M, Mollenhauer, B., Esselmann, H., Lewczuk, P., Klafki, H., Sparbier, K et al. CSF amyloid-b-peptides in Alzheimer’s disease, dementia with Lewy bodies and Parkinson’s disease dementia. Brain Res 2006, 129: 11.

211. Mehta PD, Pirttila, T., Mehta, S.P., Sersen, E.A., Aisen, P.S., and Wisniewski, H.M. Plasma and cerebrospinal fluid levels of Amyloid B proteins 1-40 and 1-42 in Alzheimer disease. Arch Neurol 2000, 57: 6.

212. Hu WT, Watts, K.D., Shaw, L.M., Howell, J.C., Trokamowski, J.Q., Basra, S. et al. CSF beta-amyloid 1-42 – what are we measuring in Alzheimer’s disease? Ann Clin Transl Neurol 2015, 2: 9.

213. Molins A, Catalán, R., Sahuquillo, J., Castellanos, M., Codina, A., and Galard, R. Somatostatin cerebrospinal fluid levels in dementia. Journal of neurology 1991, 238: 3.

214. Molchan SE, Hill, J.L., Martinez, R.A., Lawlor, B.A., Mellow, A.M., Rubinow, D.R., et al. CSF somatostatin in Alzheimer’s disease and major depression: Relationship to hypothalamic-pituitary-adrenal axis and clinical measures. Psychoneuroendocrin 1993, 18: 11.

215. Nakamura T, Shoji, M., Harigaya, Y., Watanabe, M., Hosoda, K., Cheung, T.T., et al. Amyloid beta protein levels in cerebrospinal fluid are elevated in early-onset Alzheimer’s disease. Ann Neurol 1994, 36(6): 9.

216. Patterson BW, Elbert, D.L., Mawuenyega, K.G., Kasten, T., Ovod, V., Ma, S., et al. Age and amyloid effects on human central nervous system amyloid-beta kinetics. Ann Neurol 2015, 78(3): 15.

217. Florio T, Ventra, C., Postiglione, A., and Schettini, G. Age-related alterations of somatostatin gene expression in different rat brain areas. Brain Res 1991, 557: 5.

218. Hayashi M, Yamashita, A., and Shimizu, K. Somatostatin and brain-derived neurotrophic factor mRNA expression in the primate brain: decreased levels of mRNAs during aging. Brain Res 1997, 194(2): 7.

219. Lu T, Pan, Y., Kao, S.Y., Li, C., Kohane, I., Chan, J., and Yanker, B.A. Gene regulation and DNA damage in the ageing human brain. Nature 2004, 429(6994): 9.

220. Davies P, Katzman R, Terry RD. Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer disease and Alzheimer senile dementa. Nature 1980, 288(5788): 279-280.

221. Sekiguchi H, Habuchi C, Iritani S, Arai T, Ozaki N. Expression of neprilysin, somatostatin and the somatostatin sst5 receptor in the hippocampal formation of brains from Alzheimer's disease patients. Psychogeriatrics 2009, 9(3): 132-138.

222. Winsky-Sommerer R, Spier, A.D., Fabre, V., de Lecea, L., and Criado, J.R. . Overexpression of the human beta-amyloid precursor protein downregulates cortistatin mRNA in PDAPP mice. Brain Res 2004, 1023: 6.

223. Wang J, Dickson, D.W., Trojanowski, J.Q., and Lee, V.M. The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's disease from normal and pathologic aging. Experimental neurology 1999, 158: 10.

224. Lin LC, Sibille E. Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target? Frontiers in pharmacology 2013, 4: 110.

225. Houser CR. Do structural changes in GABA neurons give rise to the epileptic state? Advances in experimental medicine and biology 2014, 813: 151-160.

226. Benes FM. The GABA system in schizophrenia: cells, molecules and microcircuitry. Schizophrenia research 2015, 167(1-3): 1-3.

227. Konradi C, Zimmerman EI, Yang CK, Lohmann KM, Gresch P, Pantazopoulos H, et al. Hippocampal interneurons in bipolar disorder. Archives of general psychiatry 2011, 68(4): 340-350.

228. Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, et al. Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 2000, 6(2): 143-150.

229. Hafez D, Huang JY, Huynh AM, Valtierra S, Rockenstein E, Bruno AM, et al. Neprilysin-2 is an important beta-amyloid degrading enzyme. The American journal of pathology 2011, 178(1): 306-312.

230. Rubio A, Perez M, de Lecea L, Avila J. Effect of cortistatin on tau phosphorylation at Ser262 site. Journal of neuroscience research 2008, 86(11): 2462-2475.

231. Drewes G, Ebneth A, Preuss U, Mandelkow EM, Mandelkow E. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 1997, 89(2): 297-308.

232. Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E. Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron 1993, 11(1): 153-163.

233. Armstrong DM, LeRoy S, Shields D, Terry RD. Somatostatin-like immunoreactivity within neuritic plaques. Brain research 1985, 338(1): 71-79.

234. Biancalana M, Koide S. Molecular mechanism of Thioflavin-T binding to amyloid fibrils. Biochim Biophys Acta 2010, 1804(7): 1405-1412.

235. Armstrong DM, Benzing WC, Evans J, Terry RD, Shields D, Hansen LA. Substance P and somatostatin coexist within neuritic plaques: implications for the pathogenesis of Alzheimer's disease. Neuroscience 1989, 31(3): 663-671.

236. Munoz DG. Chromogranin A-like immunoreactive neurites are major constituents of senile plaques. Laboratory investigation; a journal of technical methods and pathology 1991, 64(6): 826-832.

237. Jicha GA, Bowser R, Kazam IG, Davies P. Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. Journal of neuroscience research 1997, 48(2): 128-132.

238. van de Nes JA, Sluiter AA, Pool CW, Kamphorst W, Ravid R, Swaab DF. The monoclonal antibody Alz-50, used to reveal cytoskeletal changes in Alzheimer's disease, also reacts with a large subpopulation of somatostatin neurons in the normal human hypothalamus and adjoining areas. Brain Res 1994, 655(1-2): 97-109.

239. Saiz-Sanchez D, Ubeda-Bañon I, de la Rosa-Prieto C, Argandoña-Palacios L, Garcia-Muñozguren S, Insausti R, et al. Somatostatin, tau, and beta-amyloid within the anterior olfactory nucleus in Alzheimer disease. Experimental neurology 2010, 223(2): 347-350.

240. Saiz-Sanchez D, De la Rosa-Prieto C, Ubeda-Banon I, Martinez-Marcos A. Interneurons, tau and amyloid-beta in the piriform cortex in Alzheimer's disease. Brain structure & function 2015, 220(4): 2011-2025.

241. van de Nes JA, Konermann S, Nafe R, Swaab DF. Beta-protein/A4 deposits are not associated with hyperphosphorylated tau in somatostatin neurons in the hypothalamus of Alzheimer's disease patients. Acta neuropathologica 2006, 111(2): 126-138.

242. Levenga J, Krishnamurthy P, Rajamohamedsait H, Wong H, Franke TF, Cain P, et al. Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments. Acta Neuropathol Commun 2013, 1: 34.

243. Petry FR, Pelletier J, Bretteville A, Morin F, Calon F, Hebert SS, et al. Specificity of anti-tau antibodies when analyzing mice models of Alzheimer's disease: problems and solutions. PLoS One 2014, 9(5): e94251.

244. Martel G, Dutar P, Epelbaum J, Viollet C. Somatostatinergic systems: an update on brain functions in normal and pathological aging. Frontiers in Endocrinology 2012, 3: 1-15.

News & Events Latest news from Discoveries

  • 2018 | For Authors!

    PMC highlighted that a high proportion of authors of Discoveries articles are also members of our Editorial Board. As a result, from now on and for at least 1 year, we will only accept articles from authors that are NOT members of Discoveries' Editorial Board. All articles submitted by our members will be immediately rejected until further notice (one accepted article was already rejected). 

  • 2017-2018 | PubMed inclusion News!

    Discoveries successfully passed the Scientific Quality Review by NLM-NIH for PubMedCentral and PubMed indexing. This is the first and the most important step towards PubMedCentral and PubMed indexing! The second (last) step is the Technical Review.

  • April 2016 | Faster Peer-Review

    Starting on April 13th 2016, all articles selected for a peer-review will receive the post peer-review decision within 10 days. The initial pre-screening time will remain the same (48h from the submission of the manuscript). This decision will significantly accelerate the publication, with no effect on the quality of the peer-review process.

  • February 2016 | Manuscript submission

    Discoveries is commited to excellence, quality and high editorial standards. We are receiving an increasing number of manuscripts for which the identity of the authors/corresponding author can't be verified. Please NOTE that ALL these articles were and will be immediately REJECTED. Indicating an institutional email address is the easiest way to overcome this problem! Moreover, we do not accept any pressure on our editorial board to accept a manuscript. This results in a prompt rejection of the article.

    Editorial Policies
  • January 2016 | Main Objective

    After reaching all proposed milestones until now (including being indexed by Google Scholar in 2014), Discoveries' next Aim is PubMed indexing of all its articles (already published and upcoming). There will be no charge for the submission or publication of articles before Discoveries is indexed.

  • August 2015 | Discoveries - on PubMed

    We are happy to announce that our first Discoveries articles were included in PMC and PubMed. More articles (submitted by NIH funded authors) are now processed for being included.

    Discoveries articles now on PubMed
  • April 2015 | Special Issue

    DISCOVERIES published the SPECIAL ISSUE entitled "INFLAMMATION BETWEEN DEFENSE AND DISEASE: Impact on Tissue Repair and Chronic Sickness".

    Special Issue on "Inflammation"
  • 2015 | Ischemia Collection

    DISCOVERIES launched a call for papers for a Collection of Articles with focus on "ISCHEMIA". If you are interested to submit a manuscript, please contact us at info@discoveriesjournals.org

  • September 2014 | Special Issue

    DISCOVERIES just publish the SPECIAL ISSUE entitled "CELL SECRETION & MEMBRANE FUSION" in September 2014. Initially scheduled for publication between October 2014-March 2015, this issue was successfully published earlier than scheduled. 

    Special Issue
  • April 2014 | Indexed by Google Scholar

    All our published articles are now indexed by Google Scholar! First citations to Discoveries articles are included! Search for the article's title (recommended) or the authors:

    Google Scholar Search
  • 2014 | DISCOVERIES

    DOIs (Digital Object Identifiers) are now assigned to all our published manuscripts in Discoveries. DOI uniquely identifies an article and is provided by CrossRef.

  • July 2013 | Manuscript Submission

    Submit your manuscript FREE, FAST and EASY ! (in less than 1 minute)! There are NO fees for the manuscript submission or publishing of the accepted manuscripts.
    read more

  • July 2013 | DISCOVERIES

    We are now ACCEPTING MANUSCRIPTS for publishing in DISCOVERIES. We aim publishing a small number of high impact experimental articles & reviews (around 40/year) to maintain a high impact factor. Domains of interest: all areas related to Medicine, Biology and Chemistry ...

    read more
Member Login
Free Registration Click here to sign up
Copyright © 2013 Applied Systems. All Rights Reserved.