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Current Alzheimer Research

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Perspective

Bloodborne Pancreatic Amylin, a Therapeutic Target for Alzheimer's Disease

Author(s): Florin Despa*

Volume 19, Issue 14, 2022

Published on: 10 March, 2023

Page: [905 - 908] Pages: 4

DOI: 10.2174/1567205020666230217091540

Price: $65

Abstract

Alzheimer Disease (AD) pathology has been linked to brain accumulation of β amyloid (Aβ) and neurofibrillary tau tangles. An intriguing question is whether targeting factors independent of Aβ and tau pathologies could delay or even stop neurodegeneration. Amylin, a pancreatic hormone cosecreted with insulin, is believed to play a role in the central regulation of satiation and was shown to form pancreatic amyloid in persons with type-2 diabetes mellitus. Accumulating evidence demonstrates that amyloid-forming amylin secreted from the pancreas synergistically aggregates with vascular and parenchymal Aβ in the brain in both sporadic and early-onset familial AD. Pancreatic expression of amyloid-forming human amylin in AD-model rats accelerates AD-like pathology, whereas genetically suppressed amylin secretion protects against AD effects. Thus, current data suggest a role of pancreatic amyloid-forming amylin in modifying AD; further research is required to test whether lowering circulating amylin levels early during AD pathogenesis may curb cognitive decline.

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[1]
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016; 8(6): 595-608.
[http://dx.doi.org/10.15252/emmm.201606210] [PMID: 27025652]
[2]
Scheltens P, Blennow K, Breteler MMB, et al. Alzheimer’s disease. Lancet 2016; 388(10043): 505-17.
[http://dx.doi.org/10.1016/S0140-6736(15)01124-1] [PMID: 26921134]
[3]
Kahn SE, D’Alessio DA, Schwartz MW, et al. Evidence of cosecretion of islet amyloid polypeptide and insulin by beta-cells. Diabetes 1990; 39(5): 634-8.
[http://dx.doi.org/10.2337/diab.39.5.634] [PMID: 2185112]
[4]
Westermark P, Andersson A, Westermark GT. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev 2011; 91(3): 795-826.
[http://dx.doi.org/10.1152/physrev.00042.2009] [PMID: 21742788]
[5]
Lutz TA. Control of energy homeostasis by amylin. Cell Mol Life Sci 2012; 69(12): 1947-65.
[http://dx.doi.org/10.1007/s00018-011-0905-1] [PMID: 22193913]
[6]
Banks WA, Kastin AJ. Differential permeability of the blood-brain barrier to two pancreatic peptides: Insulin and amylin. Peptides 1998; 19(5): 883-9.
[http://dx.doi.org/10.1016/S0196-9781(98)00018-7] [PMID: 9663454]
[7]
Maianti JP, McFedries A, Foda ZH, et al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature 2014; 511(7507): 94-8.
[http://dx.doi.org/10.1038/nature13297] [PMID: 24847884]
[8]
Bendtzen K, Mandrup-Poulsen T, Nerup J, Nielsen JH, Dinarello CA, Svenson M. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science 1986; 232(4757): 1545-7.
[http://dx.doi.org/10.1126/science.3086977] [PMID: 3086977]
[9]
Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007; 356(15): 1517-26.
[http://dx.doi.org/10.1056/NEJMoa065213] [PMID: 17429083]
[10]
Masters SL, Dunne A, Subramanian SL, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol 2010; 11(10): 897-904.
[http://dx.doi.org/10.1038/ni.1935] [PMID: 20835230]
[11]
Jackson K, Barisone GA, Diaz E, Jin L, DeCarli C, Despa F. Amylin deposition in the brain: A second amyloid in Alzheimer disease? Ann Neurol 2013; 74(4): 517-26.
[http://dx.doi.org/10.1002/ana.23956] [PMID: 23794448]
[12]
Fawver J, Ghiwot Y, Koola C, et al. Islet amyloid polypeptide (IAPP): A second amyloid in Alzheimer’s disease. Curr Alzheimer Res 2014; 11(10): 928-40.
[http://dx.doi.org/10.2174/1567205011666141107124538] [PMID: 25387341]
[13]
Oskarsson ME, Paulsson JF, Schultz SW, Ingelsson M, Westermark P, Westermark GT. In vivo seeding and cross-seeding of localized amyloidosis: A molecular link between type 2 diabetes and Alzheimer disease. Am J Pathol 2015; 185(3): 834-46.
[http://dx.doi.org/10.1016/j.ajpath.2014.11.016] [PMID: 25700985]
[14]
Verma N, Ly H, Liu M, et al. Intraneuronal amylin deposition, peroxidative membrane injury and increased IL-1β synthesis in brains of Alzheimer’s disease patients with type-2 diabetes and in diabetic HIP rats. J Alzheimers Dis 2016; 53(1): 259-72.
[http://dx.doi.org/10.3233/JAD-160047] [PMID: 27163815]
[15]
Schultz N, Byman E, Fex M, Wennström M. Amylin alters human brain pericyte viability and NG2 expression. J Cereb Blood Flow Metab 2017; 37(4): 1470-82.
[http://dx.doi.org/10.1177/0271678X16657093] [PMID: 27354094]
[16]
Ly H, Verma N, Wu F, et al. Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia. Ann Neurol 2017; 82(2): 208-22.
[http://dx.doi.org/10.1002/ana.24992] [PMID: 28696548]
[17]
Schultz N, Byman E, Wennström M, Wennström M. Levels of retinal IAPP are altered in Alzheimer’s disease patients and correlate with vascular changes and hippocampal IAPP levels. Neurobiol Aging 2018; 69: 94-101.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.05.003] [PMID: 29864717]
[18]
Martinez-Valbuena I, Valenti-Azcarate R, Amat-Villegas I, et al. Amylin as a potential link between type 2 diabetes and alzheimer disease. Ann Neurol 2019; 86(4): 539-51.
[http://dx.doi.org/10.1002/ana.25570] [PMID: 31376172]
[19]
Ly H, Verma N, Sharma S, et al. The association of circulating amylin with β‐amyloid in familial Alzheimer’s disease. Alzheimers Dement 2021; 7(1): e12130.
[http://dx.doi.org/10.1002/trc2.12130] [PMID: 33521236]
[20]
Srodulski S, Sharma S, Bachstetter AB, et al. Neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of amylin. Mol Neurodegener 2014; 9(1): 30.
[http://dx.doi.org/10.1186/1750-1326-9-30] [PMID: 25149184]
[21]
Verma N, Liu M, Ly H, et al. Diabetic microcirculatory disturbances and pathologic erythropoiesis are provoked by deposition of amyloid-forming amylin in red blood cells and capillaries. Kidney Int 2020; 97(1): 143-55.
[http://dx.doi.org/10.1016/j.kint.2019.07.028] [PMID: 31739987]
[22]
Ilaiwy A, Liu M, Parry TL, et al. Human amylin proteotoxicity impairs protein biosynthesis, and alters major cellular signaling pathways in the heart, brain and liver of humanized diabetic rat model in vivo. Metabolomics 2016; 12(5): 95.
[http://dx.doi.org/10.1007/s11306-016-1022-9] [PMID: 28775675]
[23]
Royall DR, Palmer RF. Blood-based protein mediators of senility with replications across biofluids and cohorts. Brain Commun 2020; 2(1): fcz036.
[http://dx.doi.org/10.1093/braincomms/fcz036] [PMID: 32954311]
[24]
Roostaei T, Nazeri A, Felsky D, et al. Genome-wide interaction study of brain beta-amyloid burden and cognitive impairment in Alzheimer’s disease. Mol Psychiatry 2017; 22(2): 287-95.
[http://dx.doi.org/10.1038/mp.2016.35] [PMID: 27021820]
[25]
Wagner T, Page J, Burniston M, et al. Extracardiac 18F-florbetapir imaging in patients with systemic amyloidosis: More than hearts and minds. Eur J Nucl Med Mol Imaging 2018; 45(7): 1129-38.
[http://dx.doi.org/10.1007/s00259-018-3995-2] [PMID: 29651545]
[26]
Castle AL, Kuo CH, Han DH, Ivy JL. Amylin-mediated inhibition of insulin-stimulated glucose transport in skeletal muscle. Am J Physiol 1998; 275(3): E531-6.
[PMID: 9725822]
[27]
Leighton B, Cooper GJS. Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro. Nature 1988; 335(6191): 632-5.
[http://dx.doi.org/10.1038/335632a0] [PMID: 3050530]
[28]
Zierath JR, Galuska D, Engström A, et al. Human islet amyloid polypeptide at pharmacological levels inhibits insulin and phorbol ester-stimulated glucose transport in in vitro incubated human muscle strips. Diabetologia 1992; 35(1): 26-31.
[http://dx.doi.org/10.1007/BF00400848] [PMID: 1541378]
[29]
Venkatanarayan A, Raulji P, Norton W, et al. IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo. Nature 2015; 517(7536): 626-30.
[http://dx.doi.org/10.1038/nature13910] [PMID: 25409149]

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