sign in sign up
<<
Home , Amylin, Amyloid, Amyloidosis, Amyloid beta

Grizzanti J, Corrigan R, Servizi S, Casadesus G. Signaling in and Alzheimer’s Neuromedicine : Therapy or ?. J Neurol Neuromed (2019) 4(1): 12-16 www.jneurology.com www.jneurology.com Journal of Neurology && NeuromedicineNeuromedicine

Review Article Open Access

Amylin Signaling in Diabetes and Alzheimer’s Disease: Therapy or Pathology? John Grizzanti1, Rachel Corrigan1, Spencer Servizi1, Gemma Casadesus1,2* 1School of Biomedical Sciences, Kent State University, Ohio, USA 2Department of Biological Sciences, Kent State University, Ohio, USA

Article Info Abstract

Article Notes Growing evidence highlights the intimate relationship between type II diabetes Received: August 7, 2018 (T2D) and Alzheimer’s disease (AD). Importantly, these two share a Accepted: February 10, 2019 number of pathological similarities, including accumulation, oxidative *Correspondence: stress, , and death. To date, therapies for AD and T2D are Dr. Gemma Casadesus, PhD, 256 Cunningham Hall, lacking and there is a crucial need for the discovery and development of novel Department of Biological Sciences, Kent State University, Kent, therapeutics for these diseases. A number of and rodent studies have given Ohio 44242, USA; Telephone No: 330-672-7894; Fax No: 330- evidence that metabolic supplementation is highly valuable for improving 672-3713; Email: [email protected]. cognitive function and overall metabolic health in both T2D and AD. The pancreatic hormone amylin has arisen as a crucial component of the disease etiology of both © 2019 Casadesus G. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License T2D and AD, though the exact role that amylin plays in these diseases is not yet well understood. Here, we critically review the current literature that utilizes human amylin or its synthetic analogue, , as well as amylin receptor antagonists for the treatment of AD. Keywords: Type II Diabetes Alzheimer’s disease Introduction cognition Amylin Alzheimer’s disease (AD) is a progressive, debilitating Pramlintide neurodegenerative disease characterized by the accumulation of

hyperphosphorylated tau1. The accumulation of these pathological amyloid-beta (Aβ) plaques and neurofibrillary tangles composed of and memory, mood, affect, etc. and presents a substantial burden to the patientpeptides and contributes caregivers. to The deficits incidence in executive of AD is functions increasing such at an as alarminglearning rate in the U.S., with an estimated 5.5 million Americans living with AD 2. Furthermore,

as of 2017 and this number is expected to triple by3. 2050 While AD is clearly thea monumental cost of caring problem for and within treating the ADU.S. patients and beyond, currently treatment exceeds options $200 billionremain annuallyvery limited and 4is. onlyMany expected drug trials to increase have been conducted with a

approved by the FDA for AD and are only symptomatic treatments5, 6. To wide array of targeted approaches, yet there are currently only six

indate, clearing the majority or preventing of pharmacological pathology4 .agents As such, developed there is have a fundamental specifically targetedneed to develop the hallmark viable Aβ therapeutics or tau pathology, and preventative yet none have treatments been successful for AD. Age-related (sporadic) AD is a complicated multifactoral disease,

lifestyle are heavily implicated in the development of sporadic AD; factors suchhaving as numerous diet7-9, obesity genetic8-10, andmetabolic environmental syndrome influences.7, type II diabetes Environment (T2D) and9, 11, and cardiovascular disease12 have all been implicated in the causation of AD. Of critical importance, rates of obesity and diabetes are rapidly rising in parallel with AD12, 13. Though the relationship between obesity and AD is

Page 12 of 16 Grizzanti J, Corrigan R, Servizi S, Casadesus G. Amylin Signaling in Diabetes and Alzheimer’s Disease: Therapy or Pathology?. J Neurol Neuromed (2019) 4(1): 12-16 Journal of Neurology & Neuromedicine somewhat unclear, there is evidence that mid-life obesity plays affect long-term potentiation (LTP) in the hippocampus and a role in the development of AD10. More importantly, obesity is commonly accompanied by a number of other diseases, the brain36-39 including , hypertension, dyslipidemia, inmay these have diseases an innate or influence whether on its cognitive functional function loss through within T2D, stroke, etc.14 . However, whether amylin is a toxic insult the development of an AD remains unclear. in 10 adults) in the. The U.S. incidence have diabetes of T2D and is quickly a staggering rising, with84.1 aggregation or late stage β-cell loss in T2D contributes to The Amylin Signaling Dichotomy millionthe CDC (1 estimating in 3 adults) that have approximately prediabetes, 30.3 most million of whom people are (1 unaware of their condition. Furthermore, due to a large- There is still much debate about the involvement of scale decrease in physical activity that is accompanied by a the amylin receptor (AMYR) and amylin signaling in the simultaneous increase in food intake and poor diet, rates of disease progression and etiology of T2D and AD. The obesity, T2D, metabolic syndrome, and cardiovascular disease body of research aimed at discerning this relationship is are only proposed to increase to an estimated 600 million T2D cases worldwide by 203515. demonstrated that modulation of amylin signaling affects AD-relatedquickly expanding. pathology. All relevantThe nature research of this has relationship,consistently The body of evidence implicating metabolic function however, has yet to be concretely elucidated. Several and disease in the process of cognitive decline and aging groups have produced compelling data suggesting that is substantial16, 17 people diagnosed with T2D report cognitive impairment in vivo and in and a substantial. number For example, of T2D approximatelypatients later develop 70% of vitroamylin40-44 signaling. Importantly, is beneficial pramlintide, in preventing a recombinant AD-related non- dementia16, 18-21. Individuals diagnosed with T2D for at least pathologyaggregating andform cognitive of amylin, deficits used bothin conjunction with therapies to treat diabetes and improves glycemic AD compared to those whom have suffered from T2D for control, reduces body weight, and reduces serum markers five years have a significantly17. Together increased these data risk suggest of developing that the of OS45-47 also shows promise as an AD therapeutic. To increasing prevalence of T2D in the population may be date, however, there have been no clinical trials that have lesscontributing than five to years the rising rates of AD. aimed to utilize amylin or pramlintide as a therapeutic T2D is initially characterized by high blood glucose agent in treating dementia. Clear evidence from rodent and insulin, which leads to hyperinsulinemia; importantly, studies suggests that chronic treatment with either human of the , is co-packaged and co-secreted with insulin in reducing AD-related pathology; amylin/pramlintide andamylin, is thus a small overproduced metabolic hormone in T2D.22 produced. Importantly, by β-islet there cells are amylin or pramlintide poses strong therapeutic benefit a number of pathological features that are present in both T2D and AD: 1) decreased metabolism and metabolic improvingsupplementation cognition reduces40-42,44 .soluble The above Aβ levels, data plaque suggest burden, that a tauloss phosphorylation, of innate amylin signaling , in the CNS due and to OS aggregation while also gives rise to an increased risk for the development of AD andhormone hyperamylinemia resistance 2) leads amyloid to a number pathology of physiological 3) oxidative and is covered in more detail in Grizzanti et al. 201848. issues:stress (OS) chronic and hyperinsulinemiainflammation. Chronic, leads tohyperinsulinemia system insulin resistance22, impaired insulin transport across the blood- 23, 24 brain barrier (BBB) , and thus decreased insulin In contrast, studies also show that36-39,49 human amylin and Aβ 25 alleviated using AMYR antagonist signaling within the brain . Loss of insulin signaling have similar toxic effects and that these toxic effects can be show that in vivo treatment with AMYR antagonists yields in the brain is associated with a number of AD-related . For example, data treatment. Treatment of TgCRND8 AD mice with AC253, an AMYvery similar antagonist, physiological or its cyclic benefits counterpart to amylin cAC253 or pramlintide reduces pathological features, including increased Aβ production, R tau Furthermore,phosphorylation, amylin and neuroinflammation. shares similar pathological 26 and may be a while also improving cognition50. Similarly, in vitro/ex-vivo neuroinflammation, soluble Aβ levels, and plaque burden features with Aβ at high concentrations T2Dcommon patients pathway27-29 betweenand cause the a two number diseases. of physiologicalFor example, AC253studies or show pramlintide that low 38,39 dose, and human higher amylin doses or Aβof human causes disruptionsamylin fibrils including have been aberrant found in theCa2+ pancreas of 95% of amylin/amylindisruptions in LTPoligomers and that are theseassociated deficits with are uncontrolled blocked by 30,31, and ultimately Ca2+ 26,32. Together, 32. Furthermore, amylin readily influx, crosses increased the of pro-inflammatory cytokines influx, which is strongly linked to cell death thus a potential therapeutic mechanism for AMYR blockade. β-islet cell loss these data support a toxic function of amylin oligomers and BBB and forms amylin fibrils as well33-35 as. Amylinmixed plaques is known with to amylin can be blocked using AC25341. Thus, the therapeutic Aβ within the brain and may be responsible for AD-like In contrast, others have shown that the beneficial effects of pathology and Aβ seeding in T2D Page 13 of 16 Grizzanti J, Corrigan R, Servizi S, Casadesus G. Amylin Signaling in Diabetes and Alzheimer’s Disease: Therapy or Pathology?. J Neurol Neuromed (2019) 4(1): 12-16 Journal of Neurology & Neuromedicine potential of amylin treatment or inhibition remains unclear of pathological phenomena, including uncontrolled vesicular release, OS and mitochondrial dysfunction, , etc. in the brain and periphery. To this end, it is likely that cellular dysfunction and the and highlights the complex and dichotomous nature of development of additional AD-like pathology that arises from Piecing Together the Puzzle R There are a number of holes in the current literature and TRPV4. As such, it is necessary to discern the signaling toxic amyloid signaling is mediated through both the AMY cascades that modulate the relationship between the AMYR amylin story: 1) the nature of the innate amylin system and that need filling to give a more complete picture of the and TRVP4. Furthermore, pharmacological experiments signaling capabilities through the three main AMYR and amylinrelated receptors signaling within3) the therapeutic the brain 2) mechanisms Aβ and pramlintide by which Caare2+ warranted currents, LTP,that cAMPutilize production,Aβ and pramlintide and other over signaling a wide array of doses to determine Aβ and pramlintide’s effects on amylin/pramlintide or AMYR inhibition are mediated. cascades to determine their signaling capabilities. These

First, interesting novel data demonstrate that the AMYR is not only involved in signaling, but also in ligand transport literature with regard to the AMYR and its involvement in experiments will help to fill some of the voids in the current across the BBB. The AMYR is a heterodimeric receptor that disease states (Figure 1). is composed of a receptor and a receptor activity modifying (1-3)51 knockdown of the (a key component . To this end, a 50% global of the AMYR 50 found in the brain , indicating that AMYR located in the BBB are involved) significantly in transporting reduced these the amount ligands ofinto AC253 the brain and may also be involved in shuttling amylin and

BBB transport mechanisms suggests that amylin likely has innatepramlintide physiological into/out function of the brain. in the The brain, existence as its transport of these into the brain is tightly controlled. However, how amylin signaling or lack thereof leads to the pathological features of AD and whether the AMYR is the vehicle through which

Aβ mediates its toxic effects still remains unclear. R. Though several Next, conflicting evidence exists with regard to the relationship between Aβ and the AMY similar effects on LTP in the CNS and use of AMYR inhibitors studiesameliorates clearly these demonstrate deleterious that effects human36-39 amylin, other and evidence Aβ have

the any of the AMYR to evoke any sort of cAMP response suggestsat a wide thatvariety Aβ of(1-42) concentrations is incapable52 of signaling through activates different signaling cascades through interaction with the AMY or simply acts as .an It isinert possible competitive that Aβ Figure 1 depicts the amylin signaling paradox and pathological R similarities observed in T2D and AD. Decreased brain metabolism, inhibitor, but this has yet to be demonstrated. amyloid pathology, and inflammation are all Furthermore, a separate study demonstrated that common pathological features observed in both diseases. While not every case of T2D or AD includes each of these pathological features, every case exhibits cognitive impairment. The amylin the AMY and indirectly through TRPV4, a nonselective cation R signaling paradox comes in to play as studies have shown channeloligomeric26. Lowamylin concentrations mediates its toxicto of effectshuman directly amylin throughevoke a that both AMYR inhibition and RAMY agonism via amylin and Ca2+ response that is mediated through its native receptor. pramlintide treatment results in improved cognition, decreased However, at higher concentrations, human amylin forms inflammation, decreased plaque burden and increased LTP. The oligomers and actives aberrant signaling that results in the signaling mechanisms governed by AMYR agonism and AMYR activation of TRVP4 channels and allows for uncontrolled antagonism have yet to be fully elucidated. While amylin signaling 2+. Pharmacological blockade of is traditionally associated with cAMP and PKA signaling, it is unclear if other cascades are also activated by amylin/pramlintide. the AMY and TRPV4 demonstrates that both receptors are R Furthermore, it is unclear if AMY antagonists, amylin oligomers, or cation influx, particularly Ca R Aβ signal through the AMY or whether there are any similarities or 2+ 26 R Ca effects crosstalk between all of these AMY ligands. As such, a number of necessary for oligomeric human amylin to induce its toxic R effects on the AMYR in a similar fashion, though these data do experiments proposed in this review will help to further elucidate . As such, it is likely2+ that Aβ mediates its toxic the true nature of the AMYR. not yet exist. Uncontrolled Ca influx is linked to a number Page 14 of 16 Grizzanti J, Corrigan R, Servizi S, Casadesus G. Amylin Signaling in Diabetes and Alzheimer’s Disease: Therapy or Pathology?. J Neurol Neuromed (2019) 4(1): 12-16 Journal of Neurology & Neuromedicine

Conclusions 7. The current disparity with regard to the role of amylin Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of 8. dementia.Loef M, Walach N Engl H. J Med.Midlife 2013; obesity 369: and540-548. dementia: meta‐analysis and signaling in the brain demonstrates an essential need adjusted forecast of dementia prevalence in the United States and for further elucidation of amylin’s involvement in both China. Obesity. 2013; 21. AD and T2D. In T2D, it is likely that in the early stages 9. dementia: a meta‐analysis of prospective observational studies. Gudala K, Bansal D, Schifano F, et al. Diabetes mellitus and risk of induces aberrant signaling through its native receptor, andof the recruits disease, TRPV4 amylin to induce floods thepathological brain, forms Ca2+ oligomers, 10. Journal of diabetes investigation. 2013; 4: 640-650. age and future risk of dementia: a 27 year longitudinal population results in widespread neuronal dysfunction that manifests Whitmer RA, Gunderson EP, Barrett-Connor E, et al. Obesity in middle as OS, uncontrolled vesicular release and interneuronal influx that 11. based study. BMJ. 2005; 330: 1360. disease: the confounders, interactions, and associated mechanism may be responsible for the initial transition Vagelatos NT, Eslick GD. as a risk factor for Alzheimer’s fromdysfunction, the healthy inflammation, brain to brain and agingresulting in metabolic cell death. disease. This 12. withDebette this S,relationship. Seshadri S, Epidemiol Beiser A, Rev. et al.2013; Midlife 35: 152-160.vascular risk factor As such, AMYR or TRVP4 inhibition at certain time points in metabolic disease and in the early stages of diabetes may Neurology. 2011; 77: 461-468. exposure accelerates structural brain aging and cognitive decline. 13. Diabetes Springer. 2013; 35-41. Ginter E, Simko V. Global prevalence and future of diabetes mellitus In replacementbe warranted withto block either the toxichuman effects amylin of oligomeric or pramlintide amylin 14. reducesor Aβ. However, most of strong the major evidence AD alsorelated suggests pathology that amylin while conditions. Clin Cornerstone. 1999; 2: 17-31. Khaodhiar L, McCowen KC, Blackburn GL. Obesity and its comorbid also improving cognition in rodent models of AD. As such, 15. Federation ID. IDF diabetes atlas. Brussels: International Diabetes amylin signaling replacement with amylin or pramlintide Federation. 2013. in the mid to late stages of diabetes when amylin signaling 16. Metab Immune Drug Discov. 2013; 7: 155-165. K Dash S. Cognitive impairment and diabetes. Recent Pat Endocr may be warranted. To this end, there is also a need to 17. Leibson CL, Rocca WA, Hanson V, et al. Risk of dementia among discernis lost due the totemporal aggregation, presentation oligomerization, of pathological or β-cell events loss persons with diabetes mellitus: a population-based cohort study. Am in metabolically linked brain aging and therapeutic options for early, intermediate, and late stage disease. Critical 18. J Epidemiol. 1997; 145: 301-308. decline in type 2 diabetes and prediabetic stages: towards targeted analysis and testing of the direct nature and signaling interventions.Biessels GJ, Strachan The lancet MW, Diabetes Visseren & FL,. et al. Dementia 2014; and 2: cognitive246-255. capabilities of these amyloids as well as the therapeutic 19. the gap between AMY inhibition therapies and amylin 71:Akter 365-376. K, Lanza EA, Martin SA, et al. Diabetes mellitus and Alzheimer’s R disease: shared pathology and treatment. Br J Clin Pharmacol. 2011; replacementnature of specific therapies. temporal treatments may help to bridge 20. prediabetes and their risk factors among Bangladeshi adults: a Funding nationwideAkter S, Rahman survey. MM,Bull World Abe SK, Health et al. Organ. Prevalence 2014; 92: of 204-213A. diabetes and Funding for this article was provided by the National 21. Ott A, Stolk R, Van Harskamp F, et al. Diabetes mellitus and the risk Institutes of Aging grant 1R15AG050292-01A1. of dementia The Rotterdam Study. Neurology. 1999; 53: 1937-1937. 22. Farris W, Mansourian S, Chang Y, et al. Insulin-degrading References 1. precursor protein intracellular domain in vivo. Proceedings of the regulates the levels of insulin, amyloid β-protein, and the β-amyloid dysfunction. Trends Mol Med. 2005; 11: 170-176. National Academy of Sciences. 2003; 100: 4162-4167. LaFerla FM, Oddo S. Alzheimer’s disease: Aβ, tau and synaptic 2. 23. States (2010–2050) estimated using the 2010 census. Neurology. rats.Schwartz . MW, 1990;Figlewicz 11: 467-472.DF, Kahn SE, et al. Insulin binding to brain 2013;Hebert 80: LE, 1778-1783. Weuve J, Scherr PA, et al. Alzheimer disease in the United capillaries is reduced in genetically obese, hyperinsulinemic Zucker 24. 3. Levels Increase During Intravenous Insulin Infusions in Man*. The Alzheimer’s & Dementia. 2016; 12: 459-509. Wallum B, Taborsky Jr G, Porte Jr D, et al. Cerebrospinal Fluid Insulin Association As. 2016 Alzheimer’s disease facts and figures. 4. 25. Journal of Clinical Endocrinology & Metabolism. 1987; 64: 190-194. Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug- Res Ther. 2014; 6: 37. Gil-Bea FJ, Solas M, Solomon A, et al. Insulin levels are decreased in development pipeline: few candidates, frequent failures. Alzheimers 5. the cerebrospinal fluid of women with prodomal Alzheimer’s disease. 26. effectiveness and cost-effectiveness of acetylcholinesterase inhibitors J Alzheimers Dis. 2010; 22: 405-413. primary hippocampal . Neuropharmacology. 2017; 113: 241- andHyde C, Peters J, for Bond Alzheimer’s M, et al. Evolutiondisease: systematic of the evidence review on and the 251.Zhang N, Yang S, Wang C, et al. Multiple target of hAmylin on rat economic model. Age Ageing. 2012; 42: 14-20. 27. 6. and type 2 diabetes. Nature. 2006; 444: 840-846. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to 893-903.Howard R, McShane R, Lindesay J, et al. Donepezil and memantine 28. for moderate-to-severe Alzheimer’s disease. N Engl J Med. 2012; 366: Johnson K, O’Brien T, Jordan K, et al. Impaired glucose tolerance

Page 15 of 16 Grizzanti J, Corrigan R, Servizi S, Casadesus G. Amylin Signaling in Diabetes and Alzheimer’s Disease: Therapy or Pathology?. J Neurol Neuromed (2019) 4(1): 12-16 Journal of Neurology & Neuromedicine

is associated with increased islet amyloid polypeptide (IAPP) and brain amyloid pathology in murine models of Alzheimer’s disease. immunoreactivity in pancreatic beta cells. The American journal of Mol Psychiatry. 2015; 20: 252. pathology. 1989; 135: 245. 41. 29. pathological cascade of Alzheimer’s disease. Neuropharmacology. 2017;Zhu H, 119: Xue 170-181. X, Wang E, et al. Amylin receptor ligands reduce the Johnson KH, O’Brien TD, Betsholtz C, et al. Islet amyloid, islet-amyloid 30. polypeptide,Masters SL, Dunne and diabetes A, Subramanian mellitus. N SL, Engl et al.J Med. Activation 1989; 321: of the 513-518. NLRP3 42. Adler BL, Yarchoan M, Hwang HM, et al. Neuroprotective effects of the amylin analogue pramlintide on Alzheimer’s disease pathogenesis and cognition. Neurobiol Aging. 2014; 35: 793-801. inflammasome by islet amyloid polypeptide provides a mechanism 31. for enhanced IL-1β in type 2 diabetes. Nat Immunol. 2010; 11: 897. 43. diabetes: a systematic review and meta-analysis. Diabetes Care2013; in -1 potentiates neuronal apoptosis. Nature. 36:Wang 166-175. X, Bao W, Liu J, et al. Inflammatory markers and risk of type 2 1998;Zhang 395:Z, Hartmann 698-702. H, Do VM, et al. Destabilization of β-catenin by 32. 44. islet amylin, and protein fragment evoke intracellular free calciumKawahara elevations M, Kuroda by Y, a Arispecommon N, mechanismet al. Alzheimer’s in a hypothalamic β-amyloid, human GnRH Wang E, Zhu H, Wang X, et al. Amylin Treatment Reduces Neuroinflammation and Ameliorates Abnormal Patterns of in the of an Alzheimer’s Disease Mouse 33. neuronalVerma N, cell Ly line. H, JLiu Biol M, Chem. et al. 2000; Intraneuronal 275: 14077-14083. Amylin Deposition, 45. Model.Singh-Franco J Alzheimers D, Robles Dis. G,2017; Gazze 56: D. 47-61. Pramlintide acetate injection for the treatment of type 1 and type 2 diabetes mellitus. Clin Ther. 2007; of Alzheimer’s Disease Patients with Type-2 Diabetes and in 29: 535-562. Peroxidative Membrane Injury and Increased IL-1β Synthesis in 46. Singh‐Franco D, Perez A, Harrington C. The effect of pramlintide acetate 34. Diabetic HIP Rats. J Alzheimers Dis. 2016; 53: 259-272. on glycemic control and weight in patients with type 2 diabetes mellitus second amyloid in Alzheimer disease. Ann Neurol. 2013; 74: 517-526. and in obese patients without diabetes: a systematic review and meta‐ Jackson K, Barisone GA, Diaz E, et al. Amylin deposition in the brain: a analysis. Diabetes, Obesity and Metabolism. 2011; 13: 169-180. 35. cross-seeding of localized : a molecular link between type 47. Hollander PA, Levy P, Fineman MS, et al. Pramlintide as an adjunct to 2Oskarsson diabetes and ME, Alzheimer Paulsson disease. JF, Schultz The SW, American et al. Injournal vivo of seeding pathology. and insulin therapy improves long-term glycemic and weight control in 2015; 185: 834-846. patients with type 2 diabetes. Diabetes Care. 2003; 26: 784-790. 36. 48. pathophysiological target in Alzheimer’s disease and diabetes mellitus.Fu W, PatelFront Aging A, Jhamandas Neurosci. 2013; JH. Amylin5. receptor: a common AlzheimersGrizzanti J, Corrigan Dis. 2018; R, 1-13.Casadesus G. Neuroprotective Effects of Amylin Analogues on Alzheimer’s Disease Pathogenesis and Cognition. J 37. 49. directly activates amylin-3 receptor subtype by triggering multiple Fu W, Ruangkittisakul A, MacTavish D, et al. Amyloid β (Aβ) AmericanJhamandas journal JH, Li ofZ, pathology.Westaway 2011;D, et al. 178: Actions 140-149. of β-amyloid protein 18830. on human neurons are expressed through the amylin receptor. The intracellular signaling pathways. J Biol Chem. 2012; 287: 18820- 50. Soudy R, Patel A, Fu W, et al. Cyclic AC253, a novel amylin receptor 38. Alzheimer’s disease. Alzheimer’s & Dementia: Translational Research HippocampalKimura R, MacTavish Long-Term D, Potentiation. Yang J, et Mol al. Neurobiol. Pramlintide 2017; Antagonizes 54: 748- &antagonist, Clinical Interventions. improves cognitive2017; 3: 44-56. deficits in a mouse model of 754.Beta Amyloid (Aβ)-and Human Amylin-Induced Depression of 51. 39. behavior in islet amyloid polypeptide (amylin) knockout mice. Mol of hippocampal long-term potentiation is mediated through the BrainGebre-Medhin Res. 1998; S, 63: Mulder 180-183. H, Zhang Y, et al. Reduced nociceptive Kimura R, MacTavish D, Yang J, et al. Beta amyloid-induced depression 52. 40. amylin receptor. J Neurosci. 2012; 32: 17401-17406. nology. pancreatic peptide amylin potently reduces behavioral impairment 2014;Gingell 155: JJ, Burns 21-26. ER, Hay DL. Activity of pramlintide, rat and human Zhu H, Wang X, Wallack M, et al. Intraperitoneal injection of the amylin but not Aβ1–42 at human amylin receptors. Endocri

Page 16 of 16