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Amylin Signaling in Diabetes and Alzheimer's Disease: Therapy Or Grizzanti J, Corrigan R, Servizi S, Casadesus G. Amylin Signaling in Diabetes and Alzheimer’s Neuromedicine Disease: Therapy or Pathology?. 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 diseases share a Accepted: February 10, 2019 number of pathological similarities, including amyloid accumulation, oxidative *Correspondence: stress, inflammation, and cell death. To date, drug 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 human and rodent studies have given Ohio 44242, USA; Telephone No: 330-672-7894; Fax No: 330- evidence that metabolic hormone 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, pramlintide, 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 athe monumental cost of caring problem for and within treating the ADU.S. patients and beyond, currently treatment exceeds options $200 remainbillion 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 drugs indate, clearing the majority or preventing of pharmacological pathology4 .agents As such, developed there is have a fundamental specifically needtargeted 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 cardiovascular disease, 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 develop70% 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 and form cognitive of amylin, deficits used bothin conjunction with insulin 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 pancreas, 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 brain metabolism and metabolic improvingsupplementation cognition reduces40-42,44 .soluble The above Aβ levels, data plaque suggest burden, that a losstau phosphorylation, of innate amylin signaling neuroinflammation, 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 numberpathology of physiological3) 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 orshow pramlintide that low 38,39dose, and human higher amylin doses or ofAβ humancauses 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 readilyinflux, crossesincreased the secretion
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