HHS Public Access Author manuscript Author Manuscript
Expert Rev Proteomics. Author manuscript; available in PMC 2016 June 20. Published in final edited form as: Expert Rev Proteomics. 2015 ; 12(6): 575–577. doi:10.1586/14789450.2015.1104251.
Hyperamylinemia as a risk factor for accelerated cognitive decline in diabetes Han Ly and Department of Pharmacology and Nutritional Sciences, University of Kentucky, College of Medicine, Lexington, KY 40536, USA
Author Manuscript
Florin Despa Department of Pharmacology and Nutritional Sciences, University of Kentucky, College of Medicine, Lexington, KY 40536, USA Florin Despa: [email protected]
Abstract
Author Manuscript
Type II diabetes increases the risk for cognitive decline via multiple traits. Amylin is a pancreatic hormone that has amyloidogenic and cytotoxic properties similar to the amyloid-β peptide. The amylin hormone is overexpressed in individuals with pre-diabetic insulin resistance or obesity leading to amylin oligomerization and deposition in pancreatic islets. Amylin oligomerization was implicated in the apoptosis of the insulin-producing β-cells. Recent studies showed that brain tissue from diabetic patients with cerebrovascular dementia or Alzheimer’s disease contains significant deposits of oligomerized amylin. It has also been reported that the brain amylin deposition reduced exploratory drive, recognition memory and vestibulomotor function in a rat model that overexpresses human amylin in the pancreas. These novel findings are reviewed here and the hypothesis that type II diabetes is linked with cognitive decline by amylin accumulation in the brain is proposed. Deciphering the impact of hyperamylinemia on the brain is critical for both etiology and treatment of dementia.
Keywords Alzheimer’s disease; amylin; amyloid; Aβ; cerebrovascular disease; dementia; hyperamylinemia; hyperinsulinemia; insulin resistance; type 2 diabetes
Author Manuscript
Dementia is the most common cause of cognitive disability in the US, and estimates suggest that the prevalence is likely to upsurge. In addition to advancing age, family history and heredity, emerging evidence [1,2] indicates type II diabetes (T2D) as a risk factor for
Correspondence to: Florin Despa, [email protected]. Financial & competing interests disclosure The authors were supported by the Pilot Project from the University of Kentucky Alzheimer’s Disease Center: National Institute of Aging, 5P30 AG028383 Pilot Project DiaComp; the National Institute of Diabetes and digestive and Kidney Diseases, National Science Foundation CBET-1133339; National Heart, Lung, Heart and Blood Institute, R01HL118474 and the Alzheimer’s Association, VMF-15-363458. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Ly and Despa
Page 2
Author Manuscript
cerebrovascular disease (CVD) and Alzheimer’s disease (AD). This increased risk extends to both obesity and pre-diabetic insulin resistance (IR).[2] While the link of T2D with AD/CVD is appealing, clinical trials [3] of stringent glucose regulation failed to improve cognition and may even increase mortality, implying that hyperglycemia per se may not be the correct target for risk reduction. Other potential contributors include history of cerebrovascular injury, [1] cardiovascular disease,[2] ApoE gene [2] and hyperinsulinemia. [2]
Author Manuscript
It was hypothesized [4] that hyperinsulinemia impairs both insulin and insulin-like growth factor signaling, which may enhance amyloid precursor protein expression, production, and hyperphosphorylation of microtubule tau protein, the two hallmark pathologic features of AD. Similarly, elevated insulin in the brain may saturate the brain insulin degrading enzyme system or reduce lipoprotein receptor-related protein 1 level, which are mechanisms for Aβ clearance. [1,2] However, induction of hyperinsulinemia acutely in AD patients enhanced memory function.[5] These results [5] suggest that IR and not the elevated insulin levels per se may play a role in the development of AD/CVD pathology in T2D.
Author Manuscript
One possible mechanism by which T2D negatively affects brain function may involve increased secretion of the pancreatic hormone amylin (hyperamylinemia), which coincides always with hyperinsulinemia.[6] Hyperamylinemia was demonstrated to affect not only the pancreas [6] but also kidneys,[6] heart [7–9] and brain,[10] as we showed recently.[10] In the brain, we found [10] that amylin can form either independent deposits or mixed amylinAβ plaques. No amylin mRNA was detected in the human brain [10] demonstrating that amylin accumulates in the brain via circulation from the pancreas. Intriguingly, amylin deposits were identified [10] in blood vessels and brain parenchyma of AD patients without clinical evidence of T2D. These results [10] were interpreted as a possible effect of IR, which is common in aging. Notably, two other laboratories [11,12] independently demonstrated amylin deposition [11,12] and amylin-Aβ plaque formation [12] in brains of dementia patients. However, the potential link between brain amylin deposition and increased risk of cognitive decline has not been systematically evaluated. To fill this knowledge gap, future studies should include a broader sample of human brain pathologies, particularly to address the questions regarding mechanisms of accumulation and possible relationship of amylin accumulation with the comorbid disease (i.e., AD or/and CVD). Answering these questions could enable research opportunities for novel treatments of dementia.
Author Manuscript
Amylin may exacerbate the pathological effects of Aβ, as amylin and Aβ share a similar neurotoxicity profile.[13] For example, previous studies demonstrated that amylin and Aβ can induce neuronal apoptosis through Ca2+ dysregulation and elevated level of reactive oxygen species.[13,14] Hence, one can speculate on the convergence of these amylin-Aβ amyloid signaling pathways. This idea begins to unfold as amylin receptor was found to mediate both amylin and Aβ neurotoxicity.[14] Blocking the activity of amylin receptors attenuated the activation of caspases in Aβ-mediated apoptosis pathway.[14] However, how amylin and Aβ interacts with each other and other participating signaling factors remains unclear. Moreover, amylin, insulin and Aβ are degraded by the insulin degrading enzyme. Thus, the interaction between amylin dyshomeostasis and Aβ pathology could deteriorate
Expert Rev Proteomics. Author manuscript; available in PMC 2016 June 20.
Ly and Despa
Page 3
Author Manuscript
brain pathological condition via complex mechanisms. On the other hand, the brain amylin accumulation can impair brain function independently of Aβ pathology, as we demonstrated recently.[15]
Author Manuscript
Subtle but significant changes in brain function are frequently observed in patients with T2D even without frank dementia. [1,2] Specific disturbances include impaired psychomotor speed and memory.[1] Such changes have been difficult to reproduce in animal models,[16] which impedes the search for underlying mechanisms and treatments. Part of this problem arises from the fact that rodents do not spontaneously develop T2D. In rodents, T2D is induced by genetic manipulations. Depending on the transgene, some animal models show cognitive impairment even in the absence of hyperglycemia.[16] In other rodent models of T2D, such as the Zucker diabetic fatty (ZDF) rat, brain function remains intact,[16] despite the development of essential features of T2D, including hyperglycemia, IR and hyperinsulinemia. The resistance of ZDF rats to diabetic cognitive decline is attributed [16] to hyperinsulinemia, a condition believed to protect brain structure and function in T2D.[5] In addition to impaired glucose metabolism and hyperinsulinemia, the transgenic human islet amyloid polypeptide (HIP) rat model [15] of T2D bears a “human” hyperamylinemia. We found [15] that HIP rats accumulated brain amylin deposits even in the pre-diabetic state which was associated with reduced exploratory drive and vestibulomotor performance. Progressing to full-blown T2D in HIP rats appeared to exacerbate the amylin-induced deleterious effects on brain function leading to recognition memory deficits.[15] Thus, brain accumulation of oligomerized amylin may constitute a pathological substrate for diabetic brain injury and cognitive decline. These results demonstrated the pathological impact of amylin oligomerization on brain function in the absence of Aβ pathology.
Author Manuscript
Hyperamylinemia may negatively affect the health of both cerebrovasculature and neurons. Amylin was identified in the cerebral vessels and interstitial fluid surrounding cerebral cortex. [17] Also, an early study found that amylin induces a pattern of apoptotic genes with increasingly expressed oxidative stress genes in rat cortical neurons.[18] Based on these recent results,[10–12,15] we foresee an emerging challenge of understanding amylin signaling mechanism under pathological conditions and further characterize hyperamylinemia effects on the central nervous system.
Author Manuscript
Limiting amylin oligomerization in pancreatic islets reduced oxidative stress and retards the development of T2D [6] in animal models transgenic for human amylin. We also showed recently [9] that lowering the level of circulating amylin oligomers diminishes myocardial amylin deposition and improves heart function in HIP rats. Future studies should focus on ways to reduce the level of accumulation of oligomerized amylin in the brain. Circulating oligomerized amylin may be a novel, early, direct, and potentially treatable, pathogenic link of pancreatic dysfunction with brain injury and cognitive decline. Hormone amylin plays an important role in modulating peripheral energy balance,[6] vasorelaxation [19] and also acts centrally by diminishing exploration [15] and appetitive approach behavior [6] in rodents. A recent study [20] reported that intraperitoneal injection of amylin reduced the amyloid burden in AD mice. The authors [20] suggested that the amylin hormone mediates the translocation of Aβ peptide from the brain. However, amylin
Expert Rev Proteomics. Author manuscript; available in PMC 2016 June 20.
Ly and Despa
Page 4
Author Manuscript
may lose its function through oligomerization,[15] which can be toxic if it accumulates in tissues, as demonstrated by previous studies.[6,15] Moreover, in brain tissue from demented diabetics, we found [10] that amylin co-localized with Aβ as part of combined plaques. Given the toxicity of amylin,[10,14,15] these two amyloid species could act together or independently to accentuate neurotoxicity. In conclusion, hyperamylinemia has the potential role in the development of AD and CVD pathology in T2D. Deciphering the impact of hyperamylinemia on the brain in the presence or absence of the Aβ pathology is highly relevant for both etiology and treatment of these diseases.
References Author Manuscript Author Manuscript Author Manuscript
1. Luchsinger JA. Type 2 diabetes and cognitive impairment: linking mechanisms. J Alzheimers Dis. 2012; 30(2):S185–S198. [PubMed: 22433668] 2. Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol. 2009; 66(3):300–305. [PubMed: 19273747] 3. Launer LJ, Miller ME, Williamson JD, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label sub-study. Lancet Neurol. 2011; 10:969–977. [PubMed: 21958949] 4. de la Monte SM. Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease. Drugs. 2012; 72:49–66. [PubMed: 22191795] 5. Craft S, Newcomer J, Kanne S, et al. Memory improvement following induced hyperinsulinemia in alzheimer’s disease. Neurobiol Aging. 1996; 17(1):123–130. [PubMed: 8786794] 6. Westermark P, Andersson A, Westermark GT. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev. 2011; 91(3):795–826. [PubMed: 21742788] 7. Despa S, Margulies KB, Chen L, et al. Hyperamylinemia contributes to heart dysfunction in obesity and diabetes, a study in humans and rats. Circ Res. 2012; 110(4):598–608. [PubMed: 22275486] 8. Erickson JR, Pereira L, Wang L, et al. Diabetic hyperglycemia activates CaMKII and arrhythmias by O linked glycosylation. Nature. 2013; 502(7471):372–376. [PubMed: 24077098] 9. Despa S, Despa S, Sharma S, et al. Cardioprotection by controlling hyperamylinemia in a “humanized” diabetic rat model. J Am Heart Assoc. 2014; doi: 10.1161/JAHA.114.001015 10. Jackson K, Barisone G, Jin L-W, et al. Amylin deposition in the brain: a second amyloid in Alzheimer disease? Ann Neurol. 2013; 74(4):517–526. [PubMed: 23794448] 11. Fawver JN, Ghiwot Y, Koola C, et al. Islet amyloid polypeptide (IAPP): a second amyloid in Alzheimer’s disease. Curr Alzheimer Res. 2014; 11:928–940. [PubMed: 25387341] 12. Oskarsson ME, Paulsson JF, Schultz SW, et al. In vivo seeding and cross-seeding of localized amyloidosis: a molecular link between type 2 diabetes and Alzheimer disease. Am J Pathol. 2015; 185:834–846. [PubMed: 25700985] 13. Lim YA, Rhein V, Baysang G, et al. Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction. Proteomics. 2010; 10(8):1621–1633. [PubMed: 20186753] 14. Jhamandas JH, Mactavish D. Antagonist of the amylin receptor blocks beta-amyloid toxicity in rat cholinergic basal forebrain neurons. J Neurosci. 2004; 24(24):5579–5584. [PubMed: 15201330] 15. Srodulski S, Sharma S, Bachstetter AB, et al. Neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of amylin. Mol Neurodegener. 2014; 9:30. [PubMed: 25149184] 16. Biessels GJ, Gispen WH. The impact of diabetes on cognition: what can be learned from rodent models? Neurobiol Aging. 2005; 26(Suppl 1):36–41. [PubMed: 16223548] 17. Banks WA, Kastin AJ. Differential permeability of the blood-brain barrier to two pancreatic peptides: insulin and amylin. Peptides. 1998; 19(5):883–889. [PubMed: 9663454]
Expert Rev Proteomics. Author manuscript; available in PMC 2016 June 20.
Ly and Despa
Page 5
Author Manuscript
18. Tucker HM, Rydel RE, Wright S, et al. Human amylin induces “apoptotic” pattern of gene expression concomitant with cortical neuronal apoptosis. J Neurochem. 1998; 71(2):506–516. [PubMed: 9681440] 19. Edvinsson L, Goadsby PJ, Uddman R. Amylin: localization, effects on cerebral arteries and on local cerebral blood flow in the cat. Sci World J. 2001; 1:168–180. 20. Zhu H, Wang X, Wallack M, et al. Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer’s disease. Mol Psychiatry. 2015; 20(2):252–262. [PubMed: 24614496]
Author Manuscript Author Manuscript Author Manuscript Expert Rev Proteomics. Author manuscript; available in PMC 2016 June 20.
Expert Rev Proteomics. Author manuscript; available in PMC 2016 June 20. Published in final edited form as: Expert Rev Proteomics. 2015 ; 12(6): 575–577. doi:10.1586/14789450.2015.1104251.
Hyperamylinemia as a risk factor for accelerated cognitive decline in diabetes Han Ly and Department of Pharmacology and Nutritional Sciences, University of Kentucky, College of Medicine, Lexington, KY 40536, USA
Author Manuscript
Florin Despa Department of Pharmacology and Nutritional Sciences, University of Kentucky, College of Medicine, Lexington, KY 40536, USA Florin Despa: [email protected]
Abstract
Author Manuscript
Type II diabetes increases the risk for cognitive decline via multiple traits. Amylin is a pancreatic hormone that has amyloidogenic and cytotoxic properties similar to the amyloid-β peptide. The amylin hormone is overexpressed in individuals with pre-diabetic insulin resistance or obesity leading to amylin oligomerization and deposition in pancreatic islets. Amylin oligomerization was implicated in the apoptosis of the insulin-producing β-cells. Recent studies showed that brain tissue from diabetic patients with cerebrovascular dementia or Alzheimer’s disease contains significant deposits of oligomerized amylin. It has also been reported that the brain amylin deposition reduced exploratory drive, recognition memory and vestibulomotor function in a rat model that overexpresses human amylin in the pancreas. These novel findings are reviewed here and the hypothesis that type II diabetes is linked with cognitive decline by amylin accumulation in the brain is proposed. Deciphering the impact of hyperamylinemia on the brain is critical for both etiology and treatment of dementia.
Keywords Alzheimer’s disease; amylin; amyloid; Aβ; cerebrovascular disease; dementia; hyperamylinemia; hyperinsulinemia; insulin resistance; type 2 diabetes
Author Manuscript
Dementia is the most common cause of cognitive disability in the US, and estimates suggest that the prevalence is likely to upsurge. In addition to advancing age, family history and heredity, emerging evidence [1,2] indicates type II diabetes (T2D) as a risk factor for
Correspondence to: Florin Despa, [email protected]. Financial & competing interests disclosure The authors were supported by the Pilot Project from the University of Kentucky Alzheimer’s Disease Center: National Institute of Aging, 5P30 AG028383 Pilot Project DiaComp; the National Institute of Diabetes and digestive and Kidney Diseases, National Science Foundation CBET-1133339; National Heart, Lung, Heart and Blood Institute, R01HL118474 and the Alzheimer’s Association, VMF-15-363458. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Ly and Despa
Page 2
Author Manuscript
cerebrovascular disease (CVD) and Alzheimer’s disease (AD). This increased risk extends to both obesity and pre-diabetic insulin resistance (IR).[2] While the link of T2D with AD/CVD is appealing, clinical trials [3] of stringent glucose regulation failed to improve cognition and may even increase mortality, implying that hyperglycemia per se may not be the correct target for risk reduction. Other potential contributors include history of cerebrovascular injury, [1] cardiovascular disease,[2] ApoE gene [2] and hyperinsulinemia. [2]
Author Manuscript
It was hypothesized [4] that hyperinsulinemia impairs both insulin and insulin-like growth factor signaling, which may enhance amyloid precursor protein expression, production, and hyperphosphorylation of microtubule tau protein, the two hallmark pathologic features of AD. Similarly, elevated insulin in the brain may saturate the brain insulin degrading enzyme system or reduce lipoprotein receptor-related protein 1 level, which are mechanisms for Aβ clearance. [1,2] However, induction of hyperinsulinemia acutely in AD patients enhanced memory function.[5] These results [5] suggest that IR and not the elevated insulin levels per se may play a role in the development of AD/CVD pathology in T2D.
Author Manuscript
One possible mechanism by which T2D negatively affects brain function may involve increased secretion of the pancreatic hormone amylin (hyperamylinemia), which coincides always with hyperinsulinemia.[6] Hyperamylinemia was demonstrated to affect not only the pancreas [6] but also kidneys,[6] heart [7–9] and brain,[10] as we showed recently.[10] In the brain, we found [10] that amylin can form either independent deposits or mixed amylinAβ plaques. No amylin mRNA was detected in the human brain [10] demonstrating that amylin accumulates in the brain via circulation from the pancreas. Intriguingly, amylin deposits were identified [10] in blood vessels and brain parenchyma of AD patients without clinical evidence of T2D. These results [10] were interpreted as a possible effect of IR, which is common in aging. Notably, two other laboratories [11,12] independently demonstrated amylin deposition [11,12] and amylin-Aβ plaque formation [12] in brains of dementia patients. However, the potential link between brain amylin deposition and increased risk of cognitive decline has not been systematically evaluated. To fill this knowledge gap, future studies should include a broader sample of human brain pathologies, particularly to address the questions regarding mechanisms of accumulation and possible relationship of amylin accumulation with the comorbid disease (i.e., AD or/and CVD). Answering these questions could enable research opportunities for novel treatments of dementia.
Author Manuscript
Amylin may exacerbate the pathological effects of Aβ, as amylin and Aβ share a similar neurotoxicity profile.[13] For example, previous studies demonstrated that amylin and Aβ can induce neuronal apoptosis through Ca2+ dysregulation and elevated level of reactive oxygen species.[13,14] Hence, one can speculate on the convergence of these amylin-Aβ amyloid signaling pathways. This idea begins to unfold as amylin receptor was found to mediate both amylin and Aβ neurotoxicity.[14] Blocking the activity of amylin receptors attenuated the activation of caspases in Aβ-mediated apoptosis pathway.[14] However, how amylin and Aβ interacts with each other and other participating signaling factors remains unclear. Moreover, amylin, insulin and Aβ are degraded by the insulin degrading enzyme. Thus, the interaction between amylin dyshomeostasis and Aβ pathology could deteriorate
Expert Rev Proteomics. Author manuscript; available in PMC 2016 June 20.
Ly and Despa
Page 3
Author Manuscript
brain pathological condition via complex mechanisms. On the other hand, the brain amylin accumulation can impair brain function independently of Aβ pathology, as we demonstrated recently.[15]
Author Manuscript
Subtle but significant changes in brain function are frequently observed in patients with T2D even without frank dementia. [1,2] Specific disturbances include impaired psychomotor speed and memory.[1] Such changes have been difficult to reproduce in animal models,[16] which impedes the search for underlying mechanisms and treatments. Part of this problem arises from the fact that rodents do not spontaneously develop T2D. In rodents, T2D is induced by genetic manipulations. Depending on the transgene, some animal models show cognitive impairment even in the absence of hyperglycemia.[16] In other rodent models of T2D, such as the Zucker diabetic fatty (ZDF) rat, brain function remains intact,[16] despite the development of essential features of T2D, including hyperglycemia, IR and hyperinsulinemia. The resistance of ZDF rats to diabetic cognitive decline is attributed [16] to hyperinsulinemia, a condition believed to protect brain structure and function in T2D.[5] In addition to impaired glucose metabolism and hyperinsulinemia, the transgenic human islet amyloid polypeptide (HIP) rat model [15] of T2D bears a “human” hyperamylinemia. We found [15] that HIP rats accumulated brain amylin deposits even in the pre-diabetic state which was associated with reduced exploratory drive and vestibulomotor performance. Progressing to full-blown T2D in HIP rats appeared to exacerbate the amylin-induced deleterious effects on brain function leading to recognition memory deficits.[15] Thus, brain accumulation of oligomerized amylin may constitute a pathological substrate for diabetic brain injury and cognitive decline. These results demonstrated the pathological impact of amylin oligomerization on brain function in the absence of Aβ pathology.
Author Manuscript
Hyperamylinemia may negatively affect the health of both cerebrovasculature and neurons. Amylin was identified in the cerebral vessels and interstitial fluid surrounding cerebral cortex. [17] Also, an early study found that amylin induces a pattern of apoptotic genes with increasingly expressed oxidative stress genes in rat cortical neurons.[18] Based on these recent results,[10–12,15] we foresee an emerging challenge of understanding amylin signaling mechanism under pathological conditions and further characterize hyperamylinemia effects on the central nervous system.
Author Manuscript
Limiting amylin oligomerization in pancreatic islets reduced oxidative stress and retards the development of T2D [6] in animal models transgenic for human amylin. We also showed recently [9] that lowering the level of circulating amylin oligomers diminishes myocardial amylin deposition and improves heart function in HIP rats. Future studies should focus on ways to reduce the level of accumulation of oligomerized amylin in the brain. Circulating oligomerized amylin may be a novel, early, direct, and potentially treatable, pathogenic link of pancreatic dysfunction with brain injury and cognitive decline. Hormone amylin plays an important role in modulating peripheral energy balance,[6] vasorelaxation [19] and also acts centrally by diminishing exploration [15] and appetitive approach behavior [6] in rodents. A recent study [20] reported that intraperitoneal injection of amylin reduced the amyloid burden in AD mice. The authors [20] suggested that the amylin hormone mediates the translocation of Aβ peptide from the brain. However, amylin
Expert Rev Proteomics. Author manuscript; available in PMC 2016 June 20.
Ly and Despa
Page 4
Author Manuscript
may lose its function through oligomerization,[15] which can be toxic if it accumulates in tissues, as demonstrated by previous studies.[6,15] Moreover, in brain tissue from demented diabetics, we found [10] that amylin co-localized with Aβ as part of combined plaques. Given the toxicity of amylin,[10,14,15] these two amyloid species could act together or independently to accentuate neurotoxicity. In conclusion, hyperamylinemia has the potential role in the development of AD and CVD pathology in T2D. Deciphering the impact of hyperamylinemia on the brain in the presence or absence of the Aβ pathology is highly relevant for both etiology and treatment of these diseases.
References Author Manuscript Author Manuscript Author Manuscript
1. Luchsinger JA. Type 2 diabetes and cognitive impairment: linking mechanisms. J Alzheimers Dis. 2012; 30(2):S185–S198. [PubMed: 22433668] 2. Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol. 2009; 66(3):300–305. [PubMed: 19273747] 3. Launer LJ, Miller ME, Williamson JD, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label sub-study. Lancet Neurol. 2011; 10:969–977. [PubMed: 21958949] 4. de la Monte SM. Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease. Drugs. 2012; 72:49–66. [PubMed: 22191795] 5. Craft S, Newcomer J, Kanne S, et al. Memory improvement following induced hyperinsulinemia in alzheimer’s disease. Neurobiol Aging. 1996; 17(1):123–130. [PubMed: 8786794] 6. Westermark P, Andersson A, Westermark GT. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev. 2011; 91(3):795–826. [PubMed: 21742788] 7. Despa S, Margulies KB, Chen L, et al. Hyperamylinemia contributes to heart dysfunction in obesity and diabetes, a study in humans and rats. Circ Res. 2012; 110(4):598–608. [PubMed: 22275486] 8. Erickson JR, Pereira L, Wang L, et al. Diabetic hyperglycemia activates CaMKII and arrhythmias by O linked glycosylation. Nature. 2013; 502(7471):372–376. [PubMed: 24077098] 9. Despa S, Despa S, Sharma S, et al. Cardioprotection by controlling hyperamylinemia in a “humanized” diabetic rat model. J Am Heart Assoc. 2014; doi: 10.1161/JAHA.114.001015 10. Jackson K, Barisone G, Jin L-W, et al. Amylin deposition in the brain: a second amyloid in Alzheimer disease? Ann Neurol. 2013; 74(4):517–526. [PubMed: 23794448] 11. Fawver JN, Ghiwot Y, Koola C, et al. Islet amyloid polypeptide (IAPP): a second amyloid in Alzheimer’s disease. Curr Alzheimer Res. 2014; 11:928–940. [PubMed: 25387341] 12. Oskarsson ME, Paulsson JF, Schultz SW, et al. In vivo seeding and cross-seeding of localized amyloidosis: a molecular link between type 2 diabetes and Alzheimer disease. Am J Pathol. 2015; 185:834–846. [PubMed: 25700985] 13. Lim YA, Rhein V, Baysang G, et al. Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction. Proteomics. 2010; 10(8):1621–1633. [PubMed: 20186753] 14. Jhamandas JH, Mactavish D. Antagonist of the amylin receptor blocks beta-amyloid toxicity in rat cholinergic basal forebrain neurons. J Neurosci. 2004; 24(24):5579–5584. [PubMed: 15201330] 15. Srodulski S, Sharma S, Bachstetter AB, et al. Neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of amylin. Mol Neurodegener. 2014; 9:30. [PubMed: 25149184] 16. Biessels GJ, Gispen WH. The impact of diabetes on cognition: what can be learned from rodent models? Neurobiol Aging. 2005; 26(Suppl 1):36–41. [PubMed: 16223548] 17. Banks WA, Kastin AJ. Differential permeability of the blood-brain barrier to two pancreatic peptides: insulin and amylin. Peptides. 1998; 19(5):883–889. [PubMed: 9663454]
Expert Rev Proteomics. Author manuscript; available in PMC 2016 June 20.
Ly and Despa
Page 5
Author Manuscript
18. Tucker HM, Rydel RE, Wright S, et al. Human amylin induces “apoptotic” pattern of gene expression concomitant with cortical neuronal apoptosis. J Neurochem. 1998; 71(2):506–516. [PubMed: 9681440] 19. Edvinsson L, Goadsby PJ, Uddman R. Amylin: localization, effects on cerebral arteries and on local cerebral blood flow in the cat. Sci World J. 2001; 1:168–180. 20. Zhu H, Wang X, Wallack M, et al. Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer’s disease. Mol Psychiatry. 2015; 20(2):252–262. [PubMed: 24614496]
Author Manuscript Author Manuscript Author Manuscript Expert Rev Proteomics. Author manuscript; available in PMC 2016 June 20.
