Dement Neurocogn Disord.  2019 Jun;18(2):33-46. 10.12779/dnd.2019.18.2.33.

A Therapeutic Strategy for Alzheimer's Disease Focused on Immune-inflammatory Modulation

Affiliations
  • 1Department of Neurology, Hanyang University College of Medicine, Seoul, Korea. kimsh1@hanyang.ac.kr
  • 2Department of Neurology, Konkuk University School of Medicine, Seoul, Korea.
  • 3Department of Laboratory Medicine, Hanyang University College of Medicine, Seoul, Korea.
  • 4Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu, Korea.
  • 5Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea.
  • 6Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.

Abstract

Alzheimer's disease (AD), the most common form of dementia, has emerged as a major global public health challenge. However, the complexity of AD in its biological, genetic, and clinical aspects has hindered the development of effective therapeutic agents. Research plans that integrate new drug discoveries are urgently needed, including those based on novel and reliable biomarkers that reflect not only clinical phenotype, but also genetic and neuroimaging information. Therapeutic strategies such as stratification (i.e., subgrouping of patients having similar clinical characteristics or genetic background) and personalized medicine could be set as new directions for developing effective drugs for AD. In this review, we describe a therapeutic strategy that is based on immune-inflammation modulation for a subgroup of AD and related dementias, arguing that the use of stratification and personalized medicine is a promising way to achieve targeted medicine. The Korean AD Research Platform Initiative based on Immune-Inflammatory biomarkers (K-ARPI) has recently launched a strategy to develop novel biomarkers to identify a subpopulation of patients with AD and to develop new drug candidates for delaying the progression of AD by modulating toxic immune inflammatory response. Sphingosine kinase 1 (SphK1) and its metabolites, triggering receptor expressed on myeloid cells-2 (TREM2) related signals, and actin motility related proteins including Nck-associated protein 1 (Nap1) were selected as promising targets to modulate neuroinflammation. Their roles in stratification and personalized medicine will be discussed.

Keyword

Alzheimer's Disease; Inflammation; Personalized Medicine; Biomarkers

MeSH Terms

Actins
Alzheimer Disease*
Biomarkers
Dementia
Humans
Inflammation
Neuroimaging
Phenotype
Phosphotransferases
Precision Medicine
Public Health
Sphingosine
Actins
Biomarkers
Phosphotransferases
Sphingosine

Figure

  • Fig. 1 A comparison of drug development (A) and clinical trial paradigms (B) between the traditional model and future directions (modified from pharma 2020: the vision18). CIM: confidence in mechanism, CIS: confidence in safety.

  • Fig. 2 Characteristics of microglia showing two types of polarity (M1 and M2) and their characteristic cytokines and receptors. Possible candidates potentiating M2 polarity are summarized. M1: pro-inflammatory, M2: anti-inflammatory polarity, LPS: lipopolysaccharide, IFN: interferon, GM-CSF: granulocyte-macrophage colony-stimulating factor, TNF: tumor necrosis factor, IL: interleukin, SR: scavenger receptor, TGF: transforming growth factor, DMF: dimethylformamide, G-CSF-R: granulocyte colony-stimulating factor receptor, GSK-3: glycogen synthase kinase-3, HDAC: histone deacetylase, PPAR: peroxisome proliferator-activated receptor, AMPK: adenosine monophosphate-activated protein kinase, JAK/STAT: Janus kinase/signal transducers and activators of transcription.

  • Fig. 3 Generation of induced microglia like cells from peripheral blood mononuclear cells (A) and defected microglial phagocytosis in rapidly progressive AD compared to early AD and normal controls (B). AD: Alzheimer's disease, GM-CSF: granulocyte-macrophage colony-stimulating factor, IL-34: interleukin-34, I-MG: induced microglia, HC: healthy controls, AD (E): Alzheimer's disease (early), AD (R): Alzheimer's disease (rapidly).

  • Fig. 4 Conceptual fluid-like spectra of clinical phenotypes and functional characteristics of immune cells depending on the environment. M1: pro-inflammatory, M2: anti-inflammatory polarity, AD: Alzheimer's disease, SPM: specialized pro-resolving mediator, Th: T helper.

  • Fig. 5 Decision platform suggested by the K-ARPI. (A) Prescreening of AD patients for clustering with genetic information and clinical characteristics, imaging, biomarkers, and analysis. (B) Reclassification of prescreened clusters according to the algorithm using standardized biomarkers. (C) Schematic summary of the decision platform of the K-ARPI. K-ARPI: Korean AD Research Platform Initiative based on Immune-inflammatory biomarkers, AD: Alzheimer's disease, PET: positron emission tomography, CSF: cerebrospinal fluid.


Reference

1. Alzheimer's Association. 2017 Alzheimer's disease facts and figures. Alzheimers Dement. 2017; 13:325–373.
2. World Health Organization. Global Action Plan on the Public Health Response to Dementia 2017–2025. Geneva: World Health Organization;2017.
3. Prince M, Guerchet M, Prina M. The Epidemiology and Impact of Dementia: Current State and Future Trends. Geneva: World Health Organization;2015. p. –. .
4. National Institute of Dementia. Korean Dementia Observatory 2016. Seongnam: National Institute of Dementia;2017.
5. Karantzoulis S, Galvin JE. Distinguishing Alzheimer's disease from other major forms of dementia. Expert Rev Neurother. 2011; 11:1579–1591.
Article
6. McManus RM, Heneka MT. Role of neuroinflammation in neurodegeneration: new insights. Alzheimers Res Ther. 2017; 9:14.
Article
7. Mayeux R, Stern Y, Spanton S. Heterogeneity in dementia of the Alzheimer type: evidence of subgroups. Neurology. 1985; 35:453–461.
Article
8. Yiannopoulou KG, Papageorgiou SG. Current and future treatments for Alzheimer's disease. Ther Adv Neurol Disorder. 2013; 6:19–33.
Article
9. Zhao X, Zheng X, Fan TP, Li Z, Zhang Y, Zheng J. A novel drug discovery strategy inspired by traditional medicine philosophies. Science. 2015; 347:S38–S40.
10. Herrup K, Carrillo MC, Schenk D, Cacace A, Desanti S, Fremeau R, et al. Beyond amyloid: getting real about nonamyloid targets in Alzheimer's disease. Alzheimers Dement. 2013; 9:452–458.e1.
Article
11. Hampel H, Vergallo A, Giorgi FS, Kim SH, Depypere H, Graziani M, et al. Precision medicine and drug development in Alzheimer's disease: the importance of sexual dimorphism and patient stratification. Front Neuroendocrinol. 2018; 50:31–51.
Article
12. Hampel H, Toschi N, Babiloni C, Baldacci F, Black KL, Bokde AL, et al. Revolution of Alzheimer precision neurology. Passageway of systems biology and neurophysiology. J Alzheimers Dis. 2018; 64:S47–S105.
13. Cummings JL, Morstorf T, Zhong LK. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014; 6:37.
Article
14. Morgan P, Brown DG, Lennard S, Anderton MJ, Barrett JC, Eriksson U, et al. Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nat Rev Drug Discov. 2018; 17:167–181.
Article
15. Finger E, Berry S, Cummings J, Coleman K, Hsiung R, Feldman HH, et al. Adaptive crossover designs for assessment of symptomatic treatments targeting behaviour in neurodegenerative disease: a phase 2 clinical trial of intranasal oxytocin for frontotemporal dementia (FOXY). Alzheimers Res Ther. 2018; 10:102.
Article
16. Lam B, Masellis M, Freedman M, Stuss DT, Black SE. Clinical, imaging, and pathological heterogeneity of the Alzheimer's disease syndrome. Alzheimers Res Ther. 2013; 5:1.
Article
17. Schmidt C, Wolff M, Weitz M, Bartlau T, Korth C, Zerr I. Rapidly progressive Alzheimer disease. Arch Neurol. 2011; 68:1124–1130.
Article
18. Pricewaterhouse Coopers. Pharma 2020: the vision. Which path will you take? [Internet]. London: Pricewaterhouse Coopers;2007. cited 2007 June. Available from: https://www.pwc.com/gx/en/pharma-life-sciences/pdf/pharma2020final.pdf.
19. Pallmann P, Bedding AW, Choodari-Oskooei B, Dimairo M, Flight L, Hampson LV, et al. Adaptive designs in clinical trials: why use them, and how to run and report them. BMC Med. 2018; 16:29.
Article
20. Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014; 14:463–477.
Article
21. Hooten KG, Beers DR, Zhao W, Appel SH. Protective and toxic neuroinflammation in amyotrophic lateral sclerosis. Neurotherapeutics. 2015; 12:364–375.
Article
22. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015; 14:388–405.
Article
23. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011; 91:461–553.
Article
24. Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013; 38:792–804.
Article
25. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo . Science. 2005; 308:1314–1318.
Article
26. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A unique microglia type associated with restricting development of Alzheimer's disease. Cell. 2017; 169:1276–1290.e17.
Article
27. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell. 2018; 173:1073–1081.
Article
28. Michell-Robinson MA, Touil H, Healy LM, Owen DR, Durafourt BA, Bar-Or A, et al. Roles of microglia in brain development, tissue maintenance and repair. Brain. 2015; 138:1138–1159.
Article
29. Andreasson KI, Bachstetter AD, Colonna M, Ginhoux F, Holmes C, Lamb B, et al. Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem. 2016; 138:653–693.
Article
30. Song GJ, Suk K. Pharmacological modulation of functional phenotypes of microglia in neurodegenerative diseases. Front Aging Neurosci. 2017; 9:139.
Article
31. Malik M, Parikh I, Vasquez JB, Smith C, Tai L, Bu G, et al. Genetics ignite focus on microglial inflammation in Alzheimer's disease. Mol Neurodegener. 2015; 10:52.
Article
32. Noh MY, Lim SM, Oh KW, Cho KA, Park J, Kim KS, et al. Mesenchymal stem cells modulate the functional properties of microglia via TGF-β secretion. Stem Cells Transl Med. 2016; 5:1538–1549.
Article
33. Bianchin MM, Capella HM, Chaves DL, Steindel M, Grisard EC, Ganev GG, et al. Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy--PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects. Cell Mol Neurobiol. 2004; 24:1–24.
Article
34. Hickman SE, El Khoury J. TREM2 and the neuroimmunology of Alzheimer's disease. Biochem Pharmacol. 2014; 88:495–498.
Article
35. Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015; 160:1061–1071.
Article
36. Slattery CF, Beck JA, Harper L, Adamson G, Abdi Z, Uphill J, et al. R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia. Alzheimers Dement. 2014; 10:602–608.e4.
Article
37. Cady J, Koval ED, Benitez BA, Zaidman C, Jockel-Balsarotti J, Allred P, et al. TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol. 2014; 71:449–453.
Article
38. Palmqvist S, Mattsson N, Hansson O. Alzheimer's Disease Neuroimaging Initiative. Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography. Brain. 2016; 139:1226–1236.
Article
39. Suárez-Calvet M, Kleinberger G, Araque Caballero MÁ, Brendel M, Rominger A, Alcolea D, et al. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers. EMBO Mol Med. 2016; 8:466–476.
Article
40. David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci. 2011; 12:388–399.
Article
41. Desikan RS, Fan CC, Wang Y, Schork AJ, Cabral HJ, Cupples LA, et al. Genetic assessment of age-associated Alzheimer disease risk: development and validation of a polygenic hazard score. PLoS Med. 2017; 14:e1002258.
Article
42. Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010; 303:1832–1840.
Article
43. Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006; 312:1389–1392.
Article
44. Zhao W, Beers DR, Hooten KG, Sieglaff DH, Zhang A, Kalyana-Sundaram S, et al. Characterization of gene expression phenotype in ALS monocytes. JAMA Neurol. 2017; 74:677–685.
Article
45. Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, et al. Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis. Neuron. 2014; 81:1009–1023.
Article
46. Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004; 15:601–609.
Article
47. Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2006; 103:16021–16026.
Article
48. Komine O, Yamanaka K. Neuroinflammation in motor neuron disease. Nagoya J Med Sci. 2015; 77:537–549.
49. Spiegel S, Milstien S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol. 2011; 11:403–415.
Article
50. Nayak D, Huo Y, Kwang WX, Pushparaj PN, Kumar SD, Ling EA, et al. Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia. Neuroscience. 2010; 166:132–144.
Article
51. Lee JY, Han SH, Park MH, Baek B, Song IS, Choi MK, et al. Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer's disease. Nat Commun. 2018; 9:1479–1497.
Article
52. Pchejetski D, Nunes J, Coughlan K, Lall H, Pitson SM, Waxman J, et al. The involvement of sphingosine kinase 1 in LPS-induced Toll-like receptor 4-mediated accumulation of HIF-1α protein, activation of ASK1 and production of the pro-inflammatory cytokine IL-6. Immunol Cell Biol. 2011; 89:268–274.
Article
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