Abstract
There is now abundant evidence that chronic inflammation in the brain is central to the pathogenesis of Alzheimer's disease (AD) and that this is precipitated through accumulation of amyloid beta (Aβ) peptides. In this review, we first outline this evidence and how specific receptors on microglia and monocyte/macrophages determine whether extracellular Aβ peptides can be cleared through non‐inflammatory phagocytosis or instead result in pro‐inflammatory cytokine generation. Most efforts of treatment for AD so far have focused on reduction of Aβ levels (in particular neurotoxic oligomers of Aβ1‐42) in the brain. Recent findings suggest an alternative approach in which pro‐inflammatory responses to Aβ peptides are targeted to reduce injury. Most recently evidence has come to light that Aβ peptides resemble anti‐microbial peptides which are part of the innate defense system against infection. Such peptides act both by directly inactivating pathogens, but also by modulating responses of innate immune cells, including phagocytes. Indeed, Aβ peptides, particularly Aβ1‐42, do inhibit a range of potential pathogens, including bacteria, fungi, and viruses. Coupling this with evidence linking chronic viral, bacteria, or fungal infection to AD suggests that production of Aβ peptides in the brain is part of an innate immune response which might normally be beneficial, but which leads to harm when it is chronic or uncontrolled. This suggests that discovery of the original possibly infectious (or other inflammatory) stimulus for Aβ production would allow early intervention to prevent development of AD.
Keywords
- Inflammasome
- TREM2
- Microglia
- antimicrobial peptide
1. Introduction
Aβ accumulation is believed to contribute strongly to the pathogenesis of AD, although the actual physiological function and reason for accumulation of Aβ in the brain are not known. Aβ is a fragment of the larger β amyloid precursor protein (APP) which is a transmembrane protein which can be broken down by various proteases into a variety of fragments, including extracellular and intracellular fragments and the peptide fragments Aβ1‐42 and Aβ1‐40 which are composed partly of the extracellular and partly of the transmembrane domain of APP. Aβ1‐40 is more abundant than Aβ1‐42, but Aβ1‐42 is the more amyloidogenic and neurotoxic species [1–3]. The neurotoxicity of Aβ1‐42 has been shown to depend on the ability of this peptide to form unstable oligomers (pentamers mainly), whereas the protofibrils or fibrils formed from the peptide are less neurotoxic. Recent studies are at last starting to elucidate why accumulation of Aβ, especially the 1–42 form leads to brain injury. These studies focus on the role of Aβ as a trigger of inflammation and emphasize its interaction with glial cells in the brain. A vicious cycle appears to occur in which Aβ peptides activate glial and other phagocytic cells which in turn impairs the ability of these cells to clear Aβ peptides and plaques from the brain. The reasons for production of Aβ in the brain in the first place are less clear. Recent findings that Aβ peptides function as antibacterial and antimicrobial peptides have given rise to the hypothesis that production of Aβ peptides may have evolved as part of the innate host defense system.
If it was possible to determine the initial causes for Aβ accumulation in the brain, this might provide another approach to early intervention. One hypothesis is that infection initiates or sustains the process of Aβ accumulation. Excess accumulation of Aβ has been linked to Human Immunodeficiency Virus‐related dementia [51, 52], and the virus can cause Aβ accumulation in vitro as well [53, 54]. Similarly Herpes Simplex Virus (HSV) induced encephalitis, and HSV infection in vitro is associated with Aβ accumulation [55–59], again implying that viruses may be a stimulus of Aβ production or impaired clearance. These findings suggest that viruses that infect the brain could be triggers for accumulation of Aβ, perhaps as part of an aberrant or sustained innate immune response. Antibodies to Cytomegalovirus, Epstein Barr Virus, or Human Herpes Virus 6 (HHV6) have also been associated with AD [60, 61] in some studies. In contrast, another study showed no link between AD and antibodies to HHV6 [62]. A variety of studies have also linked bacterial infection, including with chlamydia to development of AD [63, 64]. Of great interest, recent studies found fungal forms and sequences in brains of AD patients but not in controls [65–67]. Of course of a causal connection between these infections and AD is far from proven.
The finding that Aβ peptides, especially, Aβ1‐42 act like other cationic antimicrobial peptides may also explain its ability to activate phagocytic cells. AMPs have direct antimicrobial and antiviral activities but they also trigger recruitment and activation of immune cells [34, 36, 72]. We also recently showed that Aβ1‐42 modulates responses of neutrophils and monocytes to the influenza virus [71]. Aβ1‐42 increased neutrophil uptake of influenza A virus and potentiated neutrophil respiratory burst and neutrophil extracellular trap (NET) formation in response to the virus. Aβ1‐42 also reduced inflammatory cytokine production triggered by influenza virus in monocytes. The opsonizing activity of Aβ1‐42 was again not replicated with Aβ1‐40. More recently, we found that Aβ peptides can increase neutrophil uptake of bacteria as well (unpublished data). Overall, these studies lend support to the hypothesis that Aβ peptides serve a host defense role and that chronic infectious or inflammatory stimuli may result in an aberrant prolongation of what normally would be a helpful response.
2. Conclusions
There is now abundant evidence from a variety of sources that AD is characterized by a chronic inflammatory response in the brain. The key elements in this process include the ability of Aβ peptides, especially Aβ1‐42, to directly activate phagocytic cells, most notably microglia and, to a lesser extent, monocyte/macrophages. Figure 2 summarizes the microglial receptors, cytokines, and signaling mechanisms known to be linked to responses to Aβ peptides. These phagocytic cells are at the cross‐roads of innate immune responses in the brain, and they appear to play a pivotal role in determining whether the response to Aβ peptide accumulation is non‐inflammatory phagocytosis or pro‐inflammatory cytokine production. One conclusion from these studies is that inhibition of pro‐inflammatory responses early in the evolution of Aβ related pathology could be protective. For example, inhibition of inflammasome activation has been proposed as an approach to treatment. One dilemma is that there is not a simple correlation between processes normally thought of as pro‐inflammatory and reduction of neuronal injury in AD models. As prime examples, activation of the complement system or of toll‐like receptor pathways appears to be protective in some studies. In addition, the role of TREM2, while clearly important, is not as simply as initially expected. The recent findings that Aβ peptides (especially Aβ1‐42) function like other AMPs suggest that Aβ peptides may play a beneficial physiological role in vivo and may actually be part of an innate immune response to infection. If this is so then discovery of underlying infectious triggers of AD might provide a different modality of treatment.
References
- 1.
Dahlgren KN, Manelli AM, Stine WB, Jr., Baker LK, Krafft GA, LaDu MJ. Oligomeric and fibrillar species of amyloid‐beta peptides differentially affect neuronal viability. J Biol Chem. 2002;277(35):32046–53. PubMed PMID: 12058030. - 2.
Masters CL, Selkoe DJ. Biochemistry of amyloid beta‐protein and amyloid deposits in Alzheimer disease. Cold Spring Harbor Perspect Med. 2012;2(6):a006262. doi:10.1101/cshperspect.a006262. PubMed PMID: 22675658; PubMed Central PMCID: PMC3367542. - 3.
Selkoe DJ. Biochemistry and molecular biology of amyloid beta‐protein and the mechanism of Alzheimer's disease. Handb Clin Neurol. 2008;89:245–60. doi:10.1016/S0072‐9752(07)01223‐7. PubMed PMID: 18631749. - 4.
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira‐Saecker A, et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493(7434):674–8. doi:10.1038/nature11729. PubMed PMID: 23254930; PubMed Central PMCID: PMC3812809. - 5.
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015;14(4):388–405. doi:10.1016/S1474‐4422(15)70016‐5. PubMed PMID: 25792098. - 6.
Hickman SE, El Khoury J. TREM2 and the neuroimmunology of Alzheimer's disease. Biochem Pharmacol. 2014;88(4):495–8. doi:10.1016/j.bcp.2013.11.021. PubMed PMID: 24355566; PubMed Central PMCID: PMC3972304. - 7.
Burton A. NSAIDS and Alzheimer's disease: it's only Rock and Rho. Lancet Neurol. 2004;3(1):6. PubMed PMID: 14700055. - 8.
Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001;414(6860):212–6. doi:10.1038/35102591. PubMed PMID: 11700559. - 9.
Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, et al. Complement activation by beta‐amyloid in Alzheimer disease. Proc Natl Acad Sci USA. 1992;89(21):10016–20. PubMed PMID: 1438191; PubMed Central PMCID: PMC50268. - 10.
Barrientos RM, Kitt MM, Watkins LR, Maier SF. Neuroinflammation in the normal aging hippocampus. Neuroscience. 2015;309:84–99. doi:10.1016/j.neuroscience.2015.03.007. PubMed PMID: 25772789; PubMed Central PMCID: PMC4567963. - 11.
Jiang T, Yu JT, Zhu XC, Tan MS, Gu LZ, Zhang YD, et al. Triggering receptor expressed on myeloid cells 2 knockdown exacerbates aging‐related neuroinflammation and cognitive deficiency in senescence‐accelerated mouse prone 8 mice. Neurobiol Aging. 2014;35(6):1243–51. doi:10.1016/j.neurobiolaging.2013.11.026. PubMed PMID: 24368090. - 12.
Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18. doi:10.1038/nrneurol.2012.263. PubMed PMID: 23296339; PubMed Central PMCID: PMC3726719. - 13.
Holtzman DM, Herz J, Bu G. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harbor Perspect Med. 2012;2(3):a006312. doi:10.1101/cshperspect.a006312. PubMed PMID: 22393530; PubMed Central PMCID: PMC3282491. - 14.
Hartshorn KL. Role of surfactant protein A and D (SP‐A and SP‐D) in human antiviral host defense. Front Biosci (Schol Ed). 2010;2:527–46. PubMed PMID: 20036966. - 15.
Nybo M, Andersen K, Sorensen GL, Lolk A, Kragh‐Sorensen P, Holmskov U. Serum surfactant protein D is correlated to development of dementia and augmented mortality. Clin Immunol. 2007;123(3):333–7. PubMed PMID: 17449329. - 16.
Neumann H, Daly MJ. Variant TREM2 as risk factor for Alzheimer's disease. N Engl J Med. 2013;368(2):182–4. doi:10.1056/NEJMe1213157. PubMed PMID: 23151315. - 17.
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013;368(2):107–16. doi:10.1056/NEJMoa1211103. PubMed PMID: 23150908; PubMed Central PMCID: PMC3677583. - 18.
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013;368(2):117–27. doi:10.1056/NEJMoa1211851. PubMed PMID: 23150934; PubMed Central PMCID: PMC3631573. - 19.
Griciuc A, Serrano‐Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2013;78(4):631–43. doi:10.1016/j.neuron.2013.04.014. PubMed PMID: 23623698; PubMed Central PMCID: PMC3706457. - 20.
Brouwers N, Van Cauwenberghe C, Engelborghs S, Lambert JC, Bettens K, Le Bastard N, et al. Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Mol Psychiatry. 2012;17(2):223–33. doi:10.1038/mp.2011.24. PubMed PMID: 21403675; PubMed Central PMCID: PMC3265835. - 21.
Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer's disease. Nat Immunol. 2015;16(3):229–36. doi:10.1038/ni.3102. PubMed PMID: 25689443. - 22.
Frenkel D, Wilkinson K, Zhao L, Hickman SE, Means TK, Puckett L, et al. Scara1 deficiency impairs clearance of soluble amyloid‐beta by mononuclear phagocytes and accelerates Alzheimer's‐like disease progression. Nat Commun. 2013;4:2030. doi:10.1038/ncomms3030. PubMed PMID: 23799536; PubMed Central PMCID: PMC3702268. - 23.
Wilkinson K, El Khoury J. Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer's disease. Int J Alzheimer's Dis. 2012;2012:489456. doi:10.1155/2012/489456. PubMed PMID: 22666621; PubMed Central PMCID: PMC3362056. - 24.
Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, et al. CD36 ligands promote sterile inflammation through assembly of a Toll‐like receptor 4 and 6 heterodimer. Nat Immunol. 2010;11(2):155–61. doi:10.1038/ni.1836. PubMed PMID: 20037584; PubMed Central PMCID: PMC2809046. - 25.
Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, et al. CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta‐amyloid fibrils. Am J Pathol. 2002;160(1):101–12. PubMed PMID: 11786404; PubMed Central PMCID: PMC1867121. - 26.
Carlin AF, Chang YC, Areschoug T, Lindahl G, Hurtado‐Ziola N, King CC, et al. Group B Streptococcus suppression of phagocyte functions by protein‐mediated engagement of human Siglec‐5. J Exp Med. 2009;206(8):1691–9. PubMed PMID: 19596804. - 27.
Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med. 2015;212(3):287–95. doi:10.1084/jem.20142322. PubMed PMID: 25732305; PubMed Central PMCID: PMC4354365. - 28.
Jiang T, Tan L, Zhu XC, Zhang QQ, Cao L, Tan MS, et al. Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer's disease. Neuropsychopharmacology. 2014;39(13):2949–62. doi:10.1038/npp.2014.164. PubMed PMID: 25047746; PubMed Central PMCID: PMC4229581. - 29.
Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C, Zheng H, et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J Biol Chem. 2015;290(43):26043–50. doi:10.1074/jbc.M115.679043. PubMed PMID: 26374899; PubMed Central PMCID: PMC4646257. - 30.
Li X, Montine KS, Keene CD, Montine TJ. Different mechanisms of apolipoprotein E isoform‐dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia. FASEB J. 2015;29(5):1754–62. doi:10.1096/fj.14‐262683. PubMed PMID: 25593125; PubMed Central PMCID: PMC4415020. - 31.
Rogers J, Li R, Mastroeni D, Grover A, Leonard B, Ahern G, et al. Peripheral clearance of amyloid beta peptide by complement C3‐dependent adherence to erythrocytes. Neurobiol Aging. 2006;27(12):1733–9. doi:10.1016/j.neurobiolaging.2005.09.043. PubMed PMID: 16290270. - 32.
Wyss‐Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, et al. Prominent neurodegeneration and increased plaque formation in complement‐inhibited Alzheimer's mice. Proc Natl Acad Sci USA. 2002;99(16):10837–42. doi:10.1073/pnas.162350199. PubMed PMID: 12119423; PubMed Central PMCID: PMC125059. - 33.
Michaud JP, Richard KL, Rivest S. MyD88‐adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease. Mol Neurodegener. 2011;6(1):5. doi:10.1186/1750‐1326‐6‐5. PubMed PMID: 21235801; PubMed Central PMCID: PMC3030527. - 34.
Jana M, Palencia CA, Pahan K. Fibrillar amyloid‐beta peptides activate microglia via TLR2: implications for Alzheimer's disease. J Immunol. 2008;181(10):7254–62. PubMed PMID: 18981147. - 35.
Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A, et al. Toll‐like receptor‐4 mediates neuronal apoptosis induced by amyloid beta‐peptide and the membrane lipid peroxidation product 4‐hydroxynonenal. Exp Neurol. 2008;213(1):114–21. PubMed PMID: 18586243. - 36.
Richard KL, Filali M, Prefontaine P, Rivest S. Toll‐like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1–42 and delay the cognitive decline in a mouse model of Alzheimer's disease. J Neurosci. 2008;28(22):5784–93. PubMed PMID: 18509040. - 37.
Chen K, Iribarren P, Hu J, Chen J, Gong W, Cho EH, et al. Activation of Toll‐like receptor 2 on microglia promotes cell uptake of Alzheimer disease‐associated amyloid beta peptide. J Biol Chem. 2006;281(6):3651–9. PubMed PMID: 16339765. - 38.
Michaud JP, Halle M, Lampron A, Theriault P, Prefontaine P, Filali M, et al. Toll‐like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer's disease‐related pathology. Proc Natl Acad Sci USA. 2013;110(5):1941–6. doi:10.1073/pnas.1215165110. PubMed PMID: 23322736; PubMed Central PMCID: PMC3562771. - 39.
Michaud JP, Rivest S. Anti–inflammatory signaling in microglia exacerbates Alzheimer's disease‐related pathology. Neuron. 2015;85(3):450–2. doi:10.1016/j.neuron.2015.01.021. PubMed PMID: 25654250. - 40.
Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013;14(8):812–20. doi:10.1038/ni.2639. PubMed PMID: 23812099; PubMed Central PMCID: PMC3720827. - 41.
Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid‐beta. Nat Immunol. 2008;9(8):857–65. doi:10.1038/ni.1636. PubMed PMID: 18604209; PubMed Central PMCID: PMC3101478. - 42.
Gold M, El Khoury J. beta‐amyloid, microglia, and the inflammasome in Alzheimer's disease. Semin Immunopathol. 2015;37(6):607–11. doi:10.1007/s00281‐015‐0518‐0. PubMed PMID: 26251237; PubMed Central PMCID: PMC4618770. - 43.
Lamkanfi M, Dixit VM. Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol. 2012;28:137–61. PubMed PMID: 22974247. - 44.
Krauthausen M, Kummer MP, Zimmermann J, Reyes‐Irisarri E, Terwel D, Bulic B, et al. CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer's disease model. J Clin Invest. 2015;125(1):365–78. doi:10.1172/JCI66771. PubMed PMID: 25500888; PubMed Central PMCID: PMC4382235. - 45.
Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nat Neurosci. 2010;13(4):411–3. doi:10.1038/nn.2511. PubMed PMID: 20305648; PubMed Central PMCID: PMC4072212. - 46.
Hickman SE, El Khoury J. Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease. CNS Neurol Disord Drug Targets. 2010;9(2):168–73. PubMed PMID: 20205643; PubMed Central PMCID: PMC3684802. - 47.
Lee YK, Kwak DH, Oh KW, Nam SY, Lee BJ, Yun YW, et al. CCR5 deficiency induces astrocyte activation, Abeta deposit and impaired memory function. Neurobiol Learn Memory. 2009;92(3):356–63. doi:10.1016/j.nlm.2009.04.003. PubMed PMID: 19394434. - 48.
Vom Berg J, Prokop S, Miller KR, Obst J, Kalin RE, Lopategui‐Cabezas I, et al. Inhibition of IL‐12/IL‐23 signaling reduces Alzheimer's disease‐like pathology and cognitive decline. Nat Med. 2012;18(12):1812–9. doi:10.1038/nm.2965. PubMed PMID: 23178247. - 49.
Huang TC, Lu KT, Wo YY, Wu YJ, Yang YL. Resveratrol protects rats from Abeta‐induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation. PLoS One. 2011;6(12):e29102. doi:10.1371/journal.pone.0029102. PubMed PMID: 22220203; PubMed Central PMCID: PMC3248406. - 50.
Medeiros R, Prediger RD, Passos GF, Pandolfo P, Duarte FS, Franco JL, et al. Connecting TNF‐alpha signaling pathways to iNOS expression in a mouse model of Alzheimer's disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein. J Neurosci. 2007;27(20):5394–404. doi:10.1523/JNEUROSCI.5047‐06.2007. PubMed PMID: 17507561. - 51.
Zhang J, Liu J, Katafiasz B, Fox H, Xiong H. HIV‐1 gp120‐induced axonal injury detected by accumulation of beta‐amyloid precursor protein in adult rat corpus callosum. J Neuroimmune Pharmacol. 2011;6(4):650–7. PubMed PMID: 21286834. - 52.
Andras IE, Eum SY, Toborek M. Lipid rafts and functional caveolae regulate HIV‐induced amyloid beta accumulation in brain endothelial cells. Biochem Biophys Res Commun. 2012;421(2):177–83. PubMed PMID: 22490665. - 53.
Lan X, Kiyota T, Hanamsagar R, Huang Y, Andrews S, Peng H, et al. The effect of HIV protease inhibitors on amyloid‐beta peptide degradation and synthesis in human cells and Alzheimer's disease animal model. J Neuroimmune Pharmacol. 2012;7(2):412–23. doi:10.1007/s11481‐011‐9304‐5. PubMed PMID: 21826404; PubMed Central PMCID: PMC3223330. - 54.
Lan X, Xu J, Kiyota T, Peng H, Zheng JC, Ikezu T. HIV‐1 reduces Abeta‐degrading enzymatic activities in primary human mononuclear phagocytes. J Immunol. 186(12):6925–32. PubMed PMID: 21551363. - 55.
Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB. Herpes simplex virus infection causes cellular beta‐amyloid accumulation and secretase upregulation. Neurosci Lett. 2007;429(2–3):95–100. PubMed PMID: 17980964. - 56.
Wozniak MA, Frost AL, Preston CM, Itzhaki RF. Antivirals reduce the formation of key Alzheimer's disease molecules in cell cultures acutely infected with herpes simplex virus type 1. PLoS One. 2011;6(10):e25152. PubMed PMID: 22003387. - 57.
De Chiara G, Marcocci ME, Civitelli L, Argnani R, Piacentini R, Ripoli C, et al. APP processing induced by herpes simplex virus type 1 (HSV‐1) yields several APP fragments in human and rat neuronal cells. PLoS One. 2010;5(11):e13989. PubMed PMID: 21085580. - 58.
Lukiw WJ, Cui JG, Yuan LY, Bhattacharjee PS, Corkern M, Clement C, et al. Acyclovir or Abeta42 peptides attenuate HSV‐1‐induced miRNA‐146a levels in human primary brain cells. Neuroreport. 2010;21(14):922–7. PubMed PMID: 20683212. - 59.
Piacentini R, Civitelli L, Ripoli C, Marcocci ME, De Chiara G, Garaci E, et al. HSV‐1 promotes Ca2+ ‐mediated APP phosphorylation and Abeta accumulation in rat cortical neurons. Neurobiol Aging. 2010;32(12):2323 e13–26. PubMed PMID: 20674092. - 60.
Lurain NS, Hanson BA, Martinson J, Leurgans SE, Landay AL, Bennett DA, et al. Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease. J Infect Dis. 2013;208(4):564–72. PubMed PMID: 23661800. - 61.
Carbone I, Lazzarotto T, Ianni M, Porcellini E, Forti P, Masliah E, et al. Herpes virus in Alzheimer's disease: relation to progression of the disease. Neurobiol Aging. 2013;35(1):122–9. PubMed PMID: 23916950. - 62.
Agostini S, Mancuso R, Baglio F, Cabinio M, Hernis A, Guerini FR, et al. Lack of evidence for a role of HHV‐6 in the pathogenesis of Alzheimer's disease. J Alzheimers Dis. 2015;49(1):229–35. doi:10.3233/JAD‐150464. PubMed PMID: 26444787. - 63.
Hammond CJ, Hallock LR, Howanski RJ, Appelt DM, Little CS, Balin BJ. Immunohistological detection of Chlamydia pneumoniae in the Alzheimer's disease brain. BMC Neurosci. 2010;11:121. doi:10.1186/1471‐2202‐11‐121. PubMed PMID: 20863379; PubMed Central PMCID: PMC2949767. - 64.
Gerard HC, Dreses‐Werringloer U, Wildt KS, Deka S, Oszust C, Balin BJ, et al. Chlamydophila (Chlamydia) pneumoniae in the Alzheimer's brain. FEMS Immunol Med Microbiol. 2006;48(3):355–66. doi:10.1111/j.1574‐695X.2006.00154.x. PubMed PMID: 17052268. - 65.
Pisa D, Alonso R, Rabano A, Rodal I, Carrasco L. Different brain regions are infected with Fungi in Alzheimer's disease. Sci Rep. 2015;5:15015. doi:10.1038/srep15015. PubMed PMID: 26468932; PubMed Central PMCID: PMC4606562. - 66.
Alonso R, Pisa D, Rabano A, Rodal I, Carrasco L. Cerebrospinal fluid from Alzheimer's disease patients contains fungal proteins and DNA. J Alzheimers Dis. 2015;47(4):873–6. doi:10.3233/JAD‐150382. PubMed PMID: 26401766. - 67.
Alonso R, Pisa D, Rabano A, Carrasco L. Alzheimer's disease and disseminated mycoses. Eur J Clin Microbiol Infect Dis. 2014;33(7):1125–32. doi:10.1007/s10096‐013‐2045‐z. PubMed PMID: 24452965. - 68.
Kagan BL, Jang H, Capone R, Teran Arce F, Ramachandran S, Lal R, et al. Antimicrobial properties of amyloid peptides. Mol Pharm. 2012;9(4):708–17. PubMed PMID: 22081976. - 69.
Jang H, Ma B, Lal R, Nussinov R. Models of toxic beta‐sheet channels of protegrin‐1 suggest a common subunit organization motif shared with toxic alzheimer beta‐amyloid ion channels. Biophys J. 2008;95(10):4631–42. PubMed PMID: 18708452. - 70.
Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, et al. The Alzheimer's disease‐associated amyloid beta‐protein is an antimicrobial peptide. PLoS One. 2010;5(3):e9505. PubMed PMID: 20209079. - 71.
White MR, Kandel R, Tripathi S, Condon D, Qi L, Taubenberger J, et al. Alzheimer's associated beta‐amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes. PLoS One. 2014;9(7):e101364. doi:10.1371/journal.pone.0101364. PubMed PMID: 24988208; PubMed Central PMCID: PMC4079246. - 72.
Oppenheim JJ, Yang D. Alarmins: chemotactic activators of immune responses. Curr Opin Immunol. 2005;17(4):359–65. PubMed PMID: 15955682.