Decreased immunoglobulin G in brain regions of elder female APOE4-TR mice accompany with Aβ accumulation
Tóm tắt
Apolipoprotein E4 (APOE4) and ageing are the most important known risk factors for late-onset Alzheimer’s disease (AD). In the present study, we determined the alterations of IgG, CD19, and Aβ in various brain regions of uninfected male and female APOE3- and APOE4-TR mice at the age of 3 and 10 months to elucidate impacts of AD risk factors on alterations of brain IgG. Positive staining for IgG was distributed across the brain, including neocortex, entorhinal cortex, hippocampus, thalamus and cerebellum. IgG positive staining was mainly located on microglia, but not astrocytes. Some IgG positive neurons were also observed, but only in mediodorsal thalamic nucleus. Compared with APOE3-TR mice, 10-month-old female APOE4-TR mice had lower IgG level in AD susceptible brain regions such as neocortex, entorhinal cortex and hippocampus, but no significant changes in thalamus and cerebellum, two regions nearly intact in AD. In addition, the expression of CD19, a specific marker for mature B cells, was significantly reduced in the hippocampus of 10-month-old female APOE4-TR mice. Although there were no obvious differences in plasma IgG levels between APOE4- and age matched female APOE3-TR mice, significant decreased B cell amount in blood of 10-month-old female APOE4-TR mice have also been found. Moreover, more obvious positive staining for Aβ was observed in the cortex of 10-month-old female APOE4-TR mice than other groups. Our study demonstrated that AD risk factors were associated with IgG alterations in various brain regions, which might result from the defects of humoral immunity and lead to the impairment of IgG-mediated clearance of Aβ by microglia, therefore facilitated AD progression.
Tài liệu tham khảo
Dong S, Duan Y, Hu Y, Zhao Z. Advances in the pathogenesis of Alzheimer's disease: a re-evaluation of amyloid cascade hypothesis. Transl Neurodegener. 2012;1(1):18.
2016 Alzheimer's disease facts and figures. Alzheimer's & dementia : the journal of the Alzheimer's Association 2016;12(4):459–509.
Karlamangla AS, Lachman ME, Han W, Huang M, Greendale GA. Evidence for cognitive aging in midlife women: study of Women's health across the nation. PLoS One. 2017;12(1):e0169008.
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261(5123):921–3.
Cacciottolo M, Christensen A, Moser A, Liu J, Pike CJ, Smith C, et al. The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice. Neurobiol Aging. 2016;37:47–57.
Huang YA, Zhou B, Wernig M, Sudhof TC. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Abeta secretion. Cell. 2017;168(3):427–41.e21.
Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, et al. Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med. 2011;3(89):89ra57.
Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, et al. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci U S A. 2013;110(19):E1807–E16.
Fouquet M, Besson FL, Gonneaud J, La Joie R, Chetelat G. Imaging brain effects of APOE4 in cognitively normal individuals across the lifespan. Neuropsychol Rev. 2014;24(3):290–9.
Takata K, Kitamura Y, Yanagisawa D, Morikawa S, Morita M, Inubushi T, et al. Microglial transplantation increases amyloid-beta clearance in Alzheimer model rats. FEBS Lett. 2007;581(3):475–8.
Pan XD, Zhu YG, Lin N, Zhang J, Ye QY, Huang HP, et al. Microglial phagocytosis induced by fibrillar beta-amyloid is attenuated by oligomeric beta-amyloid: implications for Alzheimer's disease. Mol Neurodegener. 2011;6:45.
Magga J, Puli L, Pihlaja R, Kanninen K, Neulamaa S, Malm T, et al. Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease. J Neuroinflammation. 2010;7(1):90.
Relkin N. Intravenous immunoglobulin for Alzheimer's disease. Clin Exp Immunol. 2014;178(Suppl 1):27–9.
Ries M, Sastre M. Mechanisms of Abeta clearance and degradation by glial cells. Front Aging Neurosci. 2016;8:160.
Sudduth TL, Greenstein A, Wilcock DM. Intracranial injection of Gammagard, a human IVIg, modulates the inflammatory response of the brain and lowers Abeta in APP/PS1 mice along a different time course than anti-Abeta antibodies. J Neurosci. 2013;33(23):9684–92.
Counts SE, Ray B, Mufson EJ, Perez SE, He B, Lahiri DK. Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer's disease. J Clin Immunol. 2014;34(Suppl 1):S80–5.
Relkin N. Clinical trials of intravenous immunoglobulin for Alzheimer's disease. J Clin Immunol. 2014;34(Suppl 1):S74–9.
Relkin NR, Thomas RG, Rissman RA, Brewer JB, Rafii MS, van Dyck CH, et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology. 2017;88(18):1768–75.
Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73(24):2061–70.
Knight EM, Gandy S. Immunomodulation and AD – down but not out. J Clin Immunol. 2014;34(1):70–3.
Zhou Y, Zhao W, Al-Muhtasib N, Rebeck GW. APOE genotype alters immunoglobulin subtypes in Knock-in mice. J Alzheimers Dis. 2015;46(2):365–74.
Zhao W, Dumanis SB, Tamboli IY, Rodriguez GA, Jo Ladu M, Moussa CE, et al. Human APOE genotype affects intraneuronal Abeta1-42 accumulation in a lentiviral gene transfer model. Hum Mol Genet. 2014;23(5):1365–75.
Zhao W, Zhang J, Davis EG, Rebeck GW. Aging reduces glial uptake and promotes extracellular accumulation of Abeta from a lentiviral vector. Front Aging Neurosci. 2014;6:210.
Sullivan PM, Mezdour H, Aratani Y, Knouff C, Najib J, Reddick RL, et al. Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem. 1997;272(29):17972–80.
Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31(3):545–8.
Zechariah A, ElAli A, Hermann DM. Combination of tissue-plasminogen activator with erythropoietin induces blood-brain barrier permeability, extracellular matrix disaggregation, and DNA fragmentation after focal cerebral ischemia in mice. Stroke. 2010;41(5):1008–12.
Zhang X, Chen XP, Lin JB, Xiong Y, Liao WJ, Wan Q. Effect of enriched environment on angiogenesis and neurological functions in rats with focal cerebral ischemia. Brain Res. 2017;1655:176–85.
Gould E, Woolley CS, McEwen BS. The hippocampal formation: morphological changes induced by thyroid, gonadal and adrenal hormones. Psychoneuroendocrinology. 1991;16(1–3):67–84.
Li XB, Inoue T, Nakagawa S, Koyama T. Effect of mediodorsal thalamic nucleus lesion on contextual fear conditioning in rats. Brain Res. 2004;1008(2):261–72.
Heo Y, Zhang Y, Gao D, Miller VM, Lawrence DA. Aberrant immune responses in a mouse with behavioral disorders. PLoS One. 2011;6(7):e20912.
Marsh SE, Abud EM, Lakatos A, Karimzadeh A, Yeung ST, Davtyan H, et al. The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A. 2016;113(9):E1316–25.
Glass LJ, Sinclair D, Boerrigter D, Naude K, Fung SJ, Brown D, et al. Brain antibodies in the cortex and blood of people with schizophrenia and controls. Transl Psychiatry. 2017;7(8):e1192.
Deane R, Sagare A, Hamm K, Parisi M, LaRue B, Guo H, et al. IgG-assisted age-dependent clearance of Alzheimer's amyloid beta peptide by the blood-brain barrier neonatal fc receptor. J Neurosci. 2005;25(50):11495–503.
Bake S, Friedman J, Sohrabji F. Reproductive age-related changes in the blood brain barrier: expression of IgG and tight junction proteins. Microvasc Res. 2009;78(3):413–24.
Ingalhalikar M, Smith A, Parker D, Satterthwaite TD, Elliott MA, Ruparel K, et al. Sex differences in the structural connectome of the human brain. Proc Natl Acad Sci. 2014;111(2):823–8.
Verthelyi D. Sex hormones as immunomodulators in health and disease. Int Immunopharmacol. 2001;1(6):983–93.
Ahmed SA, Talal N. Sex hormones and the immune system-part 2. Animal data. Baillieres Clin Rheumatol. 1990;4(1):13–31.
Fernandez-Vizarra P, Lopez-Franco O, Mallavia B, Higuera-Matas A, Lopez-Parra V, Ortiz-Munoz G, et al. Immunoglobulin G fc receptor deficiency prevents Alzheimer-like pathology and cognitive impairment in mice. Brain : a journal of neurology. 2012;135(Pt 9):2826–37.
Huang J, Sun X, Mao Y, Zhu X, Zhang P, Zhang L, et al. Expression of immunoglobulin gene with classical V-(D)-J rearrangement in mouse brain neurons. Int J Biochem Cell Biol. 2008;40(8):1604–15.
Lovato L, Willis SN, Rodig SJ, Caron T, Almendinger SE, Howell OW, et al. Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis. Brain : a journal of neurology. 2011;134(Pt 2):534–41.
Alter A, Duddy M, Hebert S, Biernacki K, Prat A, Antel JP, et al. Determinants of human B cell migration across brain endothelial cells. J Immunol. 2003;170(9):4497–505.
Zhang J, Niu N, Li B, McNutt MA. Neuron-derived IgG protects neurons from complement-dependent cytotoxicity. J Histochem Cytochem. 2013;61(12):869–79.
Zhang J, Niu N, Wang M, McNutt MA, Zhang D, Zhang B, et al. Neuron-derived IgG protects dopaminergic neurons from insult by 6-OHDA and activates microglia through the FcγR i and TLR4 pathways. Int J Biochem Cell Biol. 2013;45(8):1911–20.
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–41.
Anthony IC, Crawford DH, Bell JE. B lymphocytes in the normal brain: contrasts with HIV-associated lymphoid infiltrates and lymphomas. Brain : a journal of neurology. 2003;126(Pt 5):1058–67.
Doyle KP, Buckwalter MS. Does B lymphocyte-mediated autoimmunity contribute to post-stroke dementia? Brain Behav Immun. 2017;64:1–8.
Gylys KH, Fein JA, Tan AM, Cole GM. Apolipoprotein E enhances uptake of soluble but not aggregated amyloid-β protein into synaptic terminals. J Neurochem. 2003;84(6):1442–51.
Istrin G, Bosis E, Solomon B. Intravenous immunoglobulin enhances the clearance of fibrillar amyloid-beta peptide. J Neurosci Res. 2006;84(2):434–43.
Fu R, Shen Q, Xu P, Luo JJ, Tang Y. Phagocytosis of microglia in the central nervous system diseases. Mol Neurobiol. 2014;49(3):1422–34.