257
PERSPECTIVE
Complement pathway in
Alzheimer’s pathology and retinal neurodegenerative disorders – the road ahead
Chronic inflammation has increasingly been acknowledged as a hallmark feature of veral progressive neurodegenerative disor-ders. Accruing evidence indicates that sustained inflammation compromis the core neuroprotective mechanisms underlying neural injury in Alzheimer’s dia (AD) and retinal neurodegen-erative disorders. Innate immunity and activation of the classical complement pathways are suggested to play important roles in nor-mal central nervous system physiology and complex tissue remod-eling during the dia process (Gasque et al., 2000). The pathway is implicated in normal brain development and is also involved in the inflammatory respon in a wide range of neurodegenerative conditions either directly or indirectly through recruitment and activ
ation of immune cells. The classical, alternative and lectin complement pathways, together encompass about 30 plasma and membrane-bound proteins. The classical pathway is comprid of about 20 proteins including veral rine proteinas and protein-a inhibitors connected as part of an amplifying cascade. Activa-tion of the classical pathway is triggered once C1q is attached to the immune complexes containing IgG or IgM leading to production of the C3 converta (Merle et al., 2015).
Although complement constitutes the core of innate immune defence mechanisms in blood, veral complement proteins are also expresd in the brain and in the retina. Complement activa-tion has, interestingly, been reported in a wide range of retinal and brain disorders including AD, depression, izures, multiple scle-rosis, age related macular degeneration, diabetic retinopathy, uveo-retinitis and glaucoma. More recently, involvement of this pathway in AD pathophysiology (Winston et al., 2019) and retinal disorders (Kassa et al., 2019) has gained significant attention. C1q, C3 and C4 are well expresd in the brain and have been shown to exhibit veral fold elevated expression in AD (Zhou et al., 2008). In-cread C1q expression was also reported in glaucoma conditions. Whether the incread expression in the brain and the retina is due to augmentation in synthesis of the proteins in the neuronal and glial cells or is sourced from the blood due to compromid blood-brain
and blood-retinal barriers is not well established. The complement pathway, however, likely continues to perform its well-known functions of tissue homeostasis, and debris and pro-tein aggregate clearance in the brain and retina, or at least works in that direction. In the long term, chronic activation of complement proteins may promote neurotoxicity and induce synap and neu-ronal cell degeneration.
段晓天It is still unclear as to how the complement pathway is activated in the brain and retina, but abnormal protein aggregation in neu-rodegenerative conditions ems to be the most likely stimulus for complement activation. For instance, amyloid β and tau aggrega-tion and protein deposition may trigger complement activation in AD (Mirzaei et al., 2019). Interestingly, both the proteins are also elevated in the ganglion cell layer in glaucoma. Amyloid aggregates in drun deposits are also a key feature of age-related macular
degeneration (AMD) pathology. Amyloid deposition in the brain and retina promotes microglial and astrocytic activation that in turn may stimulate complement activation. Synaptic degenerative changes in AD mou models has been shown to be associated with complement activation and C1q levels were shown to correspond to increa tau levels in the brain. More recently, Litvinchuk et al. (2018) demonstrated C3a receptor inhibition to play a role in re-ducing tau pathology in AD mice.
Complement pathway repressor complement factor H, in contrast, was shown to be reduced in the retina of AD mou model. An in vitro study demonstrated the ac-tivation of alternative and complement pathway as a result of both fibrillar amyloid β1–40 and β1–42 peptide binding to C3 and the globular heads of C1q proteins. C1q plays a key role in intensify-ing the toxicity of soluble amyloid β oligomers on synaps as well as memory forming biochemical process in the hippocampus (Kolev et al., 2009). Multiple reports highlighting involvement of complement pathway proteins in animal models of AD and human subjects has resulted in growing interest in manipulating the com-plement pathway, in particular, the classical pathway in the brain to improve function or restore homeostasis.
Sustained elevation of C1q expression in the retina was obrved in ischemia/reperfusion injury in mice and interestingly C1q de-ficient mice demonstrated significant functional and structural protection against the inner retinal damage (Kolev et al., 2009). Similar changes in C1q expression have been identified in the ret-ina and optic nerve head of DBA/2J congenital mou glaucoma model. C3 levels were also obrved in the retinal ganglion cells in experimental glaucoma models and post-mortem human eyes and enhanced expression of C3 was evident in the retinal ganglion cells in culture under stress induced by rum deprivation of cells. C3a receptor was also shown to p
lay a role in ocular morphogenesis and mice lacking C3a and C5a receptors exhibited caspa activation and progressive retinal degenerative changes (Yu et al., 2012). Re-markably, genetic modulation of C3 was shown recently to impart significant protection against ont and progression of inner retinal injury in DBA/2J chronic mou glaucoma model. Our proteom-ics studies carried out in human post-mortem glaucoma retinas revealed that immune and inflammatory pathways associated with complement system such as C1q, C1s, C1r, C4a, C4b, C3, C5, C6, C7, C8a, C8b, C8g and C9 were over-reprented in the vitreous and retinal samples (Mirzaei et al., 2017). Apart from its roles in mediating inflammation, the complement system has also been shown to play a role in synaptic development and pruning, process-es that are negatively affected in AD and in retinal degeneration.Several complement pathway linked genetic variants such as CFI, CFH, C3 and C9 have been shown to exhibit association with AMD. A number of clinical trials targeting different components of complement pathway such as C3, C5, factor D and properdin are underway in AMD. AMD is associated with incread drun deposition and complement inhibitors such as clusterin, CD46 and vitronectin have been identified in drun (Kawa et al., 2014). The significance of the obrvations in AMD pathophysiology is not clear but amyloid β colocalization with C3 products in the AMD retinas suggests that amyloid deposition might be playing a role in complement activation in the retina, similar to its effects in the brain in AD. Complement activation products C5a and C3a ar
e constituents of drun and elevated locally that might promote choroidal neo-vascularisation in the retina. C3a, C3d, Ba, C5a, and membrane attack complex C5b-9 have been shown to be incread
Mirzaei M, Deng L, Gupta VB, Graham S, Gupta V (2020) Complement pathway in Alzheimer’s pathology and retinal neurodegenerative disorders – the road ahead. Neural Regen Res 15(2):257-258. doi:10.4103/1673-5374.265550
in blood of AMD patients. Transgenic mice lacking intact C3 and C3aR/C5aR demonstrated reduced vesl formation in lar in-duced neovascularisation model of AMD and this vascularisation was also suppresd in respon to pharmacological blockade of the receptors (Kawa et al., 2014). Incread levels of C3a, CFB and C3c have been identified in the aqueous humour of uveitis patients suggesting its role in the intraocular inflammatory dia process. Inhibition of complement pathway by neutralising factor B was shown to suppress uveitis injury by modulating T cell respons-es in a rat model.
Rearch conducted in last decade or so has significantly in-cread our understanding of the involvement of complement path-way proteins in neurodegenerative and pro-inflammatory dia process in AD and in retinal disorders. Apart from significant efforts in AMD however, where ver
佛理al clinical trials are underway targeting different complement components, we have not en a significant advancement on complement pathway regulating ther-apeutic approaches in ocular disorders. Success in gene therapy to modulate C3 in a glaucoma model and concomitant neuroprotec-tion suggests its promising role in glaucoma (Bosco et al., 2018). Until, we identify consistent beneficial effects of complement inhibition in pre-clinical and clinical trials, it might be difficult to establish whether complement activation is indeed detrimental for neural tissues or if it plays a protective role at least during initial stages of the dia process. It is possible that the process starts a protective phenomenon until it snowballs into a destructive process in chronic dia. The crosstalk between complement activation and effects of other inflammatory process such as cytokine acti-vation, microglial, dendritic cell and astrocyte function too needs to be resolved clearly for better understanding of complement path-way mediated dia process. Greater understanding of the rel-ative contribution of the different inflammatory components will facilitate combination therapies to resist cell-injury and improve neuroprotection. Another challenge in complement targeting per-haps is to design drugs that can cross blood brain and blood retinal barrier and can act specifically at the site of dia. Nevertheless, complement targeting may be a promising therapeutic approach to improve neural cell function and restore tissue homeostasis in the brain and retinal disorders.
This work was supported by Ophthalmic Rearch Institute of Aus-tralia (ORIA), NHMRC, Macquarie University, and the Australian Government’s National Collaborative Rearch Infrastructure Scheme (NCRIS).
Mehdi Mirzaei*, Liting Deng, Veer Bala Gupta, Stuart Graham, Vivek Gupta*
Department of Molecular Sciences, Macquarie University, Sydney, NSW, Australia (Mirzaei M, Deng L)
Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, Australia (Mirzaei M)
Department of Clinical Medicine, Macquarie University, Sydney, NSW, Australia (Mirzaei M, Graham S, Gupta V)
School of Medicine, Deakin University, Geelong, VIC, Australia (Gupta VB)
火祭
*Correspondence to:Mehdi Mirzaei, PhD, mehdi.mirzaei@mq.edu.au; Vivek Gupta, PhD, vivek.gupta@mq.edu.au.
orcid: 0000-0001-8727-4984 (Mehdi Mirzaei)
Received:June 9, 2019在线儿童故事
Accepted:June 26, 2019doi: 10.4103/1673-5374.265550
Copyright licen agreement: The Copyright Licen Agreement has been signed by all authors before publication.
Plagiarism check: Checked twice by iThenticate.
酱油豆腐Peer review: Externally peer reviewed.
Open access statement: This is an open access journal, and articles are dis-tributed under the terms of the Creative Commons Attribution-NonCommer-cial-ShareAlike 4.0 Licen, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licend under the identical terms. References
Bosco A, Anderson SR, Breen KT, Romero CO, Steele MR, Chiodo VA, Boye SL, Hauswirth WW, Tomlinson S, Vetter ML (2018) Complement C3-targeted gene therapy restricts ont and progression of neurodegen-eration in chronic mou glaucoma. Mol Ther 26:2379-2396.
Gasque P, Dean YD, McGreal EP, VanBeek J, Morgan BP (2000) Comple-ment components of the innate immune system in health and dia in the CNS. Immunopharmacology 49:171-186.
Kassa E, Ciulla TA, Hussain RM, Dugel PU (2019) Complement inhibition as a therapeutic strategy in retinal disorders. Expert Opin Biol Ther 19:335-342.
Kawa MP, Machalinska A, Roginska D, Machalinski B (2014) Complement system in pathogenesis of AMD: dual player in degeneration and protec-tion of retinal tissue. J Immunol Res 2014:483960.
志贺直哉Kolev MV, Ruva MM, Harris CL, Morgan BP, Donev RM (2009) Implica-tion of complement system and its regulators in Alzheimer’s dia. Curr Neuropharmacol 7:1-8.
Litvinchuk A, Wan YW, Swartzlander DB, Chen F, Cole A, Propson NE, Wang Q, Zhang B, Liu Z, Zheng H (2018) Complement C3aR inactiva-tion attenuates tau pathology and revers an immune network dereg-ulated in tauopathy models and Alzheimer’s dia. Neuron 100:1337-1353.e5.
Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT (2015) Comple-ment system part I – molecular mechanisms of activation and regulation. Front Immunol 6:262.
Mirzaei M, Gupta VB, Chick JM, Greco TM, Wu Y, Chitranshi N, Wall RV, Hone E, Deng L, Dheer Y,
Abbasi M, Rezaeian M, Braidy N, Y ou Y, Salekdeh GH, Haynes PA, Molloy MP, Martins R, Cristea IM, Gygi SP, et al. (2017) Age-related neurodegenerative dia associated pathways identified in retinal and vitreous proteome from human glaucoma eyes. Sci Rep 7:12685.
Mirzaei M, Pushpitha K, Deng L, Chitranshi N, Gupta V, Rajput R, Manga-ni AB, Dheer Y, Godinez A, McKay MJ, Kamath K, Pascovici D, Wu JX, Salekdeh GH, Karl T, Haynes PA, Graham SL, Gupta VK (2019) Upreg-ulation of proteolytic pathways and altered protein biosynthesis underlie retinal pathology in a mou model of Alzheimer’s dia. Mol Neurobi-ol doi: 10.1007/s12035-019-1479-4.
财政税收
如何学习c语言Winston CN, Goetzl EJ, Schwartz JB, Elahi FM, Rissman RA (2019) Com-plement protein levels in plasma astrocyte-derived exosomes are abnor-mal in conversion from mild cognitive impairment to Alzheimer’s dia dementia. Alzheimers Dement (Amst) 11:61-66.
Yu M, Zou W, Peachey NS, McIntyre TM, Liu J (2012) A novel role of com-plement in retinal degeneration. Invest Ophthalmol Vis Sci 53:7684-7692. Zhou J, Fonca MI, Pisalyaput K, Tenner AJ (2008) Complement C3 and C4 expression in C1q sufficient and deficient mou models of Alzhei-mer’s dia. J Neurochem 106:2080-2092.
C-Editors: Zhao M, Li JY; T-Editor: Jia Y
258
