Neuroinflammatory markers; Diagnostic and Therapeutic Targets for Neurodegenerative Diseases
, Dithu Thekkekkara2*
, Haritha P H3
, S N Manjua4
1.Lecturer, Department of pharmacology, KMCH College of Pharmacy, Coimbatore, India
2*. Lecturer, Department of Pharmacology, JSS College of Pharmacy, JSSAHER, Mysuru, India 3. M Pharm , Department of Pharmacology, KMCH College of Pharmacy, Coimbatore, India 4. Professor Department of Pharmacology, JSS College of Pharmacy, JSSAHER, Mysuru, India
5. Professor, Department of Pharmacology KMCH College of Pharmacy, Coimbatore, India
*Corresponding AuthorE-mail: [email protected]
Neuroinflammation (NI) is the earlier cardinal evidence in the central nervous system, which in progression results in various neurological disease. NI leads to release of various toxic metabolites, inflammatory mediators, and reactive oxygen species.
Insults of brain vasculature cause several physical and biochemical changes, activation of microglial cells and astrocytes and changes in the permeability of BBB. BBB changes results in the release of adhesion molecules like selectins, integrins and immunoglobulin like cellular adhesion molecules. In neuropathological conditions, various proteins like ABCG2, OATP1B1, Glut1, MRP-1, LRP-1, RAGE, MCT, Megalin and cytoskeleton filament proteins like GFAP will be overexpressed, and this considered as important evidence for NI. Especially glial cell markers are one of the important checkpoints for NI. IL-33/ST2, Toll like receptor -4, tenascin-C, TWIK-related K+ channel 1, C5aR, cathepsin D, Aquaporin-4 are some of the newly identified markers involved in NI. These various biomarkers involved in NI can be used for diagnosis and treatment of various neurodegenerative diseases in early stages of disease progression. So, the current review article covers the pathophysiology of NI and the various biomarkers involved in NI. In short, this review gives a clear detail about biomarker of NI, focusing on neurodegenerative diseases like Alzheimer's disease, Parkinson disease and multiple sclerosis, which can be used as diagnostic and therapeutic agents.
Keywords: Neuroinflammation, BBB permeability, BBB transporters, Glial cell markers, Adhesion molecules, Biomarkers.
Neuroinflammation (NI) is the earlier cardinal evidence in the central nervous system(CNS), due to the various insults of tissue damage, infection and autoimmune conditions [1,2]. It results in the release of various proinflammatory cytokines, vasoactive neuropeptides, predominantly calcitonin gene-related peptide (CGRP), substance P, neurokinin A, microglia and astrocytes. Normally the blood brain barrier (BBB) protects the brain and spinal cords from the peripheral immune response and activates the innate immune system [3, 4, 5]. In recent years, research has shown that a chronic inflammatory response can lead to the development of the neurodegenerative diseases (ND) such as Alzheimer's disease (AD), Parkinson disease (PD) and multiple sclerosis (MS) [6, 7]. Various biomarkers involved in NI can be used as an indicator for diagnostic and treatment tool for various ND in early stages of disease progression. So current review article covers various biomarker involved in the pathophysiology of NI. In short, this review gives a clear detail about biomarkers of NI focusing on various diseases like AD, PD, and MS.
Structural and molecular changes in neuroinflammation
The releases of various neuroinflammatory mediators during NI cause changes in blood-brain barrier (BBB)permeability, changes in blood brain transporters and activation of glial cells.The major NI markers are adhesion molecules are integrins, selectins and immunoglobulin-like cellular adhesion molecules, cytoskeletal filaments and various glial cells. These protein molecules are already reported for its function for maintenance of the tight junction of BBB , during NI these cells help to transmigrate the inflammatory cells and leukocytes across the endothelial barrier. (Figure 1)
Figure 1: Molecular mechanism of neuroinflammation
Changes in blood-brain barrier permeability
The Blood-brain barrier (BBB) is composed of complex network of vessels that contain specialized endothelial cells, which facilitate the rapid exchange of molecules between blood vessels and tissues . Claudin protein family members claudin-5 and occluding primarily forms BBB tight junctions. These proteins are linked to the cytoskeleton filaments of zonulaoccludens and form the tight junctions . Especially one of the junctional adhesion molecules (JAM)IgG superfamily (IgS) molecules is mediating the integrity of adjacent endothelial cells. Researchers concluded that JAM has critical role in maintaining the BBB integrity. Decreased or loss of JAM protein expression directly linked to the breakdown of BBB . (Table 1: Blood brain barrier transporter markers in neuro inflammation). Also, pinocytic vesicles of BBB help to reduce the uptake of extracellular substances due to tight junctions and results in a reduction in the membrane permeability . Limited permeability minimizes the movement of substances from the systemic circulation to the brain, which controls the brain from rapid changes in ionic or metabolic conditions. This results in protection of the brain from toxic molecules . Neurons, the extracellular matrix, astrocytes, pericytes, and vascular endothelial cells regulate BBB permeability. These cells, along with the extracellular matrix, function as a neurovascular unit to regulate BBB permeability and maintain the integrity and function of the CNS .
MARKERS PROPERTIES ROLE
ABCG2/ breast cancer resistance protein
Multi drug resistance receptor ATP–binding cassette transporter family
Used for diagnosis of MS 
Glut1 Insulin-glucose transporter receptor. BBB GLUT-1 expression reduced during AD .
MRP-I Multi drug resistance (MDR) protein1
Maintain the BBB permeability
LRP-1 LDL receptor related protein-1 Microglial LRP-1 amplifying the
NI AD .
LRP-1 cluster-I & II LDL receptor related protein-1 Microglial LRP-1 amplifying the NI
Neuronal out growth .
OATP1B1/OATP2 Organic anion transporter Decreased during epilepsy
Increased during the ischemic stroke [15, 16]
MCT1/SLC16A1 H+-linked mono carboxylate transporter-1(MCT-1)
MCT8/SLC16A2 MCT-8 Deficiency during abnormal brain
Megalin/LRP2 Megalin is a multi-ligand endocytic receptor
Reduced during AD 
MRP4/ABCC4 MDR-4 located in the astrocytes ins ubcorticalregion white matter
Resistance of the brain to several cytotoxic drugs 
OCTN1/SLC22A4 Organiccation/carnitine transporter Solute carrier superfamily -22
Neurological disorder 
RAGE/AGER receptor for advanced
AD & PD
Elevated during the depression 
Table 1: Blood brain barrier transporter markers in neuro inflammation
In normal physiological conditions, BBB prevents the transport of foreign bodies, large molecules, and most small molecules into the brain. The lipophilic components size less than 400 Daltons can cross the. Waste products BBB that are too large or too hydrophilic can cross BBB as substrates of activated efflux transporters (AET) [26, 27].
Other methods of transport through BBB are by carrier-mediated transporters (CMT) and receptor-mediated transport (RMT). However, in certain conditions such as inflammation, traumatic brain injury or ischemia, the BBB is compromised allowing for the passage of larger and hydrophilic substances . Impaired function of BBB mainly caused by the trauma, stroke, hypoxia,inflammation,neurotoxic substances, pathogens, activation of the clotting system and genetic factors . BBB disruption results in elevation of various endothelial tight junction proteins like claudins, occludin, peripheral scaffolding proteins like zonulaoccludens (ZO) protein, afadins, matrix metalloproteinase (MMP), cellular adhesion molecule (CAM), and monocytes chemoattractant protein-1(MCP-1) and various chemokines. These proteins help in regulating the transmigration and infiltration of monocyte and macrophages. Macrophage inflammatory protein 2 is small cytokines (CXCL2) that cause progression of the inflammation. During the NI condition, there will be an elevation of inflammatory enzymes like nitric oxide synthase [iNOS], phospholipase (PLA2) and Cyclooxygenase-2(COX-2). These inflammatory enzymes activities the resident lymphocytes for infiltration this leads to the development of the inflammation cycle. Besong et al showed the RANTES is a CC5 chemokine is a potential biomarker for various NI conditions in CNS. Changes in BBB permeability play a major role in depression, ischemic stroke, epilepsy, and ND etc. .
Changes in cytoskeleton Filaments and associated Proteins levels
Cytoskeleton filaments are the three-dimensional proteins that help to maintain the cell morphology, mobility, mitosis, and intracellular movements. These are divided in to three types such as microfilaments, microtubules, and intermediate filaments. Keratin, vimentin (Vim), Desmin, neurofilament protein subunit and glial fibrillary acidic protein (GFAP)are examples of cytoskeleton filament proteins.VimandGFAP increased expression during the CNS development . The function of vim is to regulate the neutrophils and macrophages during inflammation. Studies sayvim is an indicator for NI because it denotes for activated microglial cells . Example, vim expression is more in AD . GFAP is the first isolated protein from brain lesions of MS affected patients.GFAP are widely used marker for astrocytes and astrocytes related neoplasm. During NI, sometimes astrocyte morphology may get effected due to over expression of immature intermediate filaments proteins like GFAP, vim and nestin. These molecules are the cardinal hallmarks of the CNS pathological conditions. Choi JH et,al., reported that desmin and GFAP are the dynamic molecules expressed in activated astrocytes .(Figure 2 )
Figure 2: Pathological role of vimentin
Activation of Glial cells
Glial cells are specialized cells found in the CNS and PNS. Totally 70% of the glial cells distributed in the CNS and spinal cord. Glial cells classified in two types such as microglia (5-10% population of glial cells) and macroglia (astrocytes, oligodentrocytes). Microglia and macrogliainvolved in NI and neuropathic pain. Normally the inflammatory mediators change the microglial activation. So, it helps easy detection of the NI by using the microglial markers . Microglial markers involve M1, M2 M2a, M2b, and M2c (Table 2: Glial cell type and its markers)
GLIAL CELL TYPE MARKER
Neural stem cells, nonmyelinating Schwann cells, astrocytes
Neural stem cells Prominin 1
Glial cells, oligodendrocytes SRY-box transcription factor 10
Neural progenitors SRY-box transcription factor 2
Astrocytes Glutamate transporters , Glutamine synthetase, Aquaporin 4, Aldehyde dehydrogenase 1 family member L1
Glial cells, pituicytes S100 calcium binding protein B 
Radial glia HOP homebox 
Astroglia, astrocyte Vimentin 
Oligodendrocytes, Schwann cells 2', 3'-cyclic nucleotide 3'-phosphodiesterase
Oligodendrocyte progenitor cells (OPCs) NG2 Chondroitin sulfate proteoglycan 4 (CSPG4) , Platelet- derived growth factor α 
Neurons and glia P75 Neurotrophin receptor 
Oligodendrocytes, Bergmann glia Peripheral myelin protein-22, Proteolipid protein 1
Myelinating glia Oligodendrocyte transcription factor 2
Tanycytes Retina and anterior neural fold homeobox protein , Potassium channel interacting protein 3
Stem cells, progenitor cells Nestin
Table 2: Glial cell type and its markers Role of microglia in neuroinflammation
Microglia, the brain's primary resident innate immune cells, has its clear role in the development and functioning of the brain. It originates from the embryonic mesoderm and its major role is to maintain hematopoiesis and the activation of the immune system during initial stages of brain development. And later in the matured organism, it produced from white blood cells (WBC) and circulate through the blood and reaches to the CNS, where its role is to protect the homeostasis and integrity of the brain . Microglia fine-tunes neural circuits and phagocytosis of apoptotic debris in a normal CNS. They are quick responders for insult or injury. Mainly microglial activation divided into two types M1 and M2 type. M1type activation is associated with cytotoxicity and inflammatory responses. M2 type is beneficial; it is further subdivided into M2a, M2b and M2c type. M2ainvolved in repair and regeneration. M2b has its role in immune regulation and M2c involved in an acquired deactivation. Activation of microglia is a pathophysiological hallmark of all neurodegenerative disorders. All the insults of CNS like infections, massive trauma, post-ischemic or toxicity-related necrosis, haemorrhage or accumulation of neurotoxic fibers can activate inflammatory responses in innate microglia cells.NI has two phases acute and chronic. NI can stimulate microglia, which result in the release of inflammatory cytokines, phagocyte debris and dead cells. This initial response is an attempt to start tissue repair and thus, sort out the inflammatory cause. However, if the repairing mechanisms did not work out or the stimulus persists, that leads to self-propagating and persistent stage of chronic inflammation. Chronic inflammation can cause neuronal toxicity and death .
Microglial cellsactivation and various neurodegenerative diseases
NI leads to malfunction of microglial cells result in increased the secretion of chemokines, ROS, and endogenous substance retinoic acid (RA). Disruption of retinoid signaling pathways in rodent models indicates their involvement in regulating synaptic plasticity and associated learning and memory behavior. This gives a valid link between microglial activation and AD. Also, an assumption that microglial malfunction, which brings about changes in local RA concentrations, maybe the underling AD pathogenesis and proceed or facilitate the onset of AD. Thus, chronic,
"innate neuroinflammation" may provide a valuable target for preventive and therapeutic strategies for AD [57, 58].
Microglial cells representing the antigen-presenting cell (APC) in brain parenchyma during neurodegenerative disease. Also, duringND, the microglial population is the main major histocompatibility complex (MHC) class II- expressing antigen-presenting cell (APC) in the brain parenchyma, where neuronal damage can be found. The MHCII + microglia cells and T-cell accumulation are the important cardinal hallmark forND. So, this APC-T cells equilibrium can be given a better marker for Alzheimer’s disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and prion-induced neurodegeneration . Age-related cognitive impairment is due to microglial activation and neuroinflammatory changes. It's being proved by a study conducted in sedentary aged mice. In this study, Virginia Mela team tried to find out the exercise-induced re-programming of age-related metabolic changes in microglia. Aged animals showed a significant increase in glycolysis, glycolytic capacity and6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3 (PFKFB3) expression in microglia. Also, the senescent markers, like β-galactosidase and p16INK4A, were increased in microglia from sedentary aged mice .
Chronic activation of microglia due to repetitive head impact causes accumulation of tau protein, results in chronic traumatic encephalopathy associated dementia. So, microglia are one of the potential diagnostic markers for chronic traumatic encephalopathy .NF-b signaling in microglia plays an essential role in inflammatory responses by regulating cytokines and chemokines that result in astrogliosis . For regulating microglial activation, a perfect target is Phosphodiesterase 4(PDE4). Because PDE4 is involving in cyclic adenosine monophosphate (cAMP) signaling. In turn, cAMP is a regulator for microglial homeostasis. So, Phosphodiesterase-4(PDE4) inhibition is one of the solutions for regulation of NI and immune response .
During NI, miR-155 (Micro-RNA) got up-regulated in activated microglia and macrophages, result in changes of these cells towards pro-inflammatory phenotype. Hairpin inhibitors (antagomirs) can knockdown miR-155, this results in reduced release of inflammatory mediators, such as nitric oxide and interleukin-1β (IL-1β), tumor necrosis
factor-α (TNFα). So, miR-155 can be a therapeutic target for attenuate toxic neuroinflammatory responses in various neurodegenerative diseases . P2Y6 receptor mainly deals with microglial activation and phagocytosis during NI in CNS. The expression of P2Y6receptors is high in PD patients. So, this can be a potential biomarker and therapeutic agent for PD. P2Y6 receptor blocking attenuates the microglial cell activation .
Like microglial cells, other major cells involved in the normal maintenance of the integrity of the brain are astrocytes. During inflammation, there are increased stimulation astrocytes, which are regulated by the various intracellular signaling pathways and results in changes in gene expression, hypertrophy and proliferation of the astrocytes [66, 67]. The researcher found out that in AD, the beta-amyloid (β amyloid) protein expression has shown to disrupt gliotransmission, neurotransmitter (NT) uptake and changes in calcium signaling pathways in astrocytes.
Releases of pro-inflammatory agents can lead to damage the astrocytes’ function . Jo et al., showed the immune calin superfamily of Orosomucoid (ORM) acute phase protein, particularly ORM2 protein expressed by astrocytes in the brain upon NI conditions. It produces the intrinsic factors modulating microglial activation and migration. So ORM2 exploited therapeutic targets for neuroinflammatory diseases . Also, YKL-40 protein expression in CSF associated with astrocytes in the pericontusional cortex by releasing of inflammatory mediators in acute neuroinflammatory condition . Williams’s et.al, reported in NI the inflammatory cytokines mediated the astrocytes for immune cell trafficking .
Changes in BBB proteins in neuroinflammation
Molecules: Normally the interaction between the cells and extracellular matrix are controlling the cell proliferation, apoptosis and cell survival. This interaction depends upon the specialized transmembrane proteins known as adhesion molecules. Adhesion molecules act through the rolling, firm adhesion, leading and transmigration process.
Based on the molecular structure of the adhesion molecule, they are divided into four families, selectins, integrins, immunoglobulins like CAMs and cadherins. These are characterized by three types of domains like intracellular, extracellular and transmembranedomains [72-76]. Intercellular adhesion molecules (ICAM) are easily bonded with activated leukocytes and indirectly linked to the tight junctions of the cytoskeleton of BBB and act as an adaptor molecule for maintaining the homeostasis and permeability BBB.Marc-Andre Lecuye et.alstudied the role of the adhesion molecule ALCAM (activated leukocyte cell adhesion molecule) present on BBB endothelial cells in ALCAM knockout mice. ALCAM regulates and maintains tight junction stability of BBB by acting as an adaptor molecule. In the case of multiple sclerosis, multifocal lesions in the CNS produced by infiltrating leukocytes. So, this study explains the role of ALCAM in regulating leukocytes infiltration through BBB during NI .
Selectins are the carbohydrate molecules; they bind with fucosylated proteins and sialylated glycoprotein ligands.
They are commonly found in endothelial cells, platelets and leukocytes and contain N-terminal Ca+ dependent lectin domain . They consist of three types of the transmembrane family of glycoproteins such as P-selectin (CD62P), E-selectins (CD62E) and L- selectins (CD62L). L-selectin found in all granulocyte’s monocytes and most expressed in lymphocytes . P- selectin found in α granules of platelets and WPB’s (Weibel–Palade bodies) of endothelial cells, in the inner lining of endothelial cells of heart and blood vessels. Weibel–Palade bodies are the storage granules of epithelium cells . P –selectins have a major role in adhering the leukocytes to activated platelets and epithelium . E-selectin is found in skins microvessels. They were rapidly induced by the inflammatory cytokines compared to other types of selectins. Recurrent bacterial infection and inflammatory reactions occurring due to the absence of selectins and selectin ligands. In acute and chronic inflammation conditions, the selectins molecule accumulates in lymphocyte molecules of blood vessels and muscles. They target the different regions of the cellular domain, such as P-selectins targeting to secretory granules, E- selectins targeting to the plasma membrane and L – selectins are tips of micro folds on leukocytes [82, 83].
A; Role of P – selectins (CD62P) in neuro inflammation
P – selectin is a calcium dependent cellular adhesion molecule and a mucin type of glycoprotein . When platelets and endothelial cells exposed to inflammatory mediators such as histamine, ROS (Reactive Oxygen Species), lipo polysaccharides, interleukin-1 (IL-1)andtumor necrosis factor-α (TNFα) that results in increased transcriptions of mRNA, causes the mobilization of stored P selectins to the cells surface. The normal plasma concentration of selectinis100ng ml-1. During respiratory depression, plasma concentration of P selectin will be
increased [85, 86]. Main function of P-selectin is to enhance the platelets for binding to the neutrophils and monocytes and down regulate them.Angelica Salas-Perdomo et.al, reported the role of P selectinsinmemory CD4+ T cell preventing hemorrhagic transformation in ischemic stroke. P selectinsplay important role with T lymphocytes in ischemic stroke. In cerebral ischemic stroke condition,there is an increase in the level of P-selectinsand macrophage- 1 antigen (MAC-1).So, the P- selectins are the major diagnostic marker for cerebral ischemia .
B;Role of E- selectins (CD62E) in neuro inflammation
The E- selectins is a glycoprotein-ligand. Weight of E- selecins about 105-117 kDa. Releases of various mediators like histamine, reactive oxygen species, IL-1andTNF- α, substance P and endotoxins can increase the synthesis of E selectins.During NI, E selectinsgot firmly adhered to inflamed endothelial cells and bonded with the surface glycoproteins of leukocytes . Miceis deficient in E- selectins and beta chain integrin molecules. So during inflammatory condition, the severity will be high that lead to early death of mice.In a recent study HaojieYanget.al.,reported that in vitro mouse brain endothelial cells (b.End3) cell line model is used for Kruppel- like family of transcription factor 4 (KLF4) for mouse cerebral microvascular endothelial cells (MECs) and noted the aggravation of oxygen-glucose deprivation (OGD) increased the expression of E-selectin,MCP-1and IL-6 in ischemic stroke condition .
C;Role of L- selectins (CD62L) in neuro inflammation
L-selectins expressed on the lymphocytes during theinflammatory mediator’s activation. This selectin molecule involved in the lymphocyte adhesion and contributed the shed formation on the inflamed endothelial cells in peripheral lymph nodes . L-selectin is a glycoprotein about 74 to 100 kDa. It plays the crucial role in surgical trauma by recruiting the neutrophils . The research found out that L-selectins does not have a certain velocity on the expression of rolling of leukocytes. Combination of L-selectins and P-selectins enable to capture the lymphocytes at the beginning stage like rolling lymphocyte phase [93, 94].
Immunoglobulin Super family of CAMs
Immunoglobulin super family (IgSF) is the transmembrane calcium dependent glycoproteins. IgSF each moleculecontains an extracellular domain. It is used for treating the Guillain–Barré syndrome . The researchers already have been demonstrated that IgG used for reducing hind –limb functional damage.SoIgG can work as a neuroprotectiveagent . It is also involved in cell- cell interactions. They are mainly divided in to Vascular Cell Adhesion Molecules (VCAM), Neural Cell Adhesion Molecules (NCAM), Intercellular Adhesion Molecules (ICAM), Nectin and Nectin Like Family (NEC1), Platelet Endothelial Cell Adhesion Molecules (PECAM), Mucosal Adressin Cell Adhesion Molecule (MAdCAM), Junctional Adhesion Molecule (JAM), Activated Leukocyte Cell Adhesion Molecule (ALCAM, CD166) and Melanoma cell adhesion molecules (CD146).
A;Vascular Cell Adhesion Molecules (VCAM-1)
VCAM is redirected as CD106. It possess the six or seven domains of immunoglobulins and VCAM encoded the VCAM -1 gene.VCAM located in the small and large blood vessels of the endothelium membrane. After exposure of cytokines, VCAM -1 gene will get overexpressed.J.B. O'Sullivan team reported that in rat’s noradrenalin reuptake inhibitors (NRI) can suppress various neuroinflammatory mediators like chemokines, interferon inducible protein- 10(IP-10), VCAM-1 and ICAM-1in brain. So, in NI conditions the overexpression of VCAM-1 can be down regulate by noradrenalin reuptake inhibitors . Cerebrovascular inflammation occurring after ischemic and hemorrhagic strokes detected in mice by checking expression of VCAM-1 using magnetic resonance imaging MRI.
This MRI imaging of VCAM-1 can be used both as a diagonestic and therapeutic tool to prevent further NI .
B;Neural Cell Adhesion Molecules (NCAM)
NCAM is derived from FG loop (FGL) peptide and redirected as CD56, presented on surface of neurons, glial cells and skeletal muscle. It possesses five immunoglobulin domains with two fibronectin type 3 domains. NCAM involved in the neurite out growth, neural development, olfactory development and improving the learning and memory.NCAMinteracted with fibroblast growth factor receptor and easily crosses the BBB. Klein et.al reported
that FG loop mobilized into the endogenous neural stem cells and promotes endogenous regenerative capacity after stroke . Skibo et. al. reported a synthetic NCAM-derived peptide, FGL, a neural cell adhesion molecule (NCAM)-derived peptide binding to and inducing phosphorylation of the fibroblast growth factor receptor (FGFR) can be neuroprotectiveagent after an ischemic insult .
C;Intercellular Adhesion Molecules (ICAM)
Exposure of inflammatory cytokines leads to promote the adhesion of β2integrins in ICAM-1 ligands that result in activation of T cells and promote the trans endothelial migration towards the NI .Yan M et al., reported TNFα induced downexpression of Cylindromatosis(CYLD1) in studied in hypoxia /re-oxygenation induced rat model the brain microvascular endothelial cell (RBMECs) and found CylindromatosisNF-κBsignalling(CYLD1NF-κB) pathway have been a potential in therapy for NI diseases  .Liu Z et al.,reported the infiltration of cells in brain parenchyma of PD mice promotes the glial cell activation, and results in direct damage of the dopaminergic neurons via Lymphocyte function-associated antigen 1(LFA-1)/ICAM-1 interaction  . Walker DG et al., reported that anti-inflammatory protein CD200 and proinflammatory protein ICAM-1 doesn’t involved in lewy body pathology, but involved in AD pathology.CD200 negatively correlate with the density of neurofibrillary tangles, phosphorylated tau and amyloid plaques. ICAM-1 positively correlate with the AD pathology marker and analyzed by the double immunohistochemistry techniques .
D;Platelet endothelial cell adhesion molecules (PECAM)
PECAM (CD31) is a potential biomarker for the MS and cerebrovascular disorders and AD. It involved in pathomechanism of NI in neuroAIDS . AndreaHuwiler et al., reported the sphingosine 1phosphate (S1P) lipid molecules maintain the vascular endothelial barrier function and membrane integrity in normal inflammatory conditions. S1P lyase (SPL-kd) increased the expression of junctional adhesion molecules like PECAM, VE- cadherin, β catenin like basal proteins, increased the protein kinase C, AMP dependent kinase, p38 –MAPK and also significantly decreased the c-Jun, TNF-α/SPL-kd.so this result they concluded the SPL-kd is a diagnostic clue for NI diseases .
E;Nectins and nectins like family
Nectins and nectin like family (Necl) is a family Ca2+ independent Ig super family cell adhesion molecule. It is located on the cytoplasmic membrane. The nectin molecules consist of four types such as nectins (1, 2, 3, 4). Nectin- 1molecule redirected as poliovirus related ligand -1(PVRL-1) and CD111.Particularly the nectin-1 is a neural tissue specific adhesion molecule, which potentially guanylate kinase activity and found in the cell-cell contact sites [106,107]
F;Melanoma cell adhesion molecules (MCAM/CD146)
MCAM is a cell surface glycoprotein MUC18. Weight of this protein molecule contains 113kDa. it is marker for endothelial cell lineage.MECAM plays a role in melanoma metastasis, which attenuates the MMP2 and mitogen activated protein kinase kinase 8 (MAP3K8) in lung metastasis.H. Duanet.al.,reported thatsoluble form of CD146 in cerebrospinal fluid (CSF) elevated during the inflammation conditions like MS. Also, they found that CD146 protein molecule cause the over expression of ICAM-1 and VCAM-1in brain endothelial cells . Larochelle C et, al.,reported that in MS there is an increase the expression of MCAM by CD8+T lymphocyte. T cells restrict the MCAM cells transmigrated towards the NI. They concluded the MCAM is a valid target for NI . XiyunYan et.al., reported the role of CD146, for communication between the endothelial cells and pericytes during brain development. So, the MCAM are target biomarker for cerebrovascular disorder .
Integrins are the cellular adhesions molecules consist of transmembrane glycoproteins. These are heterodimer glycoproteins having two types of subunits such as α chain and β chain. The α chain comprising the 24 different types of molecules and β chain comprising the 9 different types of molecules, which is linked to the disulfide bonds.
The alpha subunit consists of 700 amino acids and beta subunits consist of 1000 amino acids . Integrins play
important roles in development of immune response,leukocyte function and many cardinal hallmarks of autoimmune disease and genetic disorders . Normally the integrins molecules are participate in development and repair of the nervous system by providing nutrition from the astrocytes.
The integrin molecules are act as anchors of leukocytes to extracellular matrix. Mainly the epithelial cells secrete these. Integrins are transmitting the electron transport signal from cell to intracellular by tyrosine kinase signaling pathway.Integrins and its receptors are having a high redundancy function and reorganization of cytoskeleton formation [112,113]. Integrin’s mainly divided into two category β1 and β2. β1subunits dimerized with 12 subunits of α integrins. β2 subunits dimerized with the 4 different types of α subunit (Figure 3: Representation of the integrin family).β1subunits mainly expressed in the surface of white blood cells. These integrins enhances the cell-cell interactions and cell-ligand interactions particularly in the endothelial cells. β1 integrinsare normally required to develop the radial glial cells and Schwann cells. The ligands of integrins were sometimes immunoglobulin (Ig) super family. The α integrins subunit is determining the ligand specificity. β intergrins subunit helps for adhesion to the intracellular matrix. β1 integrins are first identified and 14 out of 24 integrin molecules are present in the nervous system . Many of the ligand molecules are having specific binding site for integrins. Specificity of the ligand molecules concluded by the RGD tripeptide such as Arg-Gly-Asp tripeptide.H.-J.Choi, et al., founded that vascular endothelial growth factor (VEGF) is damaging the BBB permeability during the stroke condition in mice. Saxitilin is a disintegrin fusion proteins that contain the RGD (Arg-Gly-Asp) motifs that directly bonded with the integrin molecules, these integrin molecules are crosstalk to the VEGF leads to reduce the stroke . The researchers already reported that increased expression of chemokines like CCL5 and CAM’S in perivascular spaces of multiple sclerosis. Ubogu et al founded that expression of chemokines and CAM’S dependents on α4β1 and αLβ2 integrin molecules. So, these integrins have a potential diagnosis marker for MS and NI .(Table 3: Integrins biomarker used for diagnosis for NI)
Figure 3: Representation of the integrin family
LIGANDS FUNCTIONs LOCATION VIRUSES DISEASE
β 1 α 4 VLA-4 CD49d/CD29 ITGA4
Fibronectin vitronectin .
Promote the inflammation response by the immune system they recruiting the leukocytes adhesion to the damaged tissue .
Erythrocyte differentiation [119, 120]
Cancer metastasis 
Stem cell T cell B cell Monocytes Neutrophils Progenitor cells Natural killer cells Eosinophils 
Infectious bursal disease virus 
Rota virus 
Chronic disease like MS and AD 
β 1 α 5 VLA-5 CD49e/CD29 ITGA5 Fibrinonectin receptor 
RGD-binding integrins 
Angiogenesis Tumor suppressor
Long term potentiation (LTP) facilitates the learning and memory.
Reduced the magnitude of NMDA dependent hippocampal long term potentiation 
Lymphocytes Eosinophills Monocytes Endothelial cells Hematopoietic cell 
Foot and mouth virus 
Epstein barr virus 
Adeno virus 
β 1 α 6 VLA-6 CD49f/CD29 ITGA6and ITGB1 
phosphatidylinositol 4- kinase activity 
Oligodentrocyte proliferation Schwann cells adhesion Schwann cell migration .
Epithelial Oocytes cell 
Chronic inflammatory disease
Table 3: Integrins biomarker used for diagnosis for neuroinflammation Therapeutic targets for neurodegenerative disease
As previously pointed out the NI is one of the etiological reasonsto develop the various neurological diseases. NI generally associated with memory impairment at elderly aged peoples due to the oxidative stress, protein accumulations and gene mutation. The recent advancementsin researchrevealed new therapeutic perspectives for neurodegenerative disorders.This new biomarkers and targets can be used for designing the novel multi target directed ligands which is able to modulate the classical targets. Therapeutic targets for neurodegenerative diseases have shown in Table 4.
TARGETS for PD LOCATION FUNCTION
Involved in microgliosis in PD and negatively regulate the TRAF6/TLR4-mediated activation of the MAPK and NF-κB signaling pathways modulating the neuroinflammatory reaction against PD 
NF-κB Glial cells
Main role in inflammatory pathyway.IKKβ and IKKγ two specific inhibitors of NF-κB is potent to treat the chronic inflammatory disease associated PD .
DJ 1 encoded in a PARK7 gene. Its nvolves in transcriptional regulation, as a molecular chaperone and in protein degradation. [145, 146]
RGD-binding integrins vitronectin
Oligodentrocyte differentiation .
Block the migration of dentrocytes Reduce proteinuria
Fibroblasts Epithelial cells
Kaposi’s sarcoma associated herpes virus 
Epstein –Barr virus 
oligodendrocytemigration. Ocular melanoma Neurological tumors 
Echo virus 
Adeno virus 
Neurological tumors 
Gastric disease 
NLRP3 Microglia Over activation leads to mitochondrial dysfunction in PD 
TARGETS for AD
TREM2 Myeloid cells AD condition the partial loss of TREM 2 protein and changes the behavior of microglial cells 
Insulin -degrading enzyme
Neurons Synaptic dysfunction of neurons 
P2X7 receptor Microglial cells Involved in microglial function, synaptopathy, oxidative stress, and amyloidogenic APP processing. 
Nerve growth factor (NGF)
Neurotrophin family Maintain the synaptic plasticity and regeneration on cholinergic neurons to promote the memory .
Small ubiquitin-like modifier
Nerve cells Indirect role in modulating the amyloid-processing pathway .
lipoprotein receptor- related protein 1
Cerebral cells β amyloid endocytocis.
TARGETS for MS voltage-gated potassium Kv1.3 channel
Microglia and T lymphocytes
Involved in the immune responses and inflammatory responses .
GCRs, RXR-γ, VDR, ROCK.
Neurons Demyelination I 
PPARα and PPARγ Nuclear hormone receptor
Coordinate the lipid, glucose and energy metabolism.increased the elevated levels in brain during MS
Table 4: therapeutic targets for neurodegenerative disease
During NI there will be a change in integrity and permeability of BBB due to change in the expression of various proteins like selectins, immunoglobulins and integrins. So, these proteins along with glial cell markers are clears indicators of NI. So, detail knowledge on these NI mediators helps to detect various neurodegenerative diseases in advance. This helps to prevent the further progression of the diseases. So, NI mediators can be act potential markers for diagnostic and therapeutic purpose.
Conflict of Interest
There is no conflict of interest
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