Duraisamy Kempuraj1*
Kirk D. Dourvetakis1Jessica Cohen1Daniel Seth Valladares1
Rhitik Samir Joshi1Sai Puneeth Kothuru1,2Tristin Anderson1
Baskaran Chinnappan1
Amanpreet K. Cheema1
Nancy G. Klimas1,3Theoharis C. Theoharides1,4- 1Dr. Kiran C. Patel College of Osteopathic Medicine, Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, United States
- 2College of Psychology, Nova Southeastern University, Ft. Lauderdale, FL, United States
- 3Miami VA Geriatric Research Education and Clinical Center (GRECC), Miami Veterans Affairs Healthcare System, Miami, FL, United States
- 4Department of Immunology, Tufts, University School of Medicine, Boston, MA, United States
Neurovascular unit (NVU) inflammation via activation of glial cells and neuronal damage plays a critical role in neurodegenerative diseases. Though the exact mechanism of disease pathogenesis is not understood, certain biomarkers provide valuable insight into the disease pathogenesis, severity, progression and therapeutic efficacy. These markers can be used to assess pathophysiological status of brain cells including neurons, astrocytes, microglia, oligodendrocytes, specialized microvascular endothelial cells, pericytes, NVU, and blood-brain barrier (BBB) disruption. Damage or derangements in tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased permeability and neuroinflammation in various brain disorders including neurodegenerative disorders. Thus, neuroinflammatory markers can be evaluated in blood, cerebrospinal fluid (CSF), or brain tissues to determine neurological disease severity, progression, and therapeutic responsiveness. Chronic inflammation is common in age-related neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia. Neurotrauma/traumatic brain injury (TBI) also leads to acute and chronic neuroinflammatory responses. The expression of some markers may also be altered many years or even decades before the onset of neurodegenerative disorders. In this review, we discuss markers of neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders, especially those associated with neurovascular pathologies. These biomarkers can be evaluated in CSF, or brain tissues. Neurofilament light (NfL), ubiquitin C-terminal hydrolase-L1 (UCHL1), glial fibrillary acidic protein (GFAP), Ionized calcium-binding adaptor molecule 1 (Iba-1), transmembrane protein 119 (TMEM119), aquaporin, endothelin-1, and platelet-derived growth factor receptor beta (PDGFRβ) are some important neuroinflammatory markers. Recent BBB-on-a-chip modeling offers promising potential for providing an in-depth understanding of brain disorders and neurotherapeutics. Integration of these markers in clinical practice could potentially enhance early diagnosis, monitor disease progression, and improve therapeutic outcomes.
Introduction
Neuroinflammatory and neurodegenerative disorders are characterized by the presence of acute and chronic neuroinflammatory responses in the brain. Neuroinflammatory response is the initial response to protect the brain against damage, infection such as microbial infections/sepsis or exposure to toxins by activated glial cells and neurons (Kempuraj et al., 2020a; Gao and Hernandes, 2021; Tran et al., 2022). However, excessive and persistent glial cell activation leads to chronic neuroinflammation-associated neurodegeneration and increases disease severity of neurodegenerative disorders (Le Thuc et al., 2015; Kempuraj et al., 2016). The neuroimmune system is implicated in the development, normal functioning, aging, and integrity of the central nervous system (CNS) (Hickman et al., 2018). Chronic disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and traumatic brain injury (TBI) are neuroinflammatory and neurodegenerative disorders with dysfunctional neurons, synapses, glial cells and their networks (Pathak et al., 2022). Conditions such as Gulf War Illness (GWI) and Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are also chronic disorders that exhibit several neurological symptoms, neuroimmune dysfunction and neuroinflammation (Wirth et al., 2021; Cohen et al., 2024). The precise mechanisms underlying the pathogenesis of various neurodegenerative diseases are likely different and are currently not yet clearly understood. Different disease triggers can cause neuroinflammation and neuronal damage in different brain regions involving specific types of brain cells and pathways. Additionally, inflammatory mediators from peripheral inflammation can also influence neuroinflammation and neurodegeneration in the brain through a defective and vulnerable blood-brain barrier (BBB) (Kempuraj et al., 2017).
The BBB plays an important role in brain homeostasis by allowing selective molecules from peripheral blood into the brain parenchyma (Chin and Goh, 2018; Zapata-Acevedo et al., 2024). Neuroinflammation and neurodegenerative disorders disrupt the BBB, and increase permeability allowing the entry of immune cells, inflammatory mediators, toxic substances, and pathogens from the peripheral blood into the brain (Musafargani et al., 2020). Derangements and damage to the tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased BBB permeability, resulting in edema, increased neuroinflammation and neuronal damage in various brain disorders (Kempuraj et al., 2020a; Bhowmick et al., 2019). Neuroinflammation can lead to upregulation or downregulation of certain specific markers in different brain cells. Neuroinflammation can be beneficial by removing cellular debris and promoting the tissue repair process (Le Thuc et al., 2015). Neuroinflammation has also been shown to enable the proliferation and maturation of neuronal precursor cells, axonal regeneration, and remyelination over denuded axons (Yong et al., 2019). Damage/activation of glial cells, specialized brain endothelial cells, neurons, and BBB structure trigger the release of distinct markers from these cells into the cerebrospinal fluid (CSF) and blood that can be assayed by different procedures for the evaluation of disease status, progression and therapeutic efficacy. However, the dynamics of the BBB in various pathophysiological conditions are not yet clearly known. The development of BBB-on-a-chip modeling in the last decade has the potential for further understanding of BBB dynamics in pathophysiological conditions and neurotherapeutics (Peng et al., 2022; Ohbuchi et al., 2024). In this review, we present markers of neurons, glial cells, neurovascular unit (NVU), BBB proteins, neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders.
Neuroinflammation and neurodegeneration markers
Neurogenesis is a turnover process that generates new neurons during adulthood, maintaining the integrity of the brain. Neurodegeneration is a slow and progressive dysfunction, loss of axons and neurons, which is accelerated by the aging process as well as the neuroinflammatory process (Culig et al., 2022). Mature neuronal markers include nuclear protein neuronal nuclei (NeuN; nuclei), neuron-specific enolase (NSE; cell bodies/soma), neurofilament light (NfL; axons), TUJ1 (class III beta-tubulin; cytoskeleton), tau (axon, cell body, dendrites), spectrin breakdown products (SBDPs; axons), and microtubule-associated protein 2 (MAP2; dendrites) which indicate specific parts of the neuron or damage (Zetterberg and Blennow, 2016; Figure 1). Synaptic markers include synaptosomal-associated protein (SNAP25), synaptophysin (SYP), and neuroligin (Zetterberg and Blennow, 2016). Neurodegeneration can be assessed by neuronal markers MAP2, NfL, TUJ1, and SYP. However, certain markers such as amyloid precursor protein (APP), amyloid β (Aβ) and tau are more specific to AD pathology. Synaptic disorder, synaptic loss and cognitive decline are common manifestations of neurodegenerative disorders (Dejanovic et al., 2024). Neuronal damage, neurodegeneration and neuronal loss have been reported in AD, PD and TBI. Nearly 19.5% of soldiers deployed in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) were exposed to blast traumatic brain injury (bTBI) (Kempuraj et al., 2020a). Certain conditions such as TBI and stress are risk factors for the onset of progressive neurodegenerative disorders including AD and PD or dementia or can exacerbate the existing AD, PD pathologies and dementia (Kempuraj et al., 2020b; Brett et al., 2022). The levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) in the blood are U.S. Food and Drug Administration (FDA)-approved biomarkers for mild TBI (mTBI) (Wang et al., 2021a). Certain brain injury/TBI markers include UCH-L1, NSE, erythrocyte membrane protein band 4.1 (EPB41) for cell body/soma injury, NfL, tau, myelin basic protein (MBP) for axonal injury, SNCA for synaptic injury, GFAP, S100B for glial cell injury and inflammatory cytokines and neurotoxic mediators (for inflammation) (Silvestro et al., 2024; Zetterberg and Blennow, 2016). Certain chronic neuroimmune conditions such as ME/CFS and GWI are associated with neuroinflammation but may not have apparent neurodegeneration (Cohen et al., 2024; O’Callaghan and Miller, 2019). Positron emission tomography (PET) and magnetic resonance spectroscopic (MRS) neuroimaging allow for a non-invasive “read” of the brain for neuroinflammatory processes and neuronal integrity in brain diseases (Van Der Naalt, 2015; Lee et al., 2024).
Figure 1. Schematic diagram shows neuronal markers in the neurovascular unit with BBB. BBB is a dynamic structure that functions as a gatekeeper. (A) Markers in neurons in different regions. (B) neurodegeneration of dendrites, axon, synaptic area. (C) NVU is comprised of micro blood vessels, endothelial cells, BBB, pericytes, neurons, astrocytes, and microglia. (D) BBB with endothelial cells, pericytes, tight junction and adherens junctions consisting of claudin, zonula occludens (ZO-1), occuludin, junctional adhesion molecule (JAM) and cadherin that regulates BBB permeability. The presence of increased levels of these markers in the blood or CFS indicates the damage to these structures. Derangement of BBB proteins can also cause BBB dysfunction.
Activation of glial cells such as microglia and astrocytes lead to the release of molecules that trigger neuroinflammatory response and neuroinflammation. Both microglia and astrocytes can function either as neurotoxic (proinflammatory) M1 microglia and A1 astrocytes or as anti-inflammatory (neuroprotective) M2 microglia and A2 astrocytes phenotypes (Kwon and Koh, 2020; Guo et al., 2022). M1 microglia and A1 astrocytes release proinflammatory and neurotoxic molecules, whereas M2 microglia and A2 astrocytes produce neurotrophic and neuroprotective molecules that support neuronal growth and survival (Kwon and Koh, 2020). The M1/A1 or M2/A2 status (phenotype) of these cells can change during disease progression and can alter the severity of neuroinflammatory and neurodegenerative diseases (Kwon and Koh, 2020). Resting astrocytes (A0) become functional astrocytes (A1 and A2) by stimulation (Ding et al., 2021; Figure 2). Senescent dystrophic microglia have abnormal morphology with deramification (thin and short branches) and fragmented cytoplasm (Woollacott et al., 2020). The number of dystrophic microglia increases in neurodegenerative disorders such as AD in which many microglia are dysfunctional and senescent (Woollacott et al., 2020; Shahidehpour et al., 2021). Neuroinflammatory and neurodegenerative conditions impact the NVU which consists of microvascular specialized endothelial cells with BBB complex, pericytes and astrocytes (Bhowmick et al., 2019; Kempuraj et al., 2020a; Kempuraj et al., 2024). Disruption of NUV and BBB, glial activation and dementia have been reported in the recent coronavirus disease 2019 (COVID-19)/Long COVID conditions caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Kempuraj et al., 2024; Owens et al., 2024; Theoharides and Kempuraj, 2023; Shi et al., 2023; Zingaropoli et al., 2022). Inflammation in the brain activates glial cells to release inflammatory mediators which activate endothelial cells to express adhesion molecules and attract the peripheral blood leukocytes to the inflammatory site in the brain. Activated endothelial cells lead to loss of vascular integrity, increased adhesion molecule expression and cytokine and chemokine release including C-C motif ligand 2 (CCL2), CCL3, and interleukin-8 (IL-8) (Theofilis et al., 2021; Alsbrook et al., 2023). Cerebral endothelial cells express toll-like receptors (TLRs), chemokine receptors C-X-C motif chemokine receptor 1 (CXCR1), CXCR2, CXCR3, CCR3, CXCR4, and tumor necrosis factor receptors (TNFRs) TNFR1 and TNFR2. Pericytes cover the micro vessels in the brain and express various contractile and cytoskeleton proteins such as α-smooth muscle actin, nestin, myosin, vimentin, and desmin, cell surface neural/glial antigen 2 (NG2), platelet derived growth factor receptor beta (PDGFRβ), cluster of differentiation 13 (CD13), and CD146 (Alarcon-Martinez et al., 2021). Pericytes play a role in regulating the BBB, angiogenesis, removal of toxins, blood flow, stem cells, and neuroinflammation (Bhowmick et al., 2019). Pericytes can differentiate into microglia-like cells with phagocytic activity indicating that pericyte loss may increase leukocyte infiltration (Alsbrook et al., 2023). Additionally, pericytes can express TLR4 and exert a proinflammatory response. Pericyte damage can lead to BBB dysfunction allowing the influx of neurotoxic molecules in the brain from the peripheral blood. Astrocytes are the most abundant cells in the brain and are involved in the formation, maintenance and BBB permeability (Schiera et al., 2024; Rauf et al., 2022). Increased GFAP expression, an astrocyte marker, activates astrocytes and releases IL-1β, IL-6 and TNF (Giovannoni and Quintana, 2020). Astrocytes also induce anti-inflammatory effects and regulate neurotransmitter homeostasis such as glutamate. Peripheral inflammation may lead to brain endothelial activation, allowing peripheral blood inflammatory factors to enter the brain, activate perivascular macrophages and microglia, and initiate neuroinflammation without any primary injury or disease in the brain (Mayer and Fischer, 2024). Microglia are the primary innate/resident immune cells in the brain that first respond to injuries in the brain (Rauf et al., 2022). Microglia constantly sense changes in the brain tissue microenvironment for housekeeping function that helps neuronal health and functions (Mayer and Fischer, 2024). Microglia can express inflammatory cytokines and chemokines such as TNF, IL-1, IL-6, CCL2, and IL-18 to stimuli and they also express activation marker sTREM2 (soluble triggering receptor expressed on myeloid cells 2).
Figure 2. Schematic diagram shows microglial and astrocyte markers in normal, activated, anti-inflammatory and proinflammatory states. Microglia and astrocytes are activated in various neuroinflammatory and neurodegenerative disorders. Activated microglia and astrocytes express several markers that are also detected in biofluids. M1 microglia and A1 astrocytic phenotypes are neurotoxic and exacerbate neuroinflammation and neurodegeneration whereas M2 microglia and A2 astrocyte phenotypes are neuroprotective and protect the brain. These neurotoxic and neuroprotective glial cells express or secrete different molecules to exert detrimental or protective functions in the brain. AQ4, aquaporin 4; FGF, fibroblast growth factor; NO, nitric oxide; OPN, osteopontin; PTX3, pentraxin 3; ROS, reactive oxygen species; S100a10, S100 calcium-binding protein A10.
Understanding NVU/BBB dynamics in the brain’s pathophysiological conditions will improve the treatment options for brain disorders. In addition to the cells in the brain, infiltration of immunocytes, cytokines, chemokines and neurotoxic molecules from the periphery also activate glial cells, further releasing additional inflammatory mediators that accelerate neuroinflammation in the brain. Pathogenic substances that enter from the periphery to the brain also enhance inflammatory response in the brain (Kempuraj et al., 2017). There are several types of biomarkers including immunochemical analysis in tissues that involve tissue biopsy or post-mortem tissue, blood (minimally invasive)/CSF (invasive) based biomarkers, physical by physical examination such as cognitive test, urine, and brain imaging such as MRI (Chahine et al., 2014). Extracellular vehicles (EVs) released from brain cells can be detected in the blood and CSF and used as a marker for brain disorders (Gamez-Valero et al., 2019; Ollen-Bittle et al., 2022). Additionally, genomic and proteomic analysis provides molecular level biomarkers with next-generation sequencing and mass spectrometry procedures for neurological disorders (Chase Huizar et al., 2020). Abnormally activated glial cells can secrete disease-specific proteins that can be used as a novel biomarker (Kim et al., 2020). Recent progress in proteomic research has the potential for the development of novel
biomarkers for brain disorders (Kim et al., 2020). MicroRNAs (miRNAs) play an important role in inflammatory response in neuroinflammation (Su et al., 2016). Liquid biopsies such as exosomal miRNA are important biomarkers for many diseases including neurological diseases (Malhotra et al., 2023; Zhou et al., 2024).
Table 1 provides various markers of neurons, astrocytes, microglia, neuroinflammation, neurodegeneration, the NVU, and the BBB complex with their dysfunctions and associated neuropathology. This table also includes some membrane proteins, secreted proteins, signaling proteins and structural proteins associated with brain cells. Effective neurotherapeutic options should ideally target the BBB complex, address the damage and derangement of BBB proteins, and reduce BBB dysfunction.
Table 1. Neurovascular/BBB and neuroinflammatory markers.
The BBB is a crucial component of the NVU and plays an important role in the homeostasis of the brain. The NVU regulates BBB permeability, removal of toxic byproducts, and performs immune monitoring. BBB disruption and increased permeability are commonly observed in neurodegenerative disorders and neurotrauma, which increases BBB permeability causing or upregulating neuroinflammatory responses, neuroinflammation and neuronal loss (Yu et al., 2020). Therefore, we have highlighted recent advances in the study of BBB pathogenesis using the BBB-on-a-Chip model for CNS disorders and neurotherapeutics as briefly provided below.
BBB-on-a-Chip for CNS disorders and neurotherapeutics
The integrity of the BBB is maintained by astrocytes, pericytes, endothelial cells, and neurons, TJ, AdJ and GP proteins of the BBB. This integrity is crucial for normal brain function. However, chronic damage to NVU and BBB components leads to BBB dysfunction, increased BBB permeability/leakage, and neuroinflammation in many neurodegenerative diseases (Ohbuchi et al., 2024; Yoon et al., 2021). Therefore, the ability to model BBB behavior and pathogenesis is essential for the understanding of CNS disorders and neurotherapeutics. Vascularization in the brain organoids can be induced by modeling BBB micro environment using chip technology (Urrestizala-Arenaza et al., 2024). The BBB-on-a-chip (BBB chip) micro-engineered laboratory technology is a powerful in vitro model closely resembling human BBB structure to study normal and diseased states (Peng et al., 2022; Berjaoui et al., 2024). BBB-on-a-chip technology has significantly improved over the last decade and has been used to study various neurological diseases including AD, PD and Multiple Sclerosis (MS) (Berjaoui et al., 2024; Kawakita et al., 2022; Yoon et al., 2021; Palma-Florez et al., 2023). Recently neuroinflammation on-a-chip for studying MS (Berjaoui et al., 2024) and neuropathogenesis-on-chips (Amartumur et al., 2024) technology have been reported. The recently developed in vitro microfluidic/microfluidic human BBB-on-a-chip modeling using brain endothelial cells, pericytes, and astrocytes tri-culture model along with immune cell (T-cell) migration will be highly useful for understanding BBB functions, permeability, the pathogenesis of brain diseases, and evaluation of neurotherapeutic drugs that target the BBB (Ohbuchi et al., 2024). However, a fully efficient BBB-on-a-Chip model is still not available to date. A recent article described the use of built-in sensors to characterize BBB models via quasi-direct current and electrical impedance measurements, and various biosensors for the detection of metabolites, drugs, or toxic agents (Kincses et al., 2023). Microfluidic BBB-on-a-Chip provides an engineered physiological microenvironment necessary for real-time monitoring of barrier properties using human cells (Musafargani et al., 2020). The availability of AXION Maestro Edge multiwell microelectrode array (MEA) system (Axion BioSystems, Atlanta, GA) coupled with NETRI’s NeuroFluidics devices (NETRI, Lyon, France) could significantly enhance brain-on-a-Chip and BBB-on-a-Chip modeling in the study of brain disorders including neurotrauma/TBI, and development of drugs that target the BBB (Cohen et al., 2024; Ohbuchi et al., 2024). In a 3D microfluidic system, brain organoids are placed at the center chamber and endothelial cells and pericytes are placed on the side channels to create a micro vascularization system (Urrestizala-Arenaza et al., 2024) In a study, BBBs-on-chips were exposed to TNF-α and IL-1β to mimic neuroinflammation and studies the BBBs-on-chip’s barrier function, cell morphology, increased expression of cell adhesion molecules, increased permeability, and T cell adhesion, extravasation, and migration across BBB-on-chips (Nair et al., 2023). Even though brain-on-a-chip technology advanced the understanding of BBB pathophysiology, these models are still in a preliminary state, and the neurospheroids are still far from the human brain tissue. Thus, new and more advanced clinically relevant bioengineered models of human brain-on-a-chip for drug efficacy evaluation are required (Staicu et al., 2021; Cui and Cho, 2022). We are currently working on a BBB-on-a-Chip model to create disease-surrogate models for different brain disorders. Further research advancement in the BBB-on-a-Chip model could enhance the understanding of BBB dynamics in both health and disease conditions and assist in the development of treatments that target the BBB.
Conclusion
Neuroinflammation is a hallmark of many neurological disorders. Neuroinflammatory and neurodegenerative disorders are multifaceted processes involving the interaction of astrocytes, endothelial cells, neurons, microglia and infiltrating leukocytes as well as peripheral systems. Chronic release of neuroinflammatory mediators induces neuroinflammation, neurodegeneration, synaptic and neuronal loss and BBB dysfunction in the brain. Several molecules expressed by brain cells infiltrating peripheral leukocytes participate in the neuroinflammatory response in specific regions of the brain. Damage of NVU/BBB, TJ and AdJ proteins as well as neuroinflammatory markers could be assessed in the tissue as well as in CSF and blood though they are not specific to many brain disorders. Nevertheless, measuring such biomarkers is crucial for the diagnosis, severity assessment and treatment efficacy of various neurodegenerative disorders.
Author contributions
DK: Conceptualization, Writing – original draft, Writing – review and editing, Supervision. KD: Writing – review and editing. JC: Writing – review and editing. DV: Writing – review and editing. RJ: Writing – review and editing. SK: Writing – review and editing. TA: Writing – review and editing. BC: Writing – review and editing. AC: Writing – review and editing. NK: Writing – review and editing. TT: Writing – review and editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of the article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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Keywords: blood-brain barrier disruption, glial cells, neuroinflammatory biomarkers, neurodegenerative disorders, neurofilament light, neurovascular unit, tight junction proteins
Citation: Kempuraj D, Dourvetakis KD, Cohen J, Valladares DS, Joshi RS, Kothuru SP, Anderson T, Chinnappan B, Cheema AK, Klimas NG and Theoharides TC (2024) Neurovascular unit, neuroinflammation and neurodegeneration markers in brain disorders. Front. Cell. Neurosci. 18:1491952. doi: 10.3389/fncel.2024.1491952
Received: 05 September 2024; Accepted: 07 October 2024;
Published: 25 October 2024.
Edited by:
Arumugam R. Jayakumar, University of Miami, United StatesReviewed by:
Krishnapriya Thangaretnam, University of Miami, United StatesKumar Vaibhav, Augusta University, United States
Suresh Babu Rangasamy, University of Illinois Chicago, United States
Copyright © 2024 Kempuraj, Dourvetakis, Cohen, Valladares, Joshi, Kothuru, Anderson, Chinnappan, Cheema, Klimas and Theoharides. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Duraisamy Kempuraj, kduraisa@nova.edu; orcid.org/0000-0003-1148-8681