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Ma, X.; Yang, T.; Liu, L.; Peng, X.; Qian, F.; Tang, F. Ependymal Dysfunctions in the Pathogenesis of Neurodegenerative Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/43750 (accessed on 05 December 2025).
Ma X, Yang T, Liu L, Peng X, Qian F, Tang F. Ependymal Dysfunctions in the Pathogenesis of Neurodegenerative Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/43750. Accessed December 05, 2025.
Ma, Xin-Yu, Ting-Ting Yang, Lian Liu, Xiao-Chun Peng, Feng Qian, Feng-Ru Tang. "Ependymal Dysfunctions in the Pathogenesis of Neurodegenerative Diseases" Encyclopedia, https://encyclopedia.pub/entry/43750 (accessed December 05, 2025).
Ma, X., Yang, T., Liu, L., Peng, X., Qian, F., & Tang, F. (2023, May 04). Ependymal Dysfunctions in the Pathogenesis of Neurodegenerative Diseases. In Encyclopedia. https://encyclopedia.pub/entry/43750
Ma, Xin-Yu, et al. "Ependymal Dysfunctions in the Pathogenesis of Neurodegenerative Diseases." Encyclopedia. Web. 04 May, 2023.
Ependymal Dysfunctions in the Pathogenesis of Neurodegenerative Diseases
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This entry is adapted from the peer-reviewed paper 10.3390/biom13050754

The neuron loss caused by the progressive damage to the nervous system is proposed to be the main pathogenesis of neurodegenerative diseases. Ependyma is a layer of ciliated ependymal cells that participates in the formation of the brain-cerebrospinal fluid barrier (BCB). However, as the protective barrier lining the brain ventricles, the ependyma is extremely vulnerable to cytotoxic and cytolytic immune responses. When the ependyma is damaged, the integrity of BCB is destroyed, and the cerebrospinal fluid (CSF)flow and material exchange is affected, leading to brain microenvironment imbalance, which plays a vital role in the pathogenesis of neurodegenerative diseases.

neurodegenerative diseases radiation-induced brain injury ependyma

1. The Physiological Function of Ependyma

Ependymal cells (ECs) line the ventricles and the central canal of the spinal cord [1], forming the brain’s ventricular epithelium and a niche for neural stem cells in the ventricular–subventricular zone (V-SVZ) [2]. These dormant stem cells can be elicited for differentiation and migration after activation [3]. A single-cell transcriptomic study has distinguished the ECs from the ependymal neural stem cells in the V-SVZ and verified no stem cell profile in ECs [4]. In the model of spinal cord injury, ECs showed a limited contribution in astrocytic scar-forming [5]. These findings challenged the hypothesis that the mature EC could function as a neural stem cell. Most mouse immature ECs are derived from radial glial cells around embryonic days 14–16, and then differentiated and matured with cilia formation in neonatal age [6][7]. There are three subtypes of ECs, multi-ciliated, bi-ciliated and mono-ciliated ECs [8]. The bi-ciliated and mono-ciliated ECs indicate the subtypes of tanycytes—the specified ECs. The coordinated beating of those propeller-like motile cilia protruded from ECs into the brain ventricles generates a directional cerebrospinal fluid (CSF) flow, which is essential for various physiological processes [9] (Figure 1A). To organize the formation of CSF, single-layer epithelial cells cover capillaries at the bottom of the lateral ventricle, the top of the third ventricle and the lower part of the fourth ventricle near the inferior medullary velum to form the choroid plexus [10] (Figure 1B). The stroma inside the choroid plexus is a part of the pia mater. As the wall of the ventricular system, ECs and astrocytes from the brain parenchyma form a well-controlled filtration membrane, the BCB, which promotes the bi-directional substance exchange between the BIF and CSF, keeps the brain tissue toxicant-free and in physiological balance [2][3][9][11][12][13] (Figure 1C).
Biomolecules 13 00754 g001
Figure 1. Role of the ependyma in cerebrospinal fluid (CSF) flow dynamics. (A) Generation, substance exchange, circulation and draining of CSF. The blue arrows indicate the generation of CSF from the choroid plexus; the grey arrows indicate the direction of CSF flow through the brain ventricular system and subarachnoid space; the green arrows indicate the substance exchange of CSF and brain interstitial fluid (BIF) or blood at the ventricular wall; the orange arrows indicate the draining of CSF at the perivascular spaces and arachnoid granules. (B) The formation of CSF from the choroid plexus, which is formed by a single layer of epithelial cells; the stroma derived from pia mater; and the capillary endothelium. (C) Ependyma and astroglia form the ventricular wall, which functions as the brain–CSF barrier. The neural stem cell (NSC) located in the niche of subventricular zone (SVZ) may proliferate to repair the damaged ependyma and regenerate astroglia to restore the barrier. (D) Tanycytes interact with astroglia and blood vessels to form a three-directional interface facilitating substance exchange among CSF, BIF and blood. These “brain windows” of the circumventricular organs (CVOs) play a vital role in the transportation of hypothalamic regulatory peptides and other factors. (E) CSF flows into the perivascular space and drains into the subpial interstitial fluid (SPIF), which can exchange with the BIF through the astroglial barrier and the blood through the endothelium. The CSF here also acts as a glymphatic system to introduce immune supervision and facilitate waste clearance from the BIF. Arachnoid granules may function as the location for “dirty” CSF draining back into the vein sinus or lymphatic pathway.
Tanycytes are highly specialized ECs that play a vital role in forming the ependyma of the circumventricular organs (CVOs) [14]. Often described as “brain windows”, the CVOs are rich capillary networks closely contacted with tanycytes and continued with the neighboring choroid plexus. This unique structure allows a potential functional relationship of the capillary system with CSF. For example, the median eminence (ME) is a well-known CVO located in the tuberal region of the hypothalamus [15] (Figure 1D). Tanycytes are bi-ciliated or mono-ciliated ECs with less motility than multi-ciliated ECs, but have long processes that can across the hypothalamic parenchyma and link the ventricular and vascular compartments directly [8][16][17]. In the ME, the adjacent tanycytes adhere with each other by various tight junction proteins, including ZO-1, occludin, claudin 1 and claudin 5, to prevent the free passage of molecules through the paracellular pathway [18][19][20]. These tight junctions of tanycytes at the ventricular surface of the CVO can prevent the diffusion of blood-borne molecules into the CSF, even if those molecules have permeated into the parenchyma of the ME through the vasculature surface of the CVO. Tanycytes also take part in forming the BBB between the hypothalamic parenchyma and capillary to maintain the microenvironment surrounding those neuroendocrine cells and facilitate the release of hypothalamic regulatory peptides [16][17][20] (Figure 1D). In addition, the tanycytes may play a vital role in metabolic homeostasis by secreting or transporting circulatory fibroblast growth factor 21 (FGF21) into the central nervous system [21]. Unlike the stricter BBB formed intactly by astrocytes, tanycytes may provide a “window” for brain invasion while promoting substance exchange at the vasculature interface of the CVO [20][22].
The CSF produced in the brain ventricular system flows into the subarachnoid space through the median and lateral foramen of the fourth ventricle [23]. From here, the pia mater replaces the ependyma to form BCB. CSF circulating in the subarachnoid space drains into the subpial interstitial fluid (SPIF) from the perivascular spaces and exchanges substances with the BIF through the astroglial barrier or the blood through the capillary [24][25][26] (Figure 1E). Arachnoid granulations, which have been considered as the main pathway for absorbing CSF into venous sinus, may function as glymphatic–lymphatic coupling structures together with the newly unveiled subarachnoid lymphatic-like membrane (SLYM) [27][28][29]. The CSF-glymphatic communication through SLYM supervises the immune status of CSF and presents the information to the lymphatic and/or blood system through arachnoid granulations. Although the pia mater and ependyma develop from different origins, they both contribute much in maintaining the delicate balance of CSF dynamic flow and biochemical homeostasis in the brain microenvironment [30].

2. Ependymal Dysfunctions in the Pathogenesis of Neurodegenerative Diseases

Neurodegenerative diseases are associated with the abnormal transportation of metabolites or other substances among intracellular fluid, interstitial fluid, CSF and blood in the brain [31]. CSF is mainly produced in the choroid plexus and transported from the lateral ventricle to the third ventricle, aqueduct and fourth ventricle, and then is re-inhaled in the subarachnoid space [7]. As a fluid clearing pathway in the brain, the glymphatic–lymphatic pathway helps to drain the CSF from the subarachnoid space into the perivascular spaces of penetrating arteries, also known as Virchow–Robin spaces [32][33][34]. From these perivascular spaces, CSF can finally return to the brain parenchyma and/or the cerebral vasculature [32]. This lymphatic pathway dominates during sleep. It has been reported that the clearance rate of harmful metabolites (such as Aβ) during sleep was significantly higher than that during awaking [35][36]. During sleep, the BIF secreted from astroglia dilutes the extracellular metabolites and washes them away by the increased BIF advection in the larger interstitial space [37]. Recent research has demonstrated that the etiology of AD and other neurodegenerative diseases may involve the abnormal expression of lipoproteins from the reactive astrocytes, such as the intensively studied APOE4, and the neurotoxic lipids they transport [38][39][40]. These toxic lipids may disturb lipid metabolism in brain tissue and destroy the membrane structures, especially the ependyma. The tanycytes have been reported to have an important role in regulating lipid metabolism [41]. The aged mouse EC possesses more lipid droplet accumulation and loses its barrier function [42]. This metabolic alteration in EC can cause the aging of EC, the dysfunction of ependyma and cognitive impairment [43]. Neuron stem cell and other progenitors in the subependymal area, such as the SVZ, can repair the damaged ependyma; however, they sometimes induce gliosis on the surface of the ventricular wall [31][44][45]. The cross-talk between astroglial and microglia activation, perivascular macrophage migration and immune cell infiltration in SVZ after brain injury may affect periventricular interstitial fluid homeostasis and impair ependymal function [46][47].
The filtration of water through ependyma is mainly controlled by aquaporin 4 (AQP4), the most abundant aquaporin in the mammalian brain [10]. Increased AQP4 expression was detected at the gliosis site of ependyma that impaired the CSF/BIF dynamic balance and the clearance of interstitial solutes [31][48]. On the other hand, deletion of AQP4 can obviously prevent the cytotoxic edema after stroke [48][49]. The abnormal expression of AQP4 is also involved in the dysfunction of the lymphatic pathway in animal models of traumatic brain injury, AD and stroke [50]. A higher AQP4 level was found in the ECs after subarachnoid hemorrhage, and the expression level of AQP4 was related with the severity of hydrocephalus [51]. The autoimmune antibodies from the patients of neuromyelitis optica can target AQP4 on the surface of ECs to trigger the functional impairment and inflammatory response in ependyma [52]. There is no doubt that AQP4 variation is associated with genetic susceptibility to PD [53]. The choroid plexus epithelium also expresses other AQPs including AQP1, AQP5 and AQP7, which more or less contribute to CSF production [10].
The normal activity of the ependymal motile cilia ensures the necessary CSF circulation to maintain brain homoeostasis, wash out toxins, deliver signal molecules and orient the migration of new-born neurons [54]. However, the molecular mechanism underlying the maintenance of ependymal motile cilia remains unclear [55]. The highly conserved cilia project from the apical surface and the zonula adherens on the lateral surface of ECs to move the overlying fluid by coordinated beating [12]. These cilia arise from the basal bodies, which are docked on the cell surfaces and rotationally polarized toward the CSF [56][57]. It has been suggested that this complementary polarization of the ependymal cilia should be regulated by the planar cell polarity pathway, which coordinates cell behavior in a plane of tissue cells [58][59]. The motile cilia dyskinesia can cause chronic recurrent respiratory infections, infertility, hydrocephalus and laterality defect [60][61][62]. Defective ependymal cilia motility is associated with the hydrocephalus, increased intracranial pressure and many neurological diseases [63][64]. Ciliary defects in mouse ECs can disrupt the CSF flow and lead to hydrocephalus and disoriented neuroblast migration in the SVZ [65][66]. Connexin 43 (Cx43), the dominating connexin of gap junction in the brain, plays a vital role in maintaining ependymal cilia [1]. Deletion of Cx43 can reduce the ciliary activity of ECs in zebrafish and mouse [1]. Possibly, the absence of Cx43 may affect the polarization of the ependymal cilia through the planar cell polarity pathway.
The neurodegenerative diseases share similar changes in the brain at the early stage, such as hydrocephalus [67] and ventricular broadening [64]. To date, the final diagnosis of AD can only be made by histopathological detection of Aβ plaques and neurofibrillary tangles post mortem [68]. For the purpose of early diagnosis and prevention of AD, positron-emission tomography (PET) has been used to analyze the synaptic dysfunction and cerebral Aβ load in the brain of AD model mice [69]. The data indicated that the glucose metabolism was decreased and the Aβ deposition was increased in AD mouse brain. The decreased glucose metabolism in AD may be due to the dysfunction of those glucose transporters expressed in the BBB, choroid plexus and ependyma [70][71]. Interestingly, high glucose or fructose concentration can directly stimulate the expression of brain-derived neurotrophic factor (BDNF) in the mouse microglia SIM-A9 cell [72]. Besides Aβ accumulation, more activated microglia have also been reported in AD animal models and in patients [73][74]. The Aβ plaque can activate microglia to form the plaque-microglial complex, and then significantly alter the gene expression and biological function of the surrounding astrocyte and oligodendrocyte precursor cell [75]. Furthermore, vascular risk factors such as hypercholesterolemia and hyperglycemia may also be involved in the genesis of AD and other neurodegenerative diseases [35]. The severity of cerebral atherosclerosis and/or arteriolosclerosis are associated with cognitive dysfunction [76]. Improving Aβ clearance along the perivascular pathway may provide a feasible therapeutic approach to control the progression of AD [77]. Recent research demonstrated that the CSF macrophages near the border of brain parenchyma had a role in regulating CSF flow dynamics by delicate clearance of the extra accumulated extracellular matrix proteins [78]. The single-nucleus RNA sequencing data obtained from the AD patients and the animal model of AD demonstrated abnormal transcriptomic alterations in these macrophages [78]. Intracisternal injection of macrophage colony-stimulating factor can improve the function of CSF macrophages and restore the CSF flow, implicating a new strategy to counteract the deficient CSF dynamics [78].
Similarly, the early diagnosis of PD, especially the premotor phase, is difficult in a clinic setting. Intracellular accumulation of the α-syn aggregates is the major pathological change of PD [79]. A previous study demonstrated that the changes in sleep-related oscillations should be an early consequence of abnormal α-syn aggregation in the mouse model [80]. The lymphatic pathway helps to drain the harmful substances in the cerebral interstitial fluid and CSF through the perivascular spaces of penetrating arteries, especially during sleep [30]. Chronic sleep deprivation or circadian disruption may cause lymphatic pathway dysfunction in the brain. The consequent abnormal accumulation of α-syn or other harmful substances caused by this BCB dysfunction will consequently result in AD, PD, depression and anxiety [80][81][82][83].
HD is a genetic neurodegenerative disease caused by the abnormal expansion of the CAG trinucleotide repeat in the huntingtin gene, which leads to a polyglutamine strand at the N-terminus of huntingtin protein [84]. Current therapeutic strategies designed for HD focus on reducing cytoplasmic aggregation of the mutant huntingtin protein [85]. Most cases of ALS are also characterized by the abnormal cytoplasmic aggregation of different proteins including TAR DNA binding protein 43 (TDP-43), Cu–Zn superoxide dismutase (SOD1), ubiquitin/p62 and others [86][87][88]. Unlike the HD, many genetic mutants have been identified in the ALS patients. Therefore, it is complicated to explain the pathogenesis of ALS. Ageing or exogenous risk factors may accelerate these inherited sensitivities and cause the onset of neurodegeneration [86]. Without considering the initiation of neuron damage, the activation of microglia and astroglia may contribute to the progressive motor neuron loss in ALS [86][87]. In human HD brains, the inflammatory activation of astroglia in the caudate nucleus and the subependymal layer was indicated by the co-localization of RAGE with its ligands and the nucleus translocation of NF-κB [89].
Under most circumstance, preventing neuroinflammation at an early stage can improve the cognitive impairment [90][91]. However, inhibition of the proinflammatory kinase IKKβ accelerates HD progression in mice because IKKβ has a role in phosphorylating huntingtin [92]. A review article suggested that the activation of microglia and astroglia in brain tissue may promote the BBB restoration, limit the blood-derived immune cell infiltration, trap the infiltrated T cells and achieve the early resolution of neuroinflammation in multiple sclerosis [93]. The age-related cerebral microvascular dysfunction and microbleeding destroy the integrity of BBB and allow the entry of peripheral neurotoxic substances, macrophages and neutrophils [94][95][96][97][98][99]. These factors can activate microglia and astroglia in the brain to release pro-inflammatory cytokines that induce chronic neuroinflammation and further brain injury. The anti-inflammatory reagent OKN-007 has shown effects on reversing lipopolysaccharide (LPS)-induced long-term neuroinflammatory responses and BBB impairment [100].

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Subjects: Physiology
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Xin-Yu Ma
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Ting-Ting Yang
, Lian Liu , Xiao-Chun Peng , Feng Qian , Feng-Ru Tang
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Update Date: 06 May 2023
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