Alzheimer’s Disease and Choroid Plexus: History
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Subjects: Biochemistry & Molecular Biology
Contributor:
Tiago Gião

The choroid plexus (CP), located in each of the four ventricles of the brain, is formed by a monolayer of epithelial cells that surrounds a highly vascularized connective tissue with permeable capillaries. These cells are joined by tight junctions forming the blood–cerebrospinal fluid barrier (BCSFB), which strictly regulates the exchange of substances between the blood and cerebrospinal fluid (CSF). 

  • choroid plexus
  • blood–cerebrospinal fluid barrier
  • Alzheimer’s disease

1. Morphological Alterations in the Choroid Plexus (CP) in Alzheimer’s Disease (AD)

Several morphological changes have been described in the choroid plexus (CP) of Alzheimer's disease (AD) patients, including flattening of epithelial cells and thickening of the irregular basement membrane, as compared to age-matched controls [1][2]. Aβ may also induce morphological changes in the CP cells, such as nucleus and cell volume shrinkage, as shown by CPECs from Aβ-injected mice [3]. Dense fibrosis of the underlying connective tissue is also present, which could be related to the increased collagen IV content, reported later [1][2]. Biondi ring tangles, which are intracellular inclusions, were observed to be more prevalent in AD patients when compared to control individuals [4][5]. Despite the discovery of Biondi body-like inclusions in an elderly chimpanzee, these inclusions were only ever detected in aged human CP, making their study difficult [6]. Histological analysis revealed several proteins constituting these aggregates, including tau protein, fibronectin, ubiquitin, and P component, as well as the presence of lipid droplets. The occurrence of these structures in the cytoplasm can cause mechanical damage to the plasma membrane [4][5][7]. Lipofuscin granules, which arise from highly oxidized cross-linked macromolecules and affect vesicle trafficking and cellular physiology, are also found in the cytoplasm of choroid plexus epithelial cells (CPECs) from aged and AD mice [1][5][8].
The CP of AD patients and mouse AD models are also characterized by deposits of Aβ [2][9][10] that may disrupt several CP functions. However, the alterations described are not exclusive of the AD brain and have been reported in aged mice [2][11]. Nevertheless, Aβ seems to play a crucial role in the degeneration of the biochemical pathways of the brain, including in the CP, as detailed in the sections below.

2. Cerebrospinal Fluid (CSF) Dynamics and Secretion in AD

Maintenance of the composition and volume of the CSF is essential to ensure normal brain function. The CP assists in the removal of harmful compounds from the CSF [12].
For instance, Aβ must be continuously removed from the brain to prevent its accumulation and aggregation. In this process, Aβ from the brain parenchyma easily reaches the CSF and flows to the CP vicinity to be transported out [13]. However, there is a dramatic alteration in CSF dynamics of AD patients, as evidenced by the decline in the CSF turnover and production [14][15]. Augmented ventricular volume also occurs in AD patients, as a consequence of the decreased neuronal mass, which contributes to the low turnover [15]. There also appears to be increased resistance to CSF absorption, as indicated by the elevated CSF pressure [16]. In aged mice, Aβ begins to accumulate before there is any reduction in CSF production and turnover, suggesting that the accumulation of the peptide is not a consequence of the decreased CSF turnover [17].
The transport of water to the CSF is carried out primarily through the aquaporin-1 water channel (AQP1), which is mainly located on the apical side of the epithelial cell membrane [18]. Consistent with the low CSF turnover reported above, in AD, this channel has its levels lowered [2], although its gene expression is not altered [19]. Several solute transporters and associated enzymes also have altered expression in AD patients, indicating the disruption of ionic transport [19][20].
As a result of the decreased CSF turnover, there is an accumulation of harmful compounds and nutrients, preventing them from reaching the brain parenchyma [21].
The composition of CSF varies as the disease progresses, and proteins such as TTR and gelsolin, which are known as neuroprotective and produced by the CP, become reduced, due in part to the decline of this organ’s secretory abilities [2][22][23]. Microarray analysis also revealed that the vascular endothelial growth factor (VEGF) signaling pathway, an important mediator of angiogenesis and inflammation, is upregulated in the CP, in AD [24]. On the other hand, the CP has been described as being able to produce Aβ [25][26][27], and this process occurs at a faster rate in AD patients [25][27][28].

3. BCSFB Integrity in AD

Aβ increased levels in AD lead to its deposition in the CP, impacting its function and, as a result, the integrity of BCSFB. This allows unwanted molecules to be transported paracellularly, compromising CSF homeostasis. Intraventricular administration of oligomeric Aβ increased matrix metalloproteases (MMP) expression (notably the MMP-3) and downregulated tight junction proteins claudin-5, occludin, zonula occludens-1, and claudin-1 in the CP [3]. Downregulation of claudin-5, claudin-11, and claudin-18 is also found in AD patients [19][20]. The CP of AD patients and of an AD mouse model also presented increased MMP-9 levels, which co-localized with Aβ deposits, and lower levels of the tight junction protein zonula occludens-1 [10]. MMP3-deficient mice treated with oligomeric Aβ elucidated the role of these MMPs in BCSFB integrity, as these animals had less BCSFB leakage than control mice [3]. These findings support the notion that in AD, largely because of Aβ peptide, there is a decline in tight junction proteins and an increase in MMP levels in the CP that may compromise BCSFB integrity and function.

4. Transport of Aβ and Other Compounds across the BCSFB in AD

CPECs are able to carry Aβ from the CSF side to the blood side and vice versa, with efflux of the peptide into the bloodstream being favored [29]. Several classic Aβ transporters at the BBB are also involved in the clearance of Aβ through the BCSFB in the CP epithelium. The low-density lipoprotein receptor-related protein 1 (LRP-1), low-density lipoprotein receptor-related protein 2 (LRP-2), and P-glycoprotein (P-gp) are the primary carriers of Aβ to the bloodstream via BBB and BCSFB. In contrast, the receptor for advanced glycation end products (RAGE) facilitates the entry of Aβ into the CSF. However, in AD mice, the expression of LRP-1 and RAGE was found to be increased in the BCSFB [2][24]. Transcriptomic analysis confirms the upregulation of LRP-1 at the CP of AD patients [24]. On the other hand, no Aβ transporters were detected in CP vessels, which is reasonable since the high permeability of the vessels would render them useless [2]. A transcriptome analysis found that older rats had higher expression of LRP-1 and P-gp at the BCSFB, but no variations in RAGE expression, when compared to younger rats [30]. BBB LRP-1 and P-gp decline with age, and notably in AD, and there is a strong negative correlation between the expression of LRP-1 on vessels and regional Aβ accumulation, implying that the presence of Aβ impacts this transporter [11][31][32]. It is possible that the BCSFB attempts to compensate for the loss of Aβ transporters at the BBB, increasing their levels and restoring some efflux capability, although this remains to be determined.
The accumulation of Aβ, on the other hand, appears to impair the LRP-2-mediated transport across the epithelium of proteins such as leptin, albumin, and TTR [9]. Since these last two are recognized Aβ carriers, it is possible that a decrease in their levels in the CSF further exacerbates the pathology. The LRP-2 decline also affects IGF-I influx, a significant neuroprotective protein in AD [33][34].

5. Metabolic Alterations and Oxidative Stress in the CP in AD

Oxidative stress, as one of the earliest events in AD pathogenesis, plays a significant role in disease development [35]. Studies with AD subjects and with AD transgenic mice demonstrated that Aβ induces nitric oxide (NO) generation and increases reactive oxygen species (ROS) and CPEC death, as evidenced by increased caspase-3 and -9 expression [10]. The presence of oxidation markers in different proteins in the CP of late-stage AD patients as a result of increased reactive oxygen species may affect CP function [36].
According to a large-scale gene expression analysis, AD patients are characterized by an upregulation of the unfolded protein response, endoplasmic reticulum stress pathway, and the protein ubiquitin pathway, which is the reflex of the increased cellular stress [19][37]. The glutathione-mediated detoxification pathway and the urea cycle, on the other hand, were found to be downregulated in the CP, suggesting that a sink action could be impaired in AD [19].
The mitochondrial energy metabolism is also impaired in CP of AD patients, as seen by the alteration of the activity and assembly of mitochondrial respiratory chain complexes I and IV [10][38]. In addition, mitochondrial ATP synthase, which is needed for ATP synthesis, is downregulated in these patients [20].

6. Inflammation and CP in AD

The CP also performs immune surveillance of the CNS, acting as a gateway for leukocyte entry into the brain parenchyma. It constitutively expresses adhesion molecules and chemokines, allowing leukocyte trafficking by BCSFB during immune responses [39].
One of the most prominent hallmarks of AD is the neuroinflammation that occurs as a result of a disturbance of the balance of anti-inflammatory and pro-inflammatory signaling. It is proposed that AD is characterized by an early acute inflammation phase with microglial activation in response to neurotoxic molecules that can become chronic, due to the system’s inability to mount an adequate immune response [39].
The involvement of inflammation in AD in the CP is also well documented. The expression of many genes associated with acute phase response, cell adhesion, and cytokines is elevated in the CP of an AD patient [24]. This intense immune response is attributed, in part, to a failure in the recruitment of immune cells to the brain, through the CP. The gateway activity for leukocyte trafficking was found to be disrupted in AD mouse models as a consequence of decreased CP interferon-γ (IFN-γ) signaling, which affected the induction of leukocyte trafficking determinants [40][41]. Interestingly, transcriptomic analysis has revealed that the gene encoding IFN-γ was more expressed in the CP of 3-month-old AD mice compared with non-transgenic controls. IFN-γ levels in AD mice were further decreased compared to the control group at the age of 5–6 months, which lasted until 11–12 months of age. Notably, the genes involved in type I interferon response showed an overall overexpression in AD mice at the ages studied [42].
IFN-γ signaling can be regulated by Foxp3+ regulatory T cells, reducing IFN-γ availability at the CP. In AD mice, the transient depletion of these cells or pharmacological inhibition of their activity leads to decreased Aβ load, reduced neuroinflammation, and improved cognitive function. This is due to increased IFN-γ in the CP, which enhances the gateway activity, resulting in the recruitment of regulatory T cells and monocyte-derived macrophages at sites of Aβ plaque formation [40]. The immune checkpoint programmed cell death protein 1 (PD-1) regulates T cell activity by suppressing it. In AD mouse models, treatment with a blocking antibody directed at PD-1 increases IFN-γ expression in the CP and starts an IFN-γ-dependent immune response [43].
The tumor necrosis factor α (TNF-α) has also been shown to promote leukocyte entry via the CP through NFκB/p65 signaling [44]. This movement of immune cells is impaired in the presence of NO, which is increased in the CP of AD patients [10]. The administration of NO scavengers to AD mice induced NFκB/p65 pathway activation and expression of CP leukocyte trafficking determinants, restoring CP gateway activity [44].
TNF was recently identified as the most significant upstream regulatory cytokine in the CP of late-stage Alzheimer’s disease patients. Tumor necrosis factor receptor-1 (TNF-R1) ablation alleviated epithelial morphological changes, reduced CP inflammation, and restored BCSFB integrity in two different AD mouse models. In animals missing TNF-R1, the observed integrity can be explained by the decreased levels of MMPs and the preservation of tight junctions [45]. Interestingly, intracerebroventricular injection of Aβ oligomers in young mice increased TNF-α gene expression in CP, as well as interleukin-6 (Il-6) and nitric oxide synthase, strengthening its involvement in the disease [3]. The genes that code for interleukin-1 receptors are also increased in AD, being associated with acute and chronic inflammation [20].

7. Features of CP Stem Cell in AD

The formation of new neurons and glia is fundamental during embryonic development and occurs also after birth and throughout adulthood in certain brain regions. During maturity, this phenomenon is found in the olfactory bulb, the granular cell layer of the hippocampus, and the ependymal membrane of the lateral ventricles (subventricular zone) [46]. It has also been suggested that some CPECs have neural stem cell characteristics, such as the ability to proliferate and express neuronal and glial markers [47]. Others went further and suggested the existence of neural progenitor cells among the epithelial cell [48].
Regarding this function in AD, in vivo and in vitro approaches showed that Aβ regulates the proliferation and differentiation of neural progenitor cells into neurons, which, however, have reduced survival [49]. This can be seen as a compensatory process, allowing the replacement of damaged and dead neurons [50].

8. Circadian Cycle Disturbed at CP in AD

Recently, the CP was implicated in the modulation of circadian rhythm, which corresponds to the daily oscillations of diverse biological processes that keep the body rhythms in synchrony with the environment’s external light–dark cycles. The hypothalamic suprachiasmatic nucleus is the master circadian clock and coordinates circadian gene expression in the peripheral clocks [51]. On the other hand, CP has also been shown to produce melatonin, probably controlled by the CP clock, and to influence the rhythm of the master clock, the suprachiasmatic nucleus [52]. The CP was recently highlighted as one of the peripheral circadian clocks, as concluded by the expression of circadian clock genes in rat CP. Circadian oscillations in the expression of these genes were less noticeable in males than in females [53], with estrogens contributing to this difference [54].
The circadian rhythm of CP in mouse AD is unregulated, as shown by the aberrant oscillations in the expression of clock genes. The circadian rhythmicity was recovered when a CP cell line was treated with melatonin in the presence of Aβ [55]. The same group of researchers showed the impact of circadian rhythm on the secretion of Aβ scavengers—apoliprotein J (ApoJ) and TTR—in non-transgenic rat explants, with a clear pattern of fluctuations in the expression of those proteins [56].

9. CP Epithelial Cell Implants as a Therapy in AD

The CP is associated with numerous pathophysiological processes and is crucial for the maintenance of brain homeostasis. In light of the popularity of the CP in recent years, the application of epithelial cell implants in neurodegenerative diseases as cell therapy to restore brain tissue and function has become a reality. The CP ability to secrete neuroprotective growth factors, neurotrophins, hormones, and proteins, as well as the presence of epithelial cells with neural stem cell properties, are some of the points that support this therapeutic path in AD. Strengthening this idea, co-cultures of neurons and CPECs resulted in increased neuronal survival and proliferation compared to cultures with neurons alone. These results were related to reduced Aβ and increased neprilysin levels in the conditioned media, reflecting the neuroprotective potential conferred by the CPECs [57]. Taking into account the protective role of CPECs, researchers implanted these cells in the hippocampus of AD mice. Post-mortem analysis revealed a decrease in Aβ deposits, hyperphosphorylation of tau, and astrocytic inflammation. Behavior analysis also revealed improved spatial and non-spatial memory [57]. In another study, the implantation of microcapsules with CPECs in the cortex, following intrahippocampal Aβ injection, resulted in improved memory in a rat model. Brain sample analysis also revealed that transplantation of encapsulated CPECs resulted in a significant increase in neurogenesis and antioxidant activity, combined with a decrease in apoptosis, gliosis, and neuroinflammation [58].
Although not from CP, very recent data demonstrated that transplantation of human amniotic epithelial cells and treatment with lycopene or their combination can improve learning and memory abilities and decrease Aβ deposition in an acute AD rat model. Decrease levels of proinflammatory and anti-inflammatory cytokines were also detected in CSF and hippocampus via regulation of CP, as seen by the decrease in Toll-like receptor 4 and nuclear factor-κB p65 signaling at the CP. This work highlights the immunomodulatory ability of the CP [59][60].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10020224

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