Morphometry of choroid plexus epithelial cells in neurodegenerative diseases

Ryuta Murakami; Yoichi Chiba; Nobuyuki Miyatake; Yumi Miyai; Koichi Matsumoto; Keiji Wakamatsu; Yuko Saito; Manato Hara; Shigeo Murayama; Masaki Ueno

doi:10.1111/neup.13019

. 2024 Nov 27;45(3):202–209. doi: 10.1111/neup.13019

Morphometry of choroid plexus epithelial cells in neurodegenerative diseases

Ryuta Murakami ¹, Yoichi Chiba ¹, Nobuyuki Miyatake ², Yumi Miyai ¹, Koichi Matsumoto ¹, Keiji Wakamatsu ¹, Yuko Saito ³, Manato Hara ³, Shigeo Murayama ³, Masaki Ueno ^1,^✉

PMCID: PMC12129643 PMID: 39604645

Abstract

The choroid plexus not only secretes the majority of cerebrospinal fluid but also controls the circadian rhythm, which can be impaired in the presence of neurodegenerative diseases. In addition, many studies have reported the contribution of choroid plexus abnormalities to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Formalin‐fixed paraffin‐embedded blocks were obtained from the lateral ventricles of the brains of four subjects with AD, four with vascular dementia, four with Parkinson's disease, three with multiple system atrophy, and five control patients with unremarkable neuropathological findings. They were sectioned and routinely stained with hematoxylin and eosin. Morphological analysis of epithelial cells in 10 high‐power fields or a total area per case was conducted using digital images. There were no significant changes in any of the measurements: epithelial cell area, long and short axes, and ratio of the epithelial cell area to total stained area among the five groups. However, a simple linear regression analysis of epithelial cells in 20 patients showed that age was significantly correlated with the cell area, long axis, and short axis but not ratio. There were no effects of hypertension, diabetes mellitus, or calcification in the stroma on the measurements. These findings indicate that age was associated with the cell area and size in choroid plexus epithelial cells, whereas no significant changes in any epithelial cell measurements were present in neurodegenerative diseases.

Keywords: Alzheimer's disease, choroid plexus, epithelial cell, Parkinson's disease, vascular dementia

INTRODUCTION

The choroid plexus (CP) is a multifunctional structure involved in cerebrospinal fluid (CSF) secretion, immune surveillance, and blood‐CSF barrier (BCSFB) preservation. ¹ , ² , ³ In addition, it has been reported that CP plays a significant role in adjustment of the circadian rhythm. ⁴ , ⁵ CP is formed from a highly vascularized stroma and covered by epithelial cells. ² , ⁶ As endothelial cells of capillaries in the stroma are fenestrated, several kinds of intravascular substances can be moved into the stroma of CP. A monolayer of epithelial cells bound by tight and adherence junctions plays a significant role in forming BCSFB and preventing macromolecular substances from entering ventricles. However, as there are many transporters on apical and/or basolateral membranes in the cytoplasm of CP epithelial cells, several kinds of nutrients such as glucose and electrolytes can be moved into ventricles. ² , ⁶ Accordingly, it is possible to consider that damage to the choroid plexus induces various brain dysfunctions. A variety of histological and molecular abnormalities in CP and changes in nutrients and electrolytes in CSF have been reported in human samples. ⁷ , ⁸ , ⁹ As common morphological findings in CP, fibrosis and calcification in the stroma are observed. ⁷ , ¹⁰ Calcification in CP is clinically noted in the aging human brain, and the number of psammoma bodies increases with aging. ¹¹ Accumulation of calcified materials in the stroma might induce blocking of interstitial fluid flow and possibly CSF production. It was reported that CSF production is reduced in the presence of healthy aging ¹² and in dementia of the Alzheimer's type. ¹³ In addition, an experiment involving the direct measurement of CSF production in mice showed that it was reduced with aging and further reduced in aged mice overexpressing amyloid β. ¹⁴

The choroid plexus in Alzheimer's disease (AD) brains has been actively investigated using neuroimaging techniques. In a retrospective study of 532 patients with cognitive impairment who underwent 3.0‐T magnetic resonance imaging (MRI) of the brain, the CP volume was greater in those with than without AD. ¹⁵ CP volumes using MRI were significantly increased in AD patients compared with healthy individuals, correlated with age, and inversely correlated with cognitive performance in AD patients. ¹⁶ , ¹⁷ Jeong et al. reported a positive association between the CP volume and cognition in Parkinson's disease (PD) ¹⁸ and also reported an association of the CP volume with motor symptoms and dopaminergic degeneration in PD. ¹⁹ Interestingly, clinical findings on CP imaging in psychiatric patients are increasing. The CP volume in patients on the psychosis spectrum, including schizophrenia, was larger than in controls. ²⁰ , ²¹ , ²² CP enlargement in patients with schizophrenia was also significantly correlated with a greater allostatic load. ²¹

Histological examination of epithelial cells in CP has only recently begun in patients with AD and schizophrenia. CP showed similar degrees of epithelial atrophy, stromal fibrosis, blood vessel thickening, and calcifications in patients with AD and healthy individuals. ¹⁶ In contrast, in murine CP epithelial cells, age‐related changes in the flattening of epithelial cells, reduced length of microvilli, increased number of interrupted tight junctions, and decreased mitochondrial density with elongation of mitochondria were reported. ²³ An analysis with a general linear model demonstrated increased somal width of CP epithelial cells in patients with schizophrenia without antipsychotic medication but not in medicated schizophrenia patients. ²⁴ However, histological changes in CP epithelial cells in several kinds of neurodegenerative diseases have not been clarified. Accordingly, in this study, histological changes in CP epithelial cells were examined mainly in AD and PD patients’ brains, which were reported to show CP enlargement, but also in brains with vascular dementia (VD), a common type of dementia with vascular risk factors, and multiple system atrophy (MSA), which is another α‐synucleinopathy. Five brains showing unremarkable neuropathological findings in the elderly were used as controls.

MATERIALS AND METHODS

Post‐mortem brain tissues from 15 patients neuropathologically diagnosed with AD (n = 4), VD (n = 4), PD (n = 4), and MSA (n = 3) and five patients with unremarkable neuropathological findings (controls) were obtained from the Brain Banks for Aging Research in Tokyo Metropolitan Institute of Geriatrics and Gerontology. They ranged in age from 59 to 92 years, with 17 men and three women. The study protocol was approved by the ethics committees of Tokyo Metropolitan Institute of Medical Science (R19‐31) and the institutional ethics committee of the Faculty of Medicine, Kagawa University (2019‐091). All methods were performed in accordance with the relevant guidelines and regulations. All brain tissues used in this study were anonymized. Brief clinical information on the 20 patients is shown in Table 1. Clinicopathological findings whose relationship with epithelial cell morphology was evaluated were: age, presence of hypertension and diabetes mellitus, and degree of calcification in the stroma of CP. The Kruskal–Wallis test for differences in median values of age showed that there were no significant differences in median values of age among the five groups (P > 0.05, data not shown). The brains were fixed in 10% formalin, paraffin‐embedded, and cut into 5‐μm‐thick sections. All sections were evaluated with hematoxylin and eosin (HE) staining. Images were collected using an Olympus microscope (Tokyo, Japan) at ×400 total magnification and digitalized using a 2.8 MP digital camera connected to the microscope at 1920 × 1440 resolution. Ten randomly selected images per section were examined. In cases where the area of CP tissues on slides was too small to obtain 10 unduplicated views, the entire area of CP tissue in the section was examined.

Table 1.

Summary of clinicopathological profiles

Diag	Patients	Sex	Age	HT	DM	Calcification
Cont	C‐1	Male	72	0	0	1
Cont	C‐2	Male	86	1	1	1
Cont	C‐3	Male	78	1	1	2
Cont	C‐4	Male	80	0	0	2
Cont	C‐5	Male	74	0	0	0
AD	A‐1	Male	85	0	0	1
AD	A‐2	Female	83	0	0	2
AD	A‐3	Male	92	0	0	2
AD	A‐4	Male	84	0	0	2
VD	V‐1	Male	87	0	0	1
VD	V‐2	Male	79	1	0	1
VD	V‐3	Male	79	0	0	0
VD	V‐4	Male	72	1	1	2
PD	P‐1	Male	75	1	0	2
PD	P‐2	Female	85	0	0	1
PD	P‐3	Male	81	0	1	3
PD	P‐4	Male	81	1	0	3
MSA	M‐1	Female	78	0	0	3
MSA	M‐2	Male	59	0	0	2
MSA	M‐3	Male	85	0	0	3

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Epithelial cells of CP for measurement were defined as epithelial cells with a visible nucleus and clear cytoplasm in contact with the stroma, as shown in Figure 1. Mean short and long axes of the cytoplasm in epithelial cells, mean areas of the cytoplasm and nucleus in epithelial cells, and mean area ratios of total epithelial cell areas to total stained areas were calculated using the Python program OpenCV, Numpy, and Pandas as Python libraries. ²⁵ The total stained areas were defined as the contour of the cytoplasm of epithelial cells including epithelial cells and the stroma including vessels. Experimental measures were made in 117–404 epithelial cells per case and in 4846 epithelial cells in total. Calcification in the stroma of CP was evaluated as follows: frequently, occasionally, rarely, or none rated as 3+, 2+, 1+, or −, respectively.

Fig 1 — HE stained CP at ×400 magnification. Densely fibrous stroma covered with variously sized epithelial cells. Area, long axis, and short axis of epithelial cells outlined with green and total stained areas were measured. Scale bar: 10 μm.

Clinicopathological findings of age, hypertension, diabetes, and degree of calcification were treated as independent variables in separate models, whereas each cellular parameter of epithelial cells was treated as a dependent variable. The relationship between age and each of the measured variables: cell area (Area), long axis (Long axis), short axis (Short axis), and the ratio of epithelial cell area to total stained area (Ratio), was analyzed using Spearman's rank correlation coefficients. ²⁶ , ²⁷ The effect of hypertension or diabetes mellitus on the measured variables was assessed using the Mann–Whitney U‐test, whereas the effects of the degree of calcification on the measured variables was assessed using the Kruskal–Wallis test.

To evaluate differences in the measured variables among the five groups (Controls, AD, VD, PD, and MSA), the Kruskal–Wallis test was performed for each variable (Area, Long axis, Short axis, and Ratio). A P‐value less than 0.05 was considered significant.

RESULTS

Twenty unprocessed and locally enlarged images of HE staining, as shown in Figures S1A–T and 2A–2T, corresponded in order to the 20 patients presented in Table 1. HE staining revealed densely fibrous or calcified materials including psammoma bodies in the stroma and covering with variously sized epithelial cells in CP in all sections of 20 patients (Figs. S1, 2). In addition, flattening or loss of epithelial cells was sometimes noted, whereas epithelial cells with enlarged cytoplasm, including those with eosinophilic larger cytoplasm, were occasionally present (arrows in Fig. 2B, H–J, O).

Fig 2 — Representative enlarged microphotographs of HE staining of 20 human brains in control (A–E), AD (F–I), VD (J–M), PD (N–Q), and MSA (R–T) groups. Arrows in (B), (H), (I), (J), and (O) show epithelial cells with enlarged cytoplasm. Scale bars: 10 μm.

Data on the measured values in the cell area, long axis, short axis, or ratio of the epithelial cell area to total stained area are shown in Table 2. The Kruskal–Wallis test performed across the five groups (Control, AD, VD, PD, and MSA) showed no significant differences in any of the measured variables (Table 2) (P > 0.05 for all). This indicates that group assignment did not significantly affect any of the cellular parameters. However, analyses of the relationship between age and measured values of epithelial cells revealed a strong positive correlation between age and the cell area and a moderate correlation between age and the cell long or short axis (P < 0.05) (Fig. 3). ²⁶ , ²⁷ There were increases in cell area and long and short axes with aging. In contrast, no significant correlation was observed between age and the ratio of the epithelial cell area to total stained area (P > 0.05). Hypertension, diabetes mellitus, and the degree of calcification in the stroma had no significant effects on the cell area, long and short axes, or ratio of the epithelial cell area to total stained area (P > 0.05).

Table 2.

Median values (minimum and maximum values in parentheses) of four measures in five groups

Groups	Cell area	Long axis	Short axis	Ratio
Cont	122 (89–155)	15.0 (12.5–17.5)	11.4 (9.8–13.1)	0.182 (0.147–0.216)
AD	140 (95–185)	16.9 (13.3–20.5)	12.2 (10.1–14.4)	0.184 (0.096–0.272)
VD	119 (64–173)	14.9 (10.8–19.1)	11.2 (8.5–13.9)	0.164 (0.081–0.246)
PD	112 (82–142)	15.4 (12.1–18.8)	10.9 (9.4–12.4)	0.217 (0.063–0.371)
MSA	137 (88–186)	16.7 (12.9–20.8)	12.0 (9.7–14.4)	0.130 (0.04–0.219)
P‐value	0.655	0.640	0.671	0.944

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Data on four measures in five groups are shown as: μm² for cell area, μm for long and short axes, and ratio of cell area to total stained area.

The significance of differences in each variable among the five groups was assessed using the Kruskal–Wallis test.

Fig 3 — Scatterplots (A–D) of age and four measured variables in 20 samples of the five groups and Spearman's correlation coefficient of each variable (E). Data in control, AD, VD, PD, and MSA groups are marked C, A, V, P, and M in the figure, respectively. The horizontal axis shows age (A–D), whereas the vertical axis shows values of: Area (A), Long axis (B), Short axis (C), and Ratio (D). The unit of the horizontal axis is year, whereas the units of the horizontal axis in (A)–(D) are pixels. Spearman's correlation coefficient of each variable and each P‐value are shown in (E). One micrometer corresponds to 5.4 pixels.

DISCUSSION

Hematoxylin and eosin staining revealed that variously sized epithelial cells covering the stroma were present at various frequencies in all sections of the 20 patients. In addition, flattening or loss of epithelial cells were sometimes noted, whereas enlarged epithelial cells were also occasionally present. Kruskal–Wallis tests of four histological measurements of epithelial cells showed no differences among the five groups (AD, VD, PD, MSA, and controls). Conversely, age was significantly correlated with the cell area and size.

Choroid plexus volumetric changes captured by neuroimaging techniques have recently been reported to be associated with a variety of neurological disorders such as AD, ¹⁵ , ¹⁶ , ¹⁷ PD, ¹⁸ , ¹⁹ , ²⁸ amyotrophic lateral sclerosis, ²⁹ multiple sclerosis, ³⁰ , ³¹ , ³² , ³³ psychosis, ²⁰ , ²² schizophrenia, ²¹ stroke, ³⁴ and inflammation. ³⁵ , ³⁶ However, histological information on CP epithelial cells in neurological disorders has rarely been reported until recently. Increased somal width of CP epithelial cells was reported in schizophrenia patients without psychotic medication. ²⁴ CP showed similar degrees of epithelial atrophy, stromal fibrosis, blood vessel thickening, and calcifications in patients with AD and healthy individuals. ¹⁶ In this study, histological examination of CP epithelial cells in AD and VD for representative disorders with dementia, PD and MSA for representative disorders with motor disturbances, and aged people with unremarkable neuropathological findings corresponding to controls were examined. There were no significant differences in any of the four measured variables (Area, Long axis, Short axis, and Ratio) among the five groups. However, there was a significant correlation between age and the cell area, long axis, or short axis of epithelial cells. These findings indicate that there was an increase in the cell area and sizes with aging, regardless of neurodegenerative diseases. As shown in Figures 2 and S1, in calcified areas, epithelial cells sparsely covered the stroma in CP and the distance between nuclei of adjacent epithelial cells was increasing. From these findings, it might be reasonable to consider that the remaining epithelial cells are replacing the dead cells and compensating for their function by compensatory hypertrophy in areas with a low number of epithelial cells. In addition, the presence of epithelial cells with larger eosinophilic cytoplasm might have some effect on mean values of the cell area in the five groups. We consider that at least two populations of epithelial cells exist with larger eosinophilic cytoplasm. The first population is composed of cells with cytoplasm showing a longer long axis and eosinophilic properties equivalent to other cells, whereas the second is composed of cells with cytoplasm showing longer long and short axes that are more eosinophilic than other cells. Kepes ³⁷ reported that the cytoplasm of CP epithelial cells in Leigh's disease was enlarged, eosinophilic, and filled with fine granules indicating closely packed mitochondria. Shintaku ³⁸ reported that CP epithelial cells exhibited oncocytic transformation of central nervous tissue in ovarian mature teratoma. Cottrell et al. ³⁹ reported that cases with mitochondrial DNA disorders showed a biochemical deficiency in the oxidative phosphorylation pathway and exhibited characteristic oncocytic changes (considered typical of aging cells) in CP epithelial cells. The oncocytic transformation likely indicated a senescent change of metabolic abnormality leading to relative deficiency of mitochondrial enzymes and subsequent compensatory hyperplastic changes. ³⁷ , ³⁸ , ³⁹ Accordingly, some epithelial cells with larger eosinophilic cytoplasm observed in elderly subjects might be oncocytic. However, there were no significant differences in values of the cell area and size among the five groups, whereas the values tended to be higher in the AD group compared with those in the other groups. The numbers of cases in each group were three to five in this study. Further large‐scale and age‐adjusted studies are desirable in the future.

With a magnetic resonance imaging technique, chronic stages of stroke following ischemic brain injury were characterized by larger CP volumes, suggesting the contribution of neuroinflammation to compensatory enlargement of CP. ³⁴ Some neurodegenerative mechanisms, such as accumulation of toxic substances including abnormal proteins in the stroma, might cause damage to epithelial cells. Recent experimental findings suggested the contribution of systemic inflammatory substances to brain dysfunction with CP abnormalities. ⁴⁰ , ⁴¹ , ⁴² , ⁴³ As endothelial cells of capillaries in CP have fenestrations, it is reasonable to consider that circulating substances can more easily move into the stroma of CP than in areas protected by the blood–brain barrier. ² , ⁶ Accordingly, in cases of inflammation spreading from systemic circulation into the brain, CP might be a gateway; therefore, various injurious changes might become more likely to occur in the stroma ⁴⁴ and epithelial cells of CP.

DISCLOSURE

This work was supported by grants from JSPS KAKENHI JP 20K16193, 24K17847 (R.M.), 23K10827 (Y.C.), 24K10554 (M.U.), 16H06276 (AdAMS), 22H04923 (CoBiA) (Y.S., S.M.) of Japan, Integrated Research Initiative for Living Well with Dementia (IRIDE) of the Tokyo Metropolitan Institute for Geriatrics and Gerontology IRIDE (Y.S., S.M.), AMED under Grant Number JP21wm0425019 (Y.S., S.M.), and MHLW Research on rare and intractable diseases Program Grant Number JPMH23FC1008 (Y.S.).

ETHICS STATEMENT

This research using human autopsied brains has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration.

APPROVAL OF THE RESEARCH PROTOCOL

The study protocol was approved by the ethics committees of Tokyo Metropolitan Institute of Medical Science (R19‐31) and the institutional ethics committee of the Faculty of Medicine, Kagawa University (2019–091).

Supporting information

Supplemental Figure S1. Representative unprocessed microphotographs of HE staining of 20 human brains. CP tissues in control (A–E), AD (F–I), VD (J–M), PD (N–Q) and MSA (R–T) groups are shown. Scale bars: 100 μm.

NEUP-45-202-s001.tiff^{(2.1MB, tiff)}

ACKNOWLEDGMENTS

RM and MU performed microscopic observations and took pictures with microscopes; RM and NM performed statistical analyses; YC, YM, KM, and KW interpreted the data and revised the manuscript critically for content; and YS, MH, and SM conducted pathological dissection and diagnosed the 20 patients neuropathologically. All authors provided approval for the final version to be published and agreed to be accountable for all aspects of the work. The authors thank Ms. M. Kawauchi and K. Yasutomi for technical and editorial assistance, respectively.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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41. Kuhbandner K, Hammer A, Haase S et al. MAdCAM‐1‐mediated intestinal lymphocyte homing is critical for the development of active experimental autoimmune encephalomyelitis. Front Immunol 2019; 10: 1–12. 10.3389/fimmu.2019.00903 [DOI] [PMC free article] [PubMed] [Google Scholar]
42. Yang AC, Kern F, Losada PM et al. Dysregulation of brain and choroid plexus cell types in severe COVID‐19. Nature 2021; 595: 565–571. 10.1038/s41586-021-03710-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
43. Gorlé N, Blaecher C, Bauwens E et al. The choroid plexus epithelium as a novel player in the stomach‐brain axis during helicobacter infection. Brain Behav Immun 2018; 69: 35–47. 10.1016/j.bbi.2017.12.010 [DOI] [PubMed] [Google Scholar]
44. Wakamatsu K, Chiba Y, Murakami R et al. Immunohistochemical expression of osteopontin and collagens in choroid plexus of human brains. Neuropathology 2022; 42: 117–125. 10.1111/neup.12791 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

NEUP-45-202-s001.tiff^{(2.1MB, tiff)}

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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PERMALINK

Morphometry of choroid plexus epithelial cells in neurodegenerative diseases

Ryuta Murakami

Yoichi Chiba

Nobuyuki Miyatake

Yumi Miyai

Koichi Matsumoto

Keiji Wakamatsu

Yuko Saito

Manato Hara

Shigeo Murayama

Masaki Ueno

Abstract

INTRODUCTION