Choroid plexus genes for CSF production and brain homeostasis are altered in Alzheimer’s disease

Abstract

BackgroundThe roles of the choroid plexus (CP) and cerebrospinal fluid (CSF) production have drawn increasing attention in Alzheimer’s disease (AD) research. Specifically, studies document markedly decreased CSF production and turnover in moderate-to-severe AD. Moreover, reduced CP function and CSF turnover lead to impaired clearance of toxic metabolites, likely promote neuroinflammation, and may facilitate neuronal death during AD progression. We analyzed CP gene expression in AD compared with control subjects, specifically considering those genes involved with CSF production and CP structural integrity.MethodsThe Brown-Merck Gene Expression Omnibus (GEO) database (CP transcripts) was mined to examine changes in gene expression in AD compared to controls with a focus on assorted genes thought to play a role in CSF production. Specifically, genes coding for ion transporters in CP epithelium (CPE) and associated enzymes like Na–K-ATPase and carbonic anhydrase, aquaporins, mitochondrial transporters/enzymes, blood–cerebrospinal fluid barrier (BCSFB) stability proteins, and pro-inflammatory mediators were selected for investigation. Data were analyzed using t test p-value and fold-change analysis conducted by the GEO2R feature of the GEO database.ResultsSignificant expression changes for several genes were observed in AD CP. These included disruptions to ion transporters (e.g., the solute carrier gene SLC4A5, p = 0.004) and associated enzyme expressions (e.g., carbonic anhydrase CA4, p = 0.0001), along with decreased expression of genes involved in BCSFB integrity (e.g., claudin CLDN5, p = 0.039) and mitochondrial ATP synthesis (e.g., adenosine triphosphate ATP5L, p = 0.0004). Together all changes point to disrupted solute transport at the blood–CSF interface in AD. Increased expression of pro-inflammatory (e.g., interleukin IL1RL1, p = 0.00001) and potential neurodegenerative genes (e.g., amyloid precursor APBA3, p = 0.002) also implicate disturbed CP function.ConclusionsBecause the altered expression of numerous transcripts in AD-CP help explain decreased CSF production in AD, these findings represent a first step towards identifying novel therapeutic targets in AD.Electronic supplementary materialThe online version of this article (10.1186/s12987-018-0120-7) contains supplementary material, which is available to authorized users.

Genetic disruption of slc4a10 alters the capacity for cellular metabolism and vectorial ion transport in the choroid plexus epithelium

“…Na + ,K + -ATPase and AQP1 expression levels are decreased in the CP from ageing rats [28], and the CP in ageing sheep has a reduced Na + uptake, high ATP content, and relative mitochondrial deficiency in addition to a low CSF secretion rate [29]. Similar to the current study, a data mining study of Alzheimer's disease data demonstrated a downregulated expression of NKCC1, Ncbe, Na + ,K + -ATPase subunits (except for the α1 subunit), and ATP synthase subunits in the CP [37]. A transcriptome study of human Alzheimer's disease CP material documented a reduced expression of the corresponding transcripts [38].…”

Molecular abnormalities in autopsied brain tissue from the inferior horn of the lateral ventricles of nonagenarians and Alzheimer disease patients

“…Maintenance of cytoskeletal integrity is crucial to the function of the choroid plexus as it is need for the assembly and positioning of specialized intracellular junctions between epithelial cells, needed to maintain epithelia adherens junction formation and barrier characteristics of the BCSFB. This may further serve to explain why we and others [37][38][39] observed alterations in adherens junction proteins and BCSFB integrity. Dynamic changes in the cytoskeleton also serves an important factor in the cell cycle maintenance and progression of the choroid plexus epithelial cells and ependymal cells lining the walls of the inferior horn of the ventricles, needed to maintain adequate cell numbers required for efficient production and circulation of CSF.…”

“…All 5 upstream regulators were observed from our 3 combinations of Control vs AD, control vs nonagenarian and nonagenarian vs AD cases Fig. 4 Venn diagram showing list of significant proteins in the inferior horn of the lateral ventricles based on stratification with amyloid plaque score (low < 10 vs high > 10) and Braak staging (0-II vs IV-VI) adenosine triphosphate ATP5L), increased expression of pro-inflammatory mediator, interleukin 1 receptor like 1 (IL1RL1) and amyloid precursor protein (APBA3), [39]. Further supporting evidence of disruptions to CSF production, solute transport at the blood-CSF interface, brain inflammatory status, and mitochondrial bioenergetics in AD.…”

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

“…It has been described that CSF production is altered in AD probably due to thickening of the basement membrane, atrophy of CP epithelial cells [241] and decreased synthetic capacity of essential proteins for CSF production, such as carbonic anhydrase (CA) II and AQPI [233,252]. In addition, expression of ion transporters involved in CSF secretion is decreased in AD [253].…”