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Annexin A5 prevents amyloid-β-induced toxicity in choroid plexus: implication for Alzheimer's disease.

ABSTRACT: In Alzheimer's disease (AD) amyloid-β (Aβ) deposits may cause impairments in choroid plexus, a specialised brain structure which forms the blood-cerebrospinal fluid (CSF) barrier. We previously carried out a mass proteomic-based study in choroid plexus from AD patients and we found several differentially regulated proteins compared with healthy subjects. One of these proteins, annexin A5, was previously demonstrated implicated in blocking Aβ-induced cytotoxicity in neuronal cell cultures. Here, we investigated the effects of annexin A5 on Aβ toxicity in choroid plexus. We used choroid plexus tissue samples and CSF from mild cognitive impairment (MCI) and AD patients to analyse Aβ accumulation, cell death and annexin A5 levels compared with control subjects. Choroid plexus cell cultures from rats were used to analyse annexin A5 effects on Aβ-induced cytotoxicity. AD choroid plexus exhibited progressive reduction of annexin A5 levels along with progressive increased Aβ accumulation and cell death as disease stage was higher. On the other hand, annexin A5 levels in CSF from patients were found progressively increased as the disease stage increased in severity. In choroid plexus primary cultures, Aβ administration reduced endogenous annexin A5 levels in a time-course dependent manner and simultaneously increased annexin A5 levels in extracellular medium. Annexin A5 addition to choroid plexus cell cultures restored the Aβ-induced impairments on autophagy flux and apoptosis in a calcium-dependent manner. We propose that annexin A5 would exert a protective role in choroid plexus and this protection is lost as Aβ accumulates with the disease progression. Then, brain protection against further toxic insults would be jeopardised.

SUBMITTER: Bartolome F

PROVIDER: S-EPMC7286910 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Manganese dioxide nanoparticles (MnO2-NPs) have a wide range of applications in biomedicine. Given this widespread usage, it is worth noting that MnO2-NPs are definitely toxic, especially to the brain. However, the damage caused by MnO2-NPs to the choroid plexus (CP) and to the brain after crossing CP epithelial cells has not been elucidated. Therefore, this study aims to investigate these effects and elucidate potential underlying mechanisms through transcriptomics analysis. To achieve this objective, eighteen SD rats were randomly divided into three groups: the control group (control), low-dose exposure group (low-dose) and high-dose exposure group (high-dose). Animals in the two treated groups were administered with two concentrations of MnO2-NPs (200 mg kg-1 BW and 400 mg kg-1 BW) using a noninvasive intratracheal injection method once a week for three months. Finally, the neural behavior of all the animals was tested using a hot plate tester, open-field test and Y-type electric maze. The morphological characteristics of the CP and hippocampus were observed by H&E stain, and the transcriptome of CP tissues was analysed by transcriptome sequencing. The representative differentially expressed genes were quantified by qRT-PCR. We found that treatment with MnO2-NPs could induce learning capacity and memory faculty decline and destroy the structure of hippocampal and CP cells in rats. High doses of MnO2-NPs had a more obvious destructive capacity. For transcriptomic analysis, we found that there were significant differences in the numbers and types of differential genes in CP between the low- and high-dose groups compared to the control. Through GO terms and KEGG analysis, high-dose MnO2-NPs significantly affected the expression of transporters, ion channel proteins, and ribosomal proteins. There were 17 common differentially expressed genes. Most of them were transporter and binding genes on the cell membrane, and some of them had kinase activity. Three genes, Brinp, Synpr and Crmp1, were selected for qRT-PCR to confirm their expression differences among the three groups. In conclusion, high-dose MnO2-NPs exposure induced abnormal neurobehaviour, impaired memory function, destroyed the structure of the CP and changed its transcriptome in rats. The most significant DEGs in the CP were within the transport system.

Project description:IntroductionAlzheimer's disease (AD) and epilepsy are reciprocally related. Among sporadic AD patients, clinical seizures occur in 10-22% and subclinical epileptiform abnormalities occur in 22-54%. Cognitive deficits, especially short-term memory impairments, occur in most epilepsy patients. Common neurophysiological and molecular mechanisms occur in AD and epilepsy. The choroid plexus undergoes pathological changes in aging, AD, and epilepsy, including decreased CSF turnover, amyloid beta (Aβ), and tau accumulation due to impaired clearance and disrupted CSF amino acid homeostasis. This pathology may contribute to synaptic dysfunction in AD and epilepsy.MethodsWe evaluated control (n = 8), severe AD (n = 8; A3, B3, C3 neuropathology), and epilepsy autopsy cases (n = 12) using laser capture microdissection (LCM) followed by label-free quantitative mass spectrometry on the choroid plexus adjacent to the hippocampus at the lateral geniculate nucleus level.ResultsProteomics identified 2,459 proteins in the choroid plexus. At a 5% false discovery rate (FDR), 616 proteins were differentially expressed in AD vs. control, 1 protein in epilepsy vs. control, and 438 proteins in AD vs. epilepsy. There was more variability in the epilepsy group across syndromes. The top 20 signaling pathways associated with differentially expressed proteins in AD vs. control included cell metabolism pathways; activated fatty acid beta-oxidation (p = 2.00 x 10-7, z = 3.00), and inhibited glycolysis (p = 1.00 x 10-12, z = -3.46). For AD vs. epilepsy, the altered pathways included cell metabolism pathways, activated complement system (p = 5.62 x 10-5, z = 2.00), and pathogen-induced cytokine storm (p = 2.19 x 10-2, z = 3.61). Of the 617 altered proteins in AD and epilepsy vs. controls, 497 (81%) were positively correlated (p < 0.0001, R2 = 0.27).DiscussionWe found altered signaling pathways in the choroid plexus of severe AD cases and many correlated changes in the protein expression of cell metabolism pathways in AD and epilepsy cases. The shared molecular mechanisms should be investigated further to distinguish primary pathogenic changes from the secondary ones. These mechanisms could inform novel therapeutic strategies to prevent disease progression or restore normal function. A focus on dual-diagnosed AD/epilepsy cases, specific epilepsy syndromes, such as temporal lobe epilepsy, and changes across different severity levels in AD and epilepsy would add to our understanding.

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Annexin A5 prevents amyloid-β-induced toxicity in choroid plexus: implication for Alzheimer's disease.

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