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Are the 50'S, the Transition Decade, in Choroid Plexus Aging?

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Are the 50'S, the Transition Decade, in Choroid Plexus Aging? GeroScience (2021) 43:225–237 https://doi.org/10.1007/s11357-021-00329-x ORIGINAL ARTICLE Are the 50’s, the transition decade, in choroid plexus aging? Ana Tahira & Fernanda Marques & Bianca Lisboa & Arthur Feltrin & André Barbosa & Kátia Cristina de Oliveira & Carlos Alberto de Bragança Pereira & Renata Leite & Lea Grinberg & Claudia Suemoto & Renata Eloah de Lucena Ferretti-Rebustini & Carlos Augusto Pasqualucci & Wilson Jacob-Filho & Helena Brentani & Joana Almeida Palha Received: 5 November 2020 /Accepted: 25 January 2021 / Published online: 12 February 2021 # The Author(s) 2021 Abstract The choroid plexus (CP) is an important struc- nervous system, including Alzheimer’s disease. In the ture for the brain. Besides its major role in the production present study, a high-throughput sequencing of the CP of cerebrospinal fluid (CSF), it conveys signals originat- transcriptome was performed in postmortem samples of ing from the brain, and from the circulatory system, clinically healthy individuals aged 50’s through 80’s. The shaping brain function in health and in pathology. Previ- data shows an age-related profile, with the main changes ous studies in rodents have revealed altered transcriptome occurring in the transition from the 50’stothe60’s, both during aging and in various diseases of the central stabilizing thereafter. Specifically, neuronal and Ana Tahira, Fernanda Marques, Helena Brentani and Joana Almeida Palha contributed equally to this work. A. Tahira : B. Lisboa : A. Feltrin : A. Barbosa : K. C. de Oliveira : H. Brentani LIM23, Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, C. A. de Bragança Pereira Faculdade de Medicina, Universidade de São Paulo, São Paulo, Departamento de Estatistísca, Núcleo de Bioinformática, Instituto SP, Brazil de Matemática, Universidade de São Paulo, São Paulo, SP, Brazil F. Marques : J. A. Palha (*) R. Leite : L. Grinberg : C. Suemoto : Life and Health Sciences Research Institute (ICVS), School of R. E. de Lucena Ferretti-Rebustini : C. A. Pasqualucci : Medicine, University of Minho, Braga, Portugal W. Jacob-Filho e-mail: [email protected] Biobank for Aging Studies Group, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil F. Marques : J. A. Palha ICVS/3B’s-PT Government Associate Laboratory, Braga/ Guimarães, Portugal H. Brentani Departamento de Psiquiatria, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil A. Feltrin : K. C. de Oliveira Center of Mathematics, Computing and Cognition, Federal University of ABC, Santo André, SP, Brazil J. A. Palha Clinical Academic Center, Braga, Portugal A. Barbosa Inter-institutional Grad Program on Bioinformatics, University of São Paulo, São Paulo, SP, Brazil 226 GeroScience (2021) 43:225–237 membrane functions distinguish the transcriptome be- disturbance in the genes that modulate the cellular cir- tween the 50’sandthe60’s, while neuronal and axon cadian cycle, transport of nutrients, and lipid metabo- development and extracellular structure organization dif- lism [13]. These alterations support the idea that there is ferentiate the 50’sfromthe70’s. These findings suggest a clear dysfunction of the CP with aging, which impacts that changes in the CP transcriptome occur early in the the production of CSF and the integrity of the blood- aging process. Future studies will unravel whether these CSF barrier [13]. The present study intends to charac- relate with processes occurring in late- onset brain terize the CP transcriptome in postmortem samples of diseases. clinically healthy humans from 50 to >80 years of age. Keywords Choroid plexus . Human . Aging . High- throughput sequencing Methods Participants Introduction Samples were provided by the Biobank for Aging Stud- Increased life expectancy contributed to a marked in- ies from the Faculty of Medicine at the University of crease in age-associated diseases. A better understanding São Paulo (BBAS-USP), formerly known as the Brain on how organs normally age will contribute to bring Bank of the Brazilian Aging Brain Study Group additional healthy life years. In the brain, aging is a (BBBABSG) [15], which is supplied by the São Paulo complex process that causes significant structural and City Autopsy Service (SPAS). Study protocols were physiological changes [1, 2]. Several studies have ex- reviewed by the local ethics committee and approval plored the impact of aging on brain physiology and granted by the FM-USP’s Institutional Review Board behavior [2, 3], demonstrating age-related impairments under protocol number 594/05, with all experiments on cognitive functions [4], exploratory and locomotor performed in compliance with CAPPesq rules. All fam- activities [5], sensorimotor behavior [6], and depressive- ily members gave written informed consent for the use like states [7]. Accompanying these behavioral alterations of the samples and clinical information. in normal aging are structural changes of brain volume, cerebral blood flow, metabolic rate for oxygen consump- Neuropathological analysis tion, glucose oxidation, blood volume, and cerebrospinal fluid (CSF) production [8]. Of interest, the CSF is mainly Neuropathological analysis was performed following produced by the choroid plexus (CP), which is a thin the BBBABSG routine [15]. The brains were removed membrane present within the brain ventricles and that is during autopsy within 4–20 h after death (postmortem part of the brain barriers. The CP is formed by a mono- interval in hours). One brain hemisphere was cut into 1- layer of epithelial cells that surrounds and encloses a cm coronal slabs and sampled in 13 neurodegenerative central stromal space rich in fenestrated blood vasculature disease-related structures, plus any other macroscopical- (lacking the blood-brain barrier), thus not restricting the ly lesioned areas, for microscopic examination. All sec- movement of molecules. However, diffusion into the tions were stained with hematoxylin and eosin. Immu- CSF is prevented by the tight junctions that characterize nohistochemistry was performed using antibodies the CP epithelial monolayer. Similarly to other brain against β-amyloid peptide (4G8; 1/5,000; Signet Labo- regions, aged human CP also exhibits general cellular ratories, Dedhan, MA), phospho-tau (PHF-1; 1/ 1,000; atrophy, decreased enzymatic and metabolic activities gift of Peter Davies, New York, NY) and against α- (and as such of CSF production), and impaired capacity synuclein (EQV-1; 1/10,000; gift of Kenji Ueda, Tokyo, for the efflux and clearance of molecules [9–12]. Japan). In the past few years, we and others have character- Neuropathological diagnoses were performed fol- ized, in rodents, the CP transcriptome in various ages lowing internationally accepted guidelines. The Consor- and disease conditions. These studies showed upregula- tium to Establish a Register for Alzheimer’s disease tion of type I interferon (IFN-I)-dependent expression criteria (CERAD) [16] were used to classify the β- profile with aging [13], which was associated with the amyloid neuritic plaque burden as none, scarce, moder- cognitive decline observed in older animals [14], and ate, or frequent. The distribution of neurofibrillary GeroScience (2021) 43:225–237 227 tangles (NFTs) was classified according to the Braak information about population parameters of the variable, and Braak staging system [17]asstagesItoVI.The the median was used as a threshold to apply binomial usual neuropathological guidelines were used for distribution with probability of success equal to 0.5 [27]. Parkinson’s disease and other dementias [18]. For variables with more than two categories, the homo- The diagnosis of argyrophilic grain disease (AGD) geneity test was performed [28]. was based on the presence of abundant phosphorylated tau-positive grains in the CA1 sector of the hippocam- Sample preparation pus, pretangles, especially in the hippocampal CA2 sector, and oligodendrocytes with coiled bodies in the After clinical and neuropathological selection, the CP hippocampal/temporal white matter [19]. The classifi- material was obtained from the samples of the right cation as healthy cases considered the absence or rare lateral ventricle. density of neuritic plaques (CERAD 0 or A) and a Braak stage up to III for neurofibrillary tangle distribution. RNA extraction and libraries construction Assessment of vascular lesion was performed by mac- roscopic examination. Total RNA extraction was performed using In this study, the primary criterium to label a subject QIASymphony (Qiagen, CA, EUA) with miRNA CT as healthy control was clinical (see below in functional 400 V8 QIAsymphony RNA kit (931636) QIAGEN assessments). It is of relevance to refer that subjects (Qiagen) according to the manufacturer's instructions. considered healthy have some level of neuropathologi- RNA quality was measured using Bioanalyzer and all cal changes, expected to this age group, according to samples presented RNA Integrity Number (RIN) higher several independent postmortem cohorts. We excluded than 5. RNA-sequencing libraries were constructed samples whenever they met neuropathological criteria using the TruSeq Stranded Total RNA Ribo-Zero Li- for a neuropathological condition. It is commonly ac- brary Preparation Kit Illumina according to the manu- cepted that the diagnosis of Alzheimer’sdisease facturer’s instructions and the paired-end sequencing (AD) requires AD neuropathology reaching scores was performed with the HiSeq 2500 (Illumina Inc., A2B2C2 according to the most recent neuropathologi-
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