Publications by authors named "Jesus Avila"

336 Publications

Long runs of homozygosity are associated with Alzheimer's disease.

Transl Psychiatry 2021 Feb 24;11(1):142. Epub 2021 Feb 24.

Research Center and Memory clinic Fundació ACE. Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [β (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10; β (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.
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http://dx.doi.org/10.1038/s41398-020-01145-1DOI Listing
February 2021

Corrigendum to "Slower Dynamics and Aged Mitochondria in Sporadic Alzheimer's Disease".

Oxid Med Cell Longev 2021 14;2021:1643631. Epub 2021 Jan 14.

Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Nicolás Cabrera, 1. Cantoblanco 28049 Madrid, Spain.

[This corrects the article DOI: 10.1155/2017/9302761.].
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http://dx.doi.org/10.1155/2021/1643631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826234PMC
January 2021

A Multilevel View of the Development of Alzheimer's Disease.

Neuroscience 2021 03 24;457:283-293. Epub 2020 Nov 24.

College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA. Electronic address:

Every year the Alzheimer's Association publishes a report that provides facts and figures indicating the public health, social and economic impact of Alzheimer's disease (AD). In addition, there are a number of reviews on the disease for general readers. Also, at congresses, AD is analyzed at different but not always related levels, leading to an "elephant as seen by blind men situation" for many of the participants. The review presented herein seeks to provide readers with a holistic view of how AD develops from various perspectives: the whole human organism, brain, circuits, neurons, cellular hallmarks, and molecular level.
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http://dx.doi.org/10.1016/j.neuroscience.2020.11.015DOI Listing
March 2021

GSK3α, not GSK3β, drives hippocampal NMDAR-dependent LTD via tau-mediated spine anchoring.

EMBO J 2021 Jan 16;40(2):e105513. Epub 2020 Nov 16.

Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, Madrid, Spain.

Glycogen synthase kinase-3 (GSK3) is an important signalling protein in the brain and modulates different forms of synaptic plasticity. Neuronal functions of GSK3 are typically attributed to one of its two isoforms, GSK3β, simply because of its prevalent expression in the brain. Consequently, the importance of isoform-specific functions of GSK3 in synaptic plasticity has not been fully explored. We now directly address this question for NMDA receptor-dependent long-term depression (LTD) in the hippocampus. Here, we specifically target the GSK3 isoforms with shRNA knock-down in mouse hippocampus and with novel isoform-selective drugs to dissect their roles in LTD. Using electrophysiological and live imaging approaches, we find that GSK3α, but not GSK3β, is required for LTD. The specific engagement of GSK3α occurs via its transient anchoring in dendritic spines during LTD induction. We find that the major GSK3 substrate, the microtubule-binding protein tau, is required for this spine anchoring of GSK3α and mediates GSK3α-induced LTD. These results link GSK3α and tau in a common mechanism for synaptic depression and rule out a major role for GSK3β in this process.
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http://dx.doi.org/10.15252/embj.2020105513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809792PMC
January 2021

The Role of Chronic Stress as a Trigger for the Alzheimer Disease Continuum.

Front Aging Neurosci 2020 22;12:561504. Epub 2020 Oct 22.

Alzheimer Disease Research Unit, CIEN Foundation, Carlos III Institute of Health, Queen Sofía Foundation Alzheimer Center, Madrid, Spain.

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http://dx.doi.org/10.3389/fnagi.2020.561504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642953PMC
October 2020

In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice.

Stem Cell Reports 2020 11 22;15(5):1056-1066. Epub 2020 Oct 22.

Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa, CBMSO, CSIC-UAM, Madrid, Spain; Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain. Electronic address:

Post-translational epigenetic modifications take place in mouse neurons of the dentate gyrus (DG) with age. Here, we report that age-dependent reduction in H3K9 trimethylation (H3K9me3) is prevented by cyclic induction of the Yamanaka factors used for cell reprogramming. Interestingly, Yamanaka factors elevated the levels of migrating cells containing the neurogenic markers doublecortin and calretinin, and the levels of the NMDA receptor subunit GluN2B. These changes could result in an increase in the survival of newborn DG neurons during their maturation and higher synaptic plasticity in mature neurons. Importantly, these cellular changes were accompanied by an improvement in mouse performance in the object recognition test over long time. We conclude that transient cyclic reprogramming in vivo in the central nervous system could be an effective strategy to ameliorate aging of the central nervous system and neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.stemcr.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663782PMC
November 2020

Microglia in Alzheimer's Disease in the Context of Tau Pathology.

Biomolecules 2020 10 14;10(10). Epub 2020 Oct 14.

Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 1 Nicolás Cabrera, 28049 Madrid, Spain.

Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer's disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (, and ) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.
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http://dx.doi.org/10.3390/biom10101439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602223PMC
October 2020

Overexpression of GSK-3β in Adult Tet-OFF GSK-3β Transgenic Mice, and Not During Embryonic or Postnatal Development, Induces Tau Phosphorylation, Neurodegeneration and Learning Deficits.

Front Mol Neurosci 2020 10;13:561470. Epub 2020 Sep 10.

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.

GSK-3β or tau-kinase I is particularly abundant in the central nervous system (CNS), playing a key role in the pathogenesis of Alzheimer's disease (AD). Accordingly, transgenic mouse models overexpressing this kinase recapitulate some aspects of this disease, such as tau hyperphosphorylation, neuronal death, and microgliosis. These alterations have been studied in mouse models showing GSK-3β overexpression from birth. In this case, some of these alterations may be due to adaptations that occur during development. Here we explored the potential of the Tet-OFF conditional system in the murine CamKIIα-tTA/GSK-3β model to increase the activity of GSK-3β only during adulthood. To this end, the overexpression of GSK-3β remained OFF during embryonic and postnatal development by administration of doxycycline in drinking water for 6 months, while it was turned ON in adult animals by removal of the treatment for 6 months. In these conditions, the CamKIIα-tTA/GSK-3β mouse is characterized by an increase in phosphorylated tau, cell death, and microgliosis. Furthermore, the increase in GSK-3β expression in the adult animals triggered a cognitive deficit, as determined through the hippocampus-dependent object recognition test (OR). These results demonstrate that the GSK-3β plays a key role in AD and that previously published data with other transgenic models are neither caused by or a consequence of adaptations to high levels of the enzyme during development.
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http://dx.doi.org/10.3389/fnmol.2020.561470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511757PMC
September 2020

Tau phosphorylation by glycogen synthase kinase 3β modulates enzyme acetylcholinesterase expression.

J Neurochem 2020 Sep 21. Epub 2020 Sep 21.

Hospital General Universitario de Elche, FISABIO, Unidad de Investigación, Elche, Spain.

In Alzheimer's disease (AD), the enzyme acetylcholinesterase (AChE) co-localizes with hyperphosphorylated tau (P-tau) within neurofibrillary tangles. Having demonstrated that AChE expression is increased in the transgenic mouse model of tau Tg-VLW, here we examined whether modulating phosphorylated tau levels by over-expressing wild-type human tau and glycogen synthase kinase-3β (GSK3β) influences AChE expression. In SH-SY5Y neuroblastoma cells expressing higher levels of P-tau, AChE activity and protein increased by (20% ± 2%) and (440% ± 150%), respectively. Western blots and qPCR assays showed that this increment mostly corresponded to the cholinergic ACHE-T variant, for which the protein and transcript levels increased ~60% and ~23%, respectively. Moreover, in SH-SY5Y cells differentiated into neurons by exposure to retinoic acid (10 µM), over-expression of GSK3β and tau provokes an imbalance in cholinergic activity with a decrease in the neurotransmitter acetylcholine in the cell (45 ± 10%). Finally, we obtained cerebrospinal fluid (CSF) from AD patients enrolled on a clinical trial of tideglusib, an irreversible GSK3β inhibitor. In CSF of patients that received a placebo, there was an increase in AChE activity (35 ± 16%) respect to basal levels, probably because of their treatment with AChE inhibitors. However, this increase was not observed in tideglusib-treated patients. Moreover, CSF levels of P-tau at the beginning measured by commercially ELISA kits correlated with AChE activity. In conclusion, this study shows that P-tau can modulate AChE expression and it suggests that AChE may possibly increase in the initial phases of AD.
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http://dx.doi.org/10.1111/jnc.15189DOI Listing
September 2020

Protein Biomarkers for the Diagnosis of Alzheimer's Disease at Different Stages of Neurodegeneration.

Int J Mol Sci 2020 Sep 15;21(18). Epub 2020 Sep 15.

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain.

Mainly obtained from familial Alzheimer's disease patients' data, we know that some features of the neurodegenerative start several years before the appearance of clinical symptoms. In this brief review, we comment on some molecular and cellular markers appearing at different stages of the disease, before or once the clinical symptoms are evident. These markers are present in biological fluids or could be identified by image techniques. The combined use of molecular and cellular markers will be of interest to determine the development of the different phases of the disease.
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http://dx.doi.org/10.3390/ijms21186749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554800PMC
September 2020

Tau Protein as a New Regulator of Cellular Prion Protein Transcription.

Mol Neurobiol 2020 Oct 18;57(10):4170-4186. Epub 2020 Jul 18.

Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), Scientific Park of Barcelona, The Barcelona Institute for Science and Technology (BIST), Baldiri and Reixac 15-21, 08028, Barcelona, Spain.

Cellular prion protein (PrP) is largely responsible for transmissible spongiform encephalopathies (TSEs) when it becomes the abnormally processed and protease resistant form PrP. Physiological functions of PrP include protective roles against oxidative stress and excitotoxicity. Relevantly, PrP downregulates tau levels, whose accumulation and modification are a hallmark in the advance of Alzheimer's disease (AD). In addition to the accumulation of misfolded proteins, in the initial stages of AD-affected brains display both increased reactive oxygen species (ROS) markers and levels of PrP. However, the factors responsible for the upregulation of PrP are unknown. Thus, the aim of this study was to uncover the different molecular actors promoting PrP overexpression. In order to mimic early stages of AD, we used β-amyloid-derived diffusible ligands (ADDLs) and tau cellular treatments, as well as ROS generation, to elucidate their particular roles in human PRNP promoter activity. In addition, we used specific chemical inhibitors and site-specific mutations of the PRNP promoter sequence to analyze the contribution of the main transcription factors involved in PRNP transcription under the analyzed conditions. Our results revealed that tau is a new modulator of PrP expression independently of ADDL treatment and ROS levels. Lastly, we discovered that the JNK/c-jun-AP-1 pathway is involved in increased PRNP transcription activity by tau but not in the promoter response to ROS.
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http://dx.doi.org/10.1007/s12035-020-02025-xDOI Listing
October 2020

Editorial: Untangling the Role of Tau in Physiology and Pathology.

Front Aging Neurosci 2020 26;12:146. Epub 2020 May 26.

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, ISCIII, Madrid, Spain.

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http://dx.doi.org/10.3389/fnagi.2020.00146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264111PMC
May 2020

Focal cerebral ischemia induces changes in oligodendrocytic tau isoforms in the damaged area.

Glia 2020 Dec 9;68(12):2471-2485. Epub 2020 Jun 9.

Departamento de Biología (Fisiología Animal), Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.

Ischemic stroke is a major cause of death and the first leading cause of long-term disability worldwide. The only therapeutic strategy available to date is reperfusion and not all the patients are suitable for this treatment. Blood flow blockage or reduction leads to considerable brain damage, affecting both gray and white matter. The detrimental effects of ischemia have been studied extensively in the former but not in the latter. Previous reports indicate that preservation of white matter integrity reduces deleterious effect of ischemia on the brain. Oligodendrocytes are sensitive to ischemic damage, however, some reports demonstrate that oligodendrogenesis occurs after ischemia. These glial cells have a complex cytoskeletal network, including tau, that plays a key role to proper myelination. 4R-Tau/3R-Tau, which differ in the presence/absence of Exon 10, are found in oligodendrocytes; but the precise role of each isoform is not understood. Using permanent middle cerebral artery occlusion model and immunofluorescence, we demonstrate that cerebral ischemia induces an increase in 3R-Tau versus 4R-Tau in oligodendrocytes in the damaged area. In addition, cellular distribution of Tau undergoes a change after ischemia, with some oligodendrocytic processes showing positive staining for 3R-Tau. This occurs simultaneously with the amelioration of neurological damage in ischemic rats. We propose that ischemia triggers an endogenous mechanism involving 3R-Tau, that induces colonization of the ischemic damaged area by oligodendrocytes in an attempt to myelinate-injured axons. Understanding the molecular mechanism of this phenomenon could pave the way for the design of therapeutic strategies that exploit glial cells for the treatment of ischemia.
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http://dx.doi.org/10.1002/glia.23865DOI Listing
December 2020

The Role of TGF-β1 in Promoting Microglial Aβ Phagocytosis.

Authors:
Jesús Avila

Neuroscience 2020 07 18;438:215-216. Epub 2020 Apr 18.

Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa", CBMSO, CSIC-UAM, 28049 Madrid, Spain; Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain.. Electronic address:

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http://dx.doi.org/10.1016/j.neuroscience.2020.04.015DOI Listing
July 2020

A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease.

Front Immunol 2020 31;11:456. Epub 2020 Mar 31.

Sorbonne University, GRC no. 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France.

Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants-, and -potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker-drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.
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http://dx.doi.org/10.3389/fimmu.2020.00456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137904PMC
March 2020

Tauopathy Analysis in P301S Mouse Model of Alzheimer Disease Immunized With DNA and MVA Poxvirus-Based Vaccines Expressing Human Full-Length 4R2N or 3RC Tau Proteins.

Vaccines (Basel) 2020 Mar 13;8(1). Epub 2020 Mar 13.

Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología (CNB), Consejo Superior de Investigaciones Científicas (CSIC), 28049 Madrid, Spain.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive memory loss and cognitive decline that has been associated with an accumulation in the brain of intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein, and extracellular senile plaques formed by β-amyloid peptides. Currently, there is no cure for AD and after the failure of anti β-amyloid therapies, active and passive tau immunotherapeutic approaches have been developed in order to prevent, reduce or ideally reverse the disease. Vaccination is one of the most effective approaches to prevent diseases and poxviruses, particularly modified vaccinia virus Ankara (MVA), are one of the most promising viral vectors used as vaccines against several human diseases. Thus, we present here the generation and characterization of the first MVA vectors expressing human tau genes; the full-length 4R2N tau protein or a 3RC tau fragment containing 3 tubulin-binding motifs and the C-terminal region (termed MVA-Tau4R2N and MVA-Tau3RC, respectively). Both MVA-Tau recombinant viruses efficiently expressed the human tau 4R2N or 3RC proteins in cultured cells, being detected in the cytoplasm of infected cells and co-localized with tubulin. These MVA-Tau vaccines impacted the innate immune responses with a differential recruitment of innate immune cells to the peritoneal cavity of infected mice. However, no tau-specific T cell or humoral immune responses were detected in vaccinated mice. Immunization of transgenic P301S mice, a mouse model for tauopathies, with a DNA-Tau prime/MVA-Tau boost approach showed no significant differences in the hyperphosphorylation of tau, motor capacity and survival rate, when compared to non-vaccinated mice. These findings showed that a well-established and potent protocol of T and B cell activation based on DNA/MVA prime/boost regimens using DNA and MVA vectors expressing tau full-length 4R2N or 3RC proteins is not sufficient to trigger tau-specific T and B cell immune responses and to induce a protective effect against tauopathy in this P301S murine model. In the pursuit of AD vaccines, our results highlight the need for novel optimized tau immunogens and additional modes of presentation of tau protein to the immune system.
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http://dx.doi.org/10.3390/vaccines8010127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157204PMC
March 2020

Editorial: Shaping the Brain by Neuronal Cytoskeleton: From Development to Disease and Degeneration.

Front Cell Neurosci 2020 31;14:12. Epub 2020 Jan 31.

Departamento de Ciencias Médicas Básicas, Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna (ULL), Tenerife, Spain.

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http://dx.doi.org/10.3389/fncel.2020.00012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006473PMC
January 2020

Differences Between Human and Murine Tau at the N-terminal End.

Front Aging Neurosci 2020 28;12:11. Epub 2020 Jan 28.

Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Carlos III Institute of Health, Madrid, Spain.

Human tauopathies, such as Alzheimer's disease (AD), have been widely studied in transgenic mice overexpressing human tau in the brain. The longest brain isoforms of Tau in mice and humans show 89% amino acid identity; however, the expression of the isoforms of this protein in the adult brain of the two species differs. Tau 3R isoforms are not present in adult mice. In contrast, the adult human brain contains Tau 3R and also Tau 4R isoforms. In addition, the N-terminal sequence of Tau protein in mice and humans differs, a Tau peptide (residues 17-28) being present in the latter but absent in the former. Here we review the main published data on this N-terminal sequence that suggests that human and mouse Tau proteins interact with different endogenous proteins and also show distinct secretion patterns.
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http://dx.doi.org/10.3389/fnagi.2020.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999090PMC
January 2020

The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas.

Sci Transl Med 2020 01;12(527)

Neurooncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid 28220, Spain.

Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU (), a gene that has been classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wt and mut IDH1/2 in mouse and human gliomas. In IDH1/2 mut tumors, we found high expression of TAU that decreased with tumor progression. Furthermore, was almost absent from tumors with epidermal growth factor receptor () mutations, whereas its trancription negatively correlated with overall survival in gliomas carrying wt or amplified (amp) We demonstrated that the overexpression of TAU, through the stabilization of microtubules, impaired the mesenchymal/pericyte-like transformation of glioma cells by blocking EGFR, nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and the transcriptional coactivator with PDZ-binding motif (TAZ). Our data also showed that mut EGFR induced a constitutive activation of this pathway, which was no longer sensitive to TAU. By inhibiting the transdifferentiation capacity of EGFRamp/wt tumor cells, TAU protein inhibited angiogenesis and favored vascular normalization, decreasing glioma aggressiveness and increasing their sensitivity to chemotherapy.
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http://dx.doi.org/10.1126/scitranslmed.aax1501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055928PMC
January 2020

Unraveling human adult hippocampal neurogenesis.

Nat Protoc 2020 02 8;15(2):668-693. Epub 2020 Jan 8.

Department of Molecular Neuropathology, Centro de Biología Molecular 'Severo Ochoa', CBMSO, CSIC-UAM, Madrid, Spain.

Adult neurogenesis occurs in a few selected regions of the mammalian brain. One such region is the hippocampus, the so-called gateway to memory, where adult hippocampal neurogenesis (AHN) occurs. Here, we provide a comprehensive description of the methods used in our laboratory to unambiguously detect a population of immature neurons in the human hippocampus until the 10th decade of life. The criteria used to refine and develop the current protocol include obtaining post-mortem human samples of remarkable quality and under tightly controlled conditions for immunohistochemistry (IHC) studies, optimizing tissue processing and histological procedures, establishing criteria to reliably validate antibody signal and performing unbiased stereological cell counts. Moreover, we provide a detailed description of the parameters that, in our view, should be reported in human AHN studies. The opposing results obtained by introducing slight variations in the methodological conditions should be considered by future studies that seek to increase our knowledge of this fascinating process. By applying simple and inexpensive tissue pre-treatments, this protocol, which can be completed in 7 days, might be applicable to a variety of IHC studies performed on other tissues of human (or animal) origin.
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http://dx.doi.org/10.1038/s41596-019-0267-yDOI Listing
February 2020

Reelin reverts biochemical, physiological and cognitive alterations in mouse models of Tauopathy.

Prog Neurobiol 2020 03 20;186:101743. Epub 2019 Dec 20.

Vall d'Hebron Institut de Recerca, 08035, Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, and Institute of Neurosciences, University of Barcelona, 08028, Barcelona, Spain; Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain; ICREA Academia, 08010, Barcelona, Spain. Electronic address:

Reelin is an extracellular protein crucial for adult brain plasticity. Moreover, Reelin is protective against amyloid-β (Aβ) pathology in Alzheimer's Disease (AD), reducing plaque deposition, synaptic loss and cognitive decline. Given that Tau protein plays a key role in AD pathogenesis, and that the Reelin pathway modulates Tau phosphorylation, here we explored the involvement of Reelin in AD-related Tau pathology. We found that Reelin overexpression modulates the levels of Tau phosphorylation in AD-related epitopes in VLW mice expressing human mutant Tau. in vitro, Reelin reduced the Aβ-induced missorting of axonal Tau and neurofilament proteins to dendrites. Reelin also reverted in vivo the toxic somatodendritic localization of phosphorylated Tau. Finally, overexpression of Reelin in VLW mice improved long-term potentiation and long-term memory cognitive performance thus masking the cognitive and physiological deficits in VLW mice. These data suggest that the Reelin pathway, which is also protective against Aβ pathology, modulates fundamental traits of Tau pathology, strengthening the potential of Reelin as a therapeutic target in AD.
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http://dx.doi.org/10.1016/j.pneurobio.2019.101743DOI Listing
March 2020

Proteins and microRNAs are differentially expressed in tear fluid from patients with Alzheimer's disease.

Sci Rep 2019 10 28;9(1):15437. Epub 2019 Oct 28.

Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), c/Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain.

Alzheimer's disease (AD) is characterized by a progressive loss of neurons and cognitive functions. Therefore, early diagnosis of AD is critical. The development of practical and non-invasive diagnostic tests for AD remains, however, an unmet need. In the present proof-of-concept study we investigated tear fluid as a novel source of disease-specific protein and microRNA-based biomarkers for AD development using samples from patients with mild cognitive impairment (MCI) and AD. Tear protein content was evaluated via liquid chromatography-mass spectrometry and microRNA content was profiled using a genome-wide high-throughput PCR-based platform. These complementary approaches identified enrichment of specific proteins and microRNAs in tear fluid of AD patients. In particular, we identified elongation initiation factor 4E (eIF4E) as a unique protein present only in AD samples. Total microRNA abundance was found to be higher in tears from AD patients. Among individual microRNAs, microRNA-200b-5p was identified as a potential biomarker for AD with elevated levels present in AD tear fluid samples compared to controls. Our study suggests that tears may be a useful novel source of biomarkers for AD and that the identification and verification of biomarkers within tears may allow for the development of a non-invasive and cost-effective diagnostic test for AD.
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http://dx.doi.org/10.1038/s41598-019-51837-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817868PMC
October 2019

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.

Alzheimers Dement 2019 10 28;15(10):1333-1347. Epub 2019 Aug 28.

Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain. Electronic address:

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.

Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets.

Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444.

Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.
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http://dx.doi.org/10.1016/j.jalz.2019.06.4950DOI Listing
October 2019

Adeno-associated viral vector serotype 9-based gene therapy for Niemann-Pick disease type A.

Sci Transl Med 2019 08;11(506)

Centro Biologia Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain.

Niemann-Pick disease type A (NPD-A) is a lysosomal storage disorder characterized by neurodegeneration and early death. It is caused by loss-of-function mutations in the gene encoding for acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin into ceramide. Here, we evaluated the safety of cerebellomedullary (CM) cistern injection of adeno-associated viral vector serotype 9 encoding human ASM (AAV9-hASM) in nonhuman primates (NHP). We also evaluated its therapeutic benefit in a mouse model of the disease (ASM-KO mice). We found that CM injection in NHP resulted in widespread transgene expression within brain and spinal cord cells without signs of toxicity. CM injection in the ASM-KO mouse model resulted in hASM expression in cerebrospinal fluid and in different brain areas without triggering an inflammatory response. In contrast, direct cerebellar injection of AAV9-hASM triggered immune response. We also identified a minimally effective therapeutic dose for CM injection of AAV9-hASM in mice. Two months after administration, the treatment prevented motor and memory impairment, sphingomyelin (SM) accumulation, lysosomal enlargement, and neuronal death in ASM-KO mice. ASM activity was also detected in plasma from AAV9-hASM CM-injected ASM-KO mice, along with reduced SM amount and decreased inflammation in the liver. Our results support CM injection for future AAV9-based clinical trials in NPD-A as well as other lysosomal storage brain disorders.
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http://dx.doi.org/10.1126/scitranslmed.aat3738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285630PMC
August 2019

Propagation of Tau via Extracellular Vesicles.

Front Neurosci 2019 2;13:698. Epub 2019 Jul 2.

Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.

Extracellular vesicles (EVs), like exosomes, play a critical role in physiological processes, including synaptic transmission and nerve regeneration. However, exosomes in particular can also contribute to the development of neurodegenerative conditions such as Alzheimer's disease (AD), Parkinson's disease, and prion diseases. All of these disorders are characterized by protein aggregation and deposition in specific regions of the brain. Several lines of evidence indicate that protein in exosomes is released from affected neurons and propagated along neuroanatomically connected regions of the brain, thus spreading the neurodegenerative disease. Also, different cell types contribute to the progression of tauopathy, such as microglia. Several groups have reported tau release via exosomes by cultured neurons or cells overexpressing human tau. Although the exact mechanisms underlying the propagation of protein aggregates are not fully understood, recent findings have implicated EVs in this process. The AD brain has two hallmarks, namely the presence of amyloid-β-containing plaques and neurofibrillary tangles, the latter formed by hyperphosphorylated tau protein. Both amyloid peptide and tau protein are present in specific exosomes. This review summarizes recent advances in our understanding of exosomes in the pathology of AD, with a special focus on tau protein.
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http://dx.doi.org/10.3389/fnins.2019.00698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614378PMC
July 2019

Mitophagy Failure in APP and Tau Overexpression Model of Alzheimer's Disease.

J Alzheimers Dis 2019 ;70(2):525-540

Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Cantoblanco, Madrid, Spain.

Mitochondrial alterations and oxidative stress are common features of Alzheimer's disease brain and peripheral tissues. Moreover, mitochondrial recycling process by autophagy has been found altered in the sporadic form of the disease. However, the contribution of the main proteins involved in this pathology such as amyloid-β protein precursor (AβPP) and tau needs to be achieved. With this aim, human unmodified fibroblasts were transduced with lentivectors encoding APP and Tau and treated with CCCP to study the mitophagy process. Both AβPP and tau separately increased autophagy flux mainly by improving degradation phase. However, in the specific case of mitophagy, labeling of mitochondria by PINK1 and PARK2 to be degraded by autophagy seemed reduced, which correlates with the long-term accumulation of mitochondria. Nevertheless, the combination of tau and AβPP was necessary to cause a mitophagy functional impairment reflected in the accumulation of depolarized mitochondria labeled by PINK1. The overexpression of Tau and APP recapitulates the mitophagy failure previously found in sporadic Alzheimer's disease.
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http://dx.doi.org/10.3233/JAD-190086DOI Listing
October 2020

Tau is required for the function of extrasynaptic NMDA receptors.

Sci Rep 2019 06 24;9(1):9116. Epub 2019 Jun 24.

Centro de Biología Molecular Severo Ochoa (CBMSO) CSIC-UAM, Madrid, Spain.

Tau is a microtubule-associated neuronal protein found mainly in axons. However, increasing evidence indicates that it is also present in dendrites, where it serves as an essential mediator of synaptic NMDA (N-methyl-D-aspartate) receptor-dependent excitotoxicity. Of note, NMDA receptors can also be found outside synapses in the plasma membrane, and activation of extrasynaptic NMDA receptors has been shown to be more linked to excitotoxicity than the activation of synaptic ones. Little is known about the role of Tau in the activity of extrasynaptic NMDA receptors. Thus, we have used a Tau knockout mouse model (Tau mice) to analyze the consequences of Tau absence in extrasynaptic NMDA receptor activity. We demonstrate that absence of Tau leads to a decrease in functional extrasynaptic NMDA receptors in the hippocampus. We propose that this impairment in extrasynaptic NMDA receptor activity may contribute to the well-known neuroprotective effect associated with Tau deficiency under pathological conditions.
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http://dx.doi.org/10.1038/s41598-019-45547-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591308PMC
June 2019

Differences in structure and function between human and murine tau.

Biochim Biophys Acta Mol Basis Dis 2019 08 12;1865(8):2024-2030. Epub 2018 Aug 12.

Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), CSIC-UAM, Madrid, Spain; Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain. Electronic address:

The main difference between the primary structures of human and mouse tau can be found at the N-terminal end of the protein. Residues 17 to 28 in human tau are not present in the mouse form of the molecule. Here we tested the capacity of these human tau residues to bind to specific proteins. Several proteins were observed to bind to these residues. Among those that showed the greatest binding were three related to energetic processes: enolase, glyceraldehyde 3 phosphate dehydrogenase and creatine kinase B. The latter did not bind to tau from brain extracts taken from patients with Alzheimer's disease (AD). This lack of binding could be due to the modification of CKB by oxidation in AD.
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http://dx.doi.org/10.1016/j.bbadis.2018.08.010DOI Listing
August 2019

Lithium as a Treatment for Alzheimer's Disease: The Systems Pharmacology Perspective.

J Alzheimers Dis 2019 ;69(3):615-629

Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, F-75013, Paris, France.

Systems pharmacology is a novel framework for drug research that models traditional and innovative pharmacological parameters and provides the overall efficacy and safety profile of a drug across body systems and complex, non-linear, molecular interactions. Lithium chloride, a pharmacological compound approved for the therapy of psychiatric disorders, represents a poorly explored compound for the treatment of Alzheimer's disease (AD). Lithium has been shown to reduce downstream effects associated with the aberrant overactivation of certain molecular pathways, such as glycogen synthase kinase 3 subunit β (GSK3-β)-related pathways, involved in AD-related pathophysiology. It seems that overactivation and overexpression of GSK3-β lead to an impairment of long-term potentiation and amyloid-β induced neurotoxicity that can be normalized using lithium. Moreover, a growing body of evidence has demonstrated that lithium's GSK3-β inhibitory effect prevents tau phosphorylation in mouse models of tauopathies. Clinical data have been inconclusive, partly due to methodological limitations. The lack of studies exploring the dynamics of protein misfolding in AD and investigating the specific tau-isoforms appearing prior to the accumulation of neurofibrillary tangles calls for new and optimized clinical trials. Advanced computer modeling based on a formal implementation of quantitative parameters and basic enzymatic insights into a mechanism-based model would present a good start to tackle these non-linear interactions. This innovative approach will pave the way for developing "molecularly" biomarker-guided targeted therapies, i.e., treatments specifically adapted ("tailored") to the individual, consistently with the primary objectives and key conceptual points of precision medicine and precision pharmacology.
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http://dx.doi.org/10.3233/JAD-190197DOI Listing
September 2020

Activity-Dependent Reconnection of Adult-Born Dentate Granule Cells in a Mouse Model of Frontotemporal Dementia.

J Neurosci 2019 07 27;39(29):5794-5815. Epub 2019 May 27.

Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa", CBMSO, CSIC-UAM, 28049 Madrid, Spain,

Frontotemporal dementia (FTD) is characterized by neuronal loss in the frontal and temporal lobes of the brain. Here, we provide the first evidence of striking morphological alterations in dentate granule cells (DGCs) of FTD patients and in a mouse model of the disease, Tau mice. Taking advantage of the fact that the hippocampal dentate gyrus (DG) gives rise to newborn DGCs throughout the lifetime in rodents, we used RGB retroviruses to study the temporary course of these alterations in newborn DGCs of female Tau mice. In addition, retroviruses that encode either PSD95:GFP or Syn:GFP revealed striking alterations in the afferent and efferent connectivity of newborn Tau DGCs, and monosynaptic retrograde rabies virus tracing showed that these cells are disconnected from distal brain regions and local sources of excitatory innervation. However, the same cells exhibited a predominance of local inhibitory innervation. Accordingly, the expression of presynaptic and postsynaptic markers of inhibitory synapses was markedly increased in the DG of Tau mice and FTD patients. Moreover, an increased number of neuropeptide Y-positive interneurons in the DG correlated with a reduced number of activated egr-1 DGCs in Tau mice. Finally, we tested the therapeutic potential of environmental enrichment and chemoactivation to reverse these alterations in mice. Both strategies reversed the morphological alterations of newborn DGCs and partially restored their connectivity in a mouse model of the disease. Moreover, our data point to remarkable morphological similarities between the DGCs of Tau mice and FTD patients. We show, for the first time to our knowledge, that the population of dentate granule cells is disconnected from other regions of the brain in the neurodegenerative disease frontotemporal dementia (FTD). These alterations were observed in FTD patients and in a mouse model of this disease. Moreover, we tested the therapeutic potential of two strategies, environmental enrichment and chemoactivation, to stimulate the activity of these neurons in mice. We found that some of the alterations were reversed by these therapeutic interventions.
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http://dx.doi.org/10.1523/JNEUROSCI.2724-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636081PMC
July 2019