Neuronal nuclear tau and neurodegeneration

Tau is a well-known microtubule-associated protein related to its cytoplasmic localization in a neuronal cell. However, tau has been located at the cell nucleus where it could be a nucleic acid-associated protein by its preferential binding to DNA sequences present in the nucleolus and pericentromeric heterochromatin. This less well-known localization of tau could not be trivial, since during aging, an increase in the amount of nuclear tau takes place and it may be related to the described role of tau in the activation of transposons and further aging accelerationWork in the laboratory of JA is funded by grants from the Spanish Ministry of Economy and Competitiveness (PGC-2018-09177-B-100). Work in the laboratory of FH is funded by grants from the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía, Industria y Competitividad, Gobierno de España, PID2020-113204GB-I00) and was co-financed from the Comunidad de Madrid through Structural Funds of the European Union [S2017/BMD-3700 (NEUROMETAB-CM)

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

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 patternsThis study was funded by grants from Spanish Ministry of Economy and Competitiveness (Ministerio de Economía, Industria y Competitividad, Gobierno de España; BFU2016-77885-P), Structural Funds of the European Union from the Comunidad de Madrid [S2017/BMD-3700 (NEUROMETAB-CM)], institutional funding from the Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), and an institutional grant from the Fundación R. Areces. JM-R has a fellowship from the Fundación La Caix

Mouse and human tau expression in different brain areas

Background: An increase in tau protein is believed to be necessary for tau aggregation. However, whether this is due to increased expression of the endogenous tau promoter or protein accumulation due to proteostasis failure remains uncertain. Objective: To analyze the expression of GFP protein under endogenous tau promoter across different ages and within different brain areas. Methods: We have measured direct expression of Mapt gene promotor by western blot and immunofluorescence, by means of a commercial tau knock-out mice generated by integrating GFP-encoding cDNA into exon 1 of the Mapt gene. Besides, we have analyzed the MAPT gene expression in human samples. Results: Mapt expression is similar in the cortex, hippocampus, and cerebellum in mice and in human samples although some differences exist between dentate gyrus and CA1 hippocampal areas in mice. Besides, we have analyzed the murine Mapt gene expression during aging (at 2, 6, 12, and 18 moths) and no differences in endogenous tau promoter expression were observed. Conclusion: Our results suggest that Mapt promoter activity is similar in the brain areas studied and, therefore, tau accumulation due to aging is likely due to proteostasis failure rather than occurring at the transcriptional levelWork in the laboratory of JA is funded by grants from the Spanish Ministry of Economy and Competitiveness (PGC-2018-09177-B-100). Work in the laboratory of FH is funded by grants from the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía, Industria y Competitividad, Gobierno de España, PID2020-113204GB-I00) and was co-financed from the Comunidad de Madrid through Structural Funds of the European Union [S2017/BMD-3700 (NEUROMETAB-CM)

Nuevas funciones para la proteína tau en el Sistema Nervioso Central y tejidos periféricos

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 29-04-2022Esta tesis tiene embargado el acceso al texto completo hasta el 29-10-2023Tau es una proteína del citoesqueleto que se expresa principalmente en neuronas y está involucrada en diversos procesos celulares, como la estabilización de microtúbulos, el mantenimiento axonal, el transporte intracelular o la regulación de los poros nucleares. El metabolismo alterado de tau está estrechamente relacionado con diferentes tauopatías, siendo la enfermedad de Alzheimer (AD) la más importante. En estas situaciones vemos alterada la morfología y el metabolismo nuclear como consecuencia de una hiperfosforilación de tau y una agregación aberrante de la misma en el Sistema Nervioso Central. Este trabajo se centra en el estudio de nuevas funciones de tau y se divide en dos capítulos: En la primera parte nos centramos en el estudio de la expresión del promotor endógeno de tau en el ratón tauGFP knock-in/knock-out, al que se le ha insertado en el primer exón del gen Mapt la proteína eGFP y, por tanto, es un knock-out para la proteína tau. Encontramos que la expresión de tau varía en función de la edad y de la región del cerebro, pero en ningún caso de una forma demasiado marcada como ocurre en el desarrollo embrionario. Además, el reportero eGFP nos ha permitido demostrar que tau se encuentra en los podocitos de los glomérulos de la corteza renal, en concreto la isoforma Tau4R. Los estudios de microscopía electrónica de transmisión demostraron daño glomerular, daño que se reflejó en una disminución de la creatinina urinaria. Todos estos resultados demuestran, por tanto, que tau tiene un papel importante en el metabolismo renal en condiciones fisiológicas. En el segundo capítulo de este trabajo, nos hemos centrado en estudiar el efecto de tau en la activación de la transposición asociada a la edad. Se ha observado recientemente que la desregulación de los transposones (TE) se asocia a enfermedades neurodegenerativas. En este trabajo hemos descrito un aumento de la inserción de los TE in vitro, y un cambio de localización de la proteína ORF1p del transposón LINE-1, en presencia de tau. Para intentar revertir o proteger de la neurodegeneración promovida por TE, hemos analizado el efecto de un inhibidor de la transcriptasa reversa, como es Lamivudina (3TC), en un modelo de tauopatía murino (P301S). Este tratamiento en agua de bebida reduce las marcas histopatológicas propias de las tauopatías como son: tau fosforilado, inflamación, muerte neuronal y atrofia ventricular, además de un aumento de la supervivencia del 30% y reducción del fenotipo motor. Nuestros datos sugieren que la progresión de la tauopatía puede ser atenuada o frenada con la administración de 3TC cuando comiencen los primeros síntomas de la neuropatologí

Microtubule-associated protein tau in murine kidney: role in podocyte architecture

Tau is a cytoskeletal protein that is expressed mainly in neurons and is involved in several cellular processes, such as microtubule stabilization, axonal maintenance, and transport. Altered tau metabolism is related to different tauopathies being the most important Alzheimer’s disease where aberrant hyperphosphorylated and aggregated tau is found in the central nervous system. Here, we have analyzed that function in kidney by using tau knockout mice generated by integrating GFP-encoding cDNA into exon 1 of MAPT (here referred to as TauGFP/GFP). IVIS Lumina from PerkinElmer demonstrated GFP expression in the kidney. We then demonstrated by qPCR that the main tau isoform in the kidney is Tau4R. The GFP reporter allowed us to demonstrate that tau is found in the glomeruli of the renal cortex, and specifically in podocytes. This was further confirmed by immunohistochemistry. TauGFP/GFP mice present a podocyte cytoskeleton more dynamic as they contain higher levels of detyrosinated tubulin than wild-type mice. In addition, transmission electron microscopy studies demonstrated glomerular damage with a decrease in urinary creatinine. Our results prove that tau has an important role in kidney metabolism under normal physiological conditionsOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Work in the laboratory of JA is funded by grants from the Spanish Ministry of Economy and Competitiveness (PGC-2018-09177-B-100). Work in the laboratory of FH is funded by grants from the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía, Industria y Competitividad, Gobierno de España, PID2020-113204GB-I00) and was co-fnanced from the Comunidad de Madrid through Structural Funds of the European Union [S2017/BMD-3700 (NEUROMETAB-CM)

Lamivudine (3TC), a Nucleoside Reverse Transcriptase Inhibitor, Prevents the Neuropathological Alterations Present in Mutant Tau Transgenic Mice

The dysregulation of transposable elements contributes to neurodegenerative disorders. Previous studies have reported an increase in retrotransposon transcription in Drosophila models as well as in human tauopathies. In this context, we tested the possible protective effects of a reverse transcriptase inhibitor, namely lamivudine (also known as 3TC), in P301S mice, an animal model of Alzheimer’s disease based on FTDP-17-tau overexpression. Transgenic P301S mice administered lamivudine through drinking water showed a decrease in the following histopathological marks typical of tauopathies: tau phosphorylation; inflammation; neuronal death; and hippocampal atrophy. Lamivudine treatment attenuated motor deficits (Rotarod test) and improved short-term memory (Y-maze test). To evaluate the role of tau in retrotransposition, we cotransfected HeLa cells with a plasmid containing a complete LINE-1 sequence and a neomycin reporter cassette designed for retrotransposition assays, and a plasmid with the tau sequence. LINE-1 insertion increased considerably in the cotransfection compared to the transfection without tau. In addition, lamivudine inhibited the insertion of LINE-1. Our data suggest that the progression of the tauopathy can be attenuated by the administration of lamivudine upon the first symptoms of neuropathology

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

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.Spanish Ministry of Economy and Competitiveness (Ministerio de Economía, Industria y Competitividad, Gobierno de España; BFU2016-77885-P), Structural Funds of the European Union from the Comunidad de Madrid [S2017/BMD-3700 (NEUROMETABCM)], institutional funding from the Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), and an institutional grant from the Fundación R. Areces. JM-R has a fellowship from the Fundación La Caixa

In vivo cyclic overexpression of Yamanaka factors restricted to neurons reverses age-associated phenotypes and enhances memory performance

Abstract In recent years, there has been success in partially reprogramming peripheral organ cells using cyclic Yamanaka transcription factor (YF) expression, resulting in the reversal of age-related pathologies. In the case of the brain, the effects of partial reprogramming are scarcely known, and only some of its effects have been observed through the widespread expression of YF. This study is the first to exclusively partially reprogram a specific subpopulation of neurons in the cerebral cortex of aged mice. The in vivo model demonstrate that YF expression in postmitotic neurons does not dedifferentiate them, and it avoids deleterious effects observed with YF expression in other cell types. Additionally, our study demonstrates that only cyclic, not continuous, expression of YF result in a noteworthy enhancement of cognitive function in adult mice. This enhancement is closely tied to increased neuronal activation in regions related to memory processes, reversed aging-related epigenetic markers and to increased plasticity, induced by the reorganization of the extracellular matrix. These findings support the therapeutic potential of targeted partial reprogramming of neurons in addressing age-associated phenotypes and neurodegenerative diseases correlated with aging

2023 02 14 Hippocampus 14 31

Detection of intron 3 and intron 12 retaining MAPT species by digital droplet PCR in hippocampal samples of non-demented individuals and Alzheimer's disease patients. Each retention was detected in a different fluorophore. There are species that retain both introns TIR3+12-MAPT (Fam +, Hex +) which would be translated into DW-Tau (double intron retention), species that retain only intron 3 TIR3-MAPT (Fam +, Hex -) which would be translated into NW-Tau (Nt truncation) or species that retain only intron 12 TIR12-MAPT (Fam -, Hex +) which would be translated into CW-Tau (Ct truncation).</p

2021 06 02 total-MAPT cortex cerebellum 13 52

Detection of intron total MAPT species by digital droplet PCR in frontal lateral cortex and cerebellum samples of non-demented individuals and Alzheimer's disease patients.</p