Estudio de la neurogénesis adulta en un modelo murino de sobreexpresión condicional de la glucógeno sintasa quinasa-3 beta

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 02-11-201

Different Susceptibility to Neurodegeneration of Dorsal and Ventral Hippocampal Dentate Gyrus: A Study with Transgenic Mice Overexpressing GSK3β

Dorsal hippocampal regions are involved in memory and learning processes, while ventral areas are related to emotional and anxiety processes. Hippocampal dependent memory and behaviour alterations do not always come out in neurodegenerative diseases at the same time. In this study we have tested the hypothesis that dorsal and ventral dentate gyrus (DG) regions respond in a different manner to increased glycogen synthase kinase-3β (GSK3β) levels in GSK3β transgenic mice, a genetic model of neurodegeneration. Reactive astrocytosis indicate tissue stress in dorsal DG, while ventral area does not show that marker. These changes occurred with a significant reduction of total cell number and with a significantly higher level of cell death in dorsal area than in ventral one as measured by fractin-positive cells. Biochemistry analysis showed higher levels of phosphorylated GSK3β in those residues that inactivate the enzyme in hippocampal ventral areas compared with dorsal area suggesting that the observed susceptibility is in part due to different GSK3 regulation. Previous studies carried out with this animal model had demonstrated impairment in Morris Water Maze and Object recognition tests point out to dorsal hippocampal atrophy. Here, we show that two tests used to evaluate emotional status, the light–dark box and the novelty suppressed feeding test, suggest that GSK3β mice do not show any anxiety-related disorder. Thus, our results demonstrate that in vivo overexpression of GSK3β results in dorsal but not ventral hippocampal DG neurodegeneration and suggest that both areas do not behave in a similar manner in neurodegenerative processes

Function of tau protein in adult newborn neurons

AbstractLevels of tau phosphorylation are high during the developmental period of intense neurite outgrowth, but decrease later. We here investigated whether tau protein plays a role in adult neurogenesis. First we demonstrate that new neurons generated in the subgranular zone express tau in a hyperphosphorylated form. Phospho-tau expression colocalized with doublecortin but not with glial fibrillary acidic protein, Ki67 or calbindin. The same was observed in the subventricular zone. Tau knockout mice did not show a significant decrease in the number of doublecortin-positive cells, although a deficit in migration was observed. These findings suggest that basal tau phosphorylation present in adult animals is in part due to neurogenesis, and from Tau knockout mice it seems that tau is involved in normal migration of new neurons

Tau spreading mechanisms; Implications for dysfunctional tauopathies

Tauopathies comprise a group of progressive age-associated neurodegenerative diseases where tau protein deposits are found as the predominant pathological signature (primary tauopathies) or in combination with the presence of other toxic aggregates (secondary tauopathies). In recent years, emerging evidence suggests that abnormal tau accumulation is mediated through spreading of seeds of the protein from cell to cell, favouring the hypothesis of a prion-like transmission of tau to explain the propagation of the pathology. This would also support the concept that the pathology initiates in a very small part of the brain before becoming symptomatic and spreads across the brain over time. To date, many key questions still remain unclear, such as the nature of the tau species involved in the spreading, the precise seeding/template and uptaking mechanisms or the selectivity explaining why certain neurons are affected and some others are not. A better understanding of the tau spreading machinery will contribute to the development of new therapeutic approaches focused on halting the abnormal propagation, offering also new perspectives for early diagnosis and preventive therapies. In this review, we will cover the most recent advances in tau spreading mechanisms as well as the implications of these findings for dysfunctional tauopathies.Peer Reviewe

Role of neuroinflammation in adult neurogenesis and Alzheimer disease: Therapeutic approaches

Neuroinflammation, a specialized immune response that takes place in the central nervous system, has been linked to neurodegenerative diseases, and specially, it has been considered as a hallmark of Alzheimer disease, the most common cause of dementia in the elderly nowadays. Furthermore, neuroinflammation has been demonstrated to affect important processes in the brain, such as the formation of new neurons, commonly known as adult neurogenesis. For this, many therapeutic approaches have been developed in order to avoid or mitigate the deleterious effects caused by the chronic activation of the immune response. Considering this, in this paper we revise the relationships between neuroinflammation, Alzheimer disease, and adult neurogenesis, as well as the current therapeutic approaches that have been developed in the field.This work was supported by Grants from the Spanish Ministry of Science and Technology (SAF2010-15525), the Comunidad de Madrid (S-SAL-0253-2006), the Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), and the Spanish Plan Nacional.Peer Reviewe

GSK3: A possible link between beta amyloid peptide and tau protein

Tau is a neuronal microtubule-associated phosphoprotein that is highly phosphorylated by glycogen synthase kinase 3 (GSK3). Tau phosphorylation by GSK3 regulates tau binding to microtubules, tau degradation and tau aggregation. Tau phosphorylation is important in Alzheimer disease pathology and in other tauopathies. In Alzheimer disease, it has been proposed that the peptide beta amyloid promotes GSK3 activation, resulting in tau phosphorylation. In this work, we review the links between beta amyloid peptide, tau protein and GSK3 that occur in familial Alzheimer disease. We also discuss the possible links between GSK3 and sporadic Alzheimer disease. Finally, we include a brief review of the pathology of animal models overexpressing GSK3.This work was supported by grants from the Comunidad de Madrid (NEURODEGMODELS-CM), the Spanish Comisión Interministerial de Ciencia y Tecnología and the CIBER on Neurodegeneration and by institutional grants from the Fundación Ramón Areces.Peer reviewe

Peripherally triggered and GSK-3β-driven brain inflammation differentially skew adult hippocampal neurogenesis, behavioral pattern separation and microglial activation in response to ibuprofen

Both familial and sporadic forms of Alzheimer disease (AD) present memory impairments. It has been proposed that these impairments are related to inflammation in relevant brain areas such as the hippocampus. Whether peripherally triggered and neuron-driven brain inflammation produce similar and equally reversible alterations is a matter of discussion. Here we studied the effects of ibuprofen administration on a familial AD mouse model overexpressing GSK-3β that presents severe brain inflammation. We compared these effects with those observed in a peripherally triggered brain inflammation model based on chronic lipopolysaccharide (LPS) administration. Both proinflammatory stimuli produced equivalent reversible morphological alterations in granule neurons; however, GSK-3β had a much more prominent role in newborn neuron connectivity, causing alterations that were not reversed by ibuprofen. Although both insults triggered similar behavioral impairments, ibuprofen rescued this defect in LPS-treated mice but did not produce any improvement in GSK-3β-overexpressing animals. This observation could be attributable to the different microglial phenotype induced by ibuprofen treatment. These data may be clinically relevant for AD therapies, as GSK-3β appears to determine the efficacy of ibuprofen treatment.Spanish Ministry of Health (SAF 2006-02424, BFU-2008-03980, BFU-2010-21507), the Comunidad de Madrid (SAL/0202-/2006), the Fundación M. Botín, the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII) and the Fundación R. Arece

Tau isoform with three microtubule binding domains is a marker of new axons generated from the subgranular zone in the hippocampal dentate gyrus: Implications for alzheimer's disease

In the adult hippocampal dentate gyrus, newborn granule cells grow dendrites into the molecular layer and send axons into the CA3 region. Several molecular markers have been used to analyze production of these new neurons; however, no good markers for new axons have been described. Here we demonstrate that tau protein isoform with three microtubule binding domains (3R-Tau) is a marker of those axons following an antigen retrieval protocol. By using retrovirus-mediated GFP transduction, GFP can be detected in a period of 7-14 days after viral infection. We also provide a >proof of principle> demonstration of the power of that labeling showing modulation of 3R-Tau positive axons under physiological conditions (exercise and aging) as well as in a FTDP-17 neurodegenerative model and Alzheimer's disease models (mice overexpressing AβPPsw, ind or GSK3β). We conclude that 3R-Tau would be an efficient marker and a valuable tool to study new axons in adult neurogenesis as well as in neurodegenerative processes. © 2012-IOS Press and the authors. All rights reserved.Spanish Ministry of Health (SAF 2006-02424; SAF2010-15525); Comunidad de Madrid (SAL/0202/2006); Fundación CIEN (PI 008-09); Fundación M. Botín; Fundación Ramón ArecesPeer Reviewe

The role of GSK3 in Alzheimer disease

Mutations in app, ps-1 and ps-2 genes result in the appearance of Familial Alzheimer disease (FAD). Although, in many cases, those mutations result in an increase of the amount of beta amyloid peptide, there is not a clear correlation between that amount and the time of the onset of the disease. Thus, other factors may explain how mutations in those genes result in the appearance of neurodegeneration. In this minireview we propose that GSK3 could be one of those factors.Peer reviewe