Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis.

Pallas-Bazarra N, Jurado-Arjona J, Navarrete M, Esteban JA, Hernández F, Ávila J, Llorens-Martín M.

EMBO Journal.
doi: 10.15252/embj.201593518.

Tau is a microtubule-associated neuronal protein found mainly in axons. However, its presence in dendrites and dendritic spines is particularly relevant due to its involvement in synaptic plasticity and neurodegeneration. Here, we show that Tau plays a novel in vivo role in the morphological and synaptic maturation of newborn hippocampal granule neurons under basal conditions. Furthermore, we reveal that Tau is involved in the selective cell death of immature granule neurons caused by acute stress. Also, Tau deficiency protects newborn neurons from the stress-induced dendritic atrophy and loss of postsynaptic densities (PSDs). Strikingly, we also demonstrate that Tau regulates the increase in newborn neuron survival triggered by environmental enrichment (EE). Moreover, newborn granule neurons from Tau(-/-) mice did not show any stimulatory effect of EE on dendritic development or on PSD generation. Thus, our data demonstrate that Tau(-/-) mice show impairments in the maturation of newborn granule neurons under basal conditions and that they are insensitive to the modulation of adult hippocampal neurogenesis exerted by both stimulatory and detrimental stimuli.

Retroviral induction of GSK-3β expression blocks the stimulatory action of physical exercise on the maturation of newborn neurons.

Llorens-Martín M, Teixeira CM, Jurado-Arjona J, Rakwal R, Shibato J, Soya H, Ávila J.

Cellular and Molecular Life Sciences.
doi: 10.1007/s00018-016-2181-6.

Adult hippocampal neurogenesis (AHN) is a key process for certain types of hippocampal-dependent learning. Alzheimer's disease (AD) is accompanied by memory deficits related to alterations in AHN. Given that the increased activity of GSK-3β has been related to alterations in the population of hippocampal granule neurons in AD patients, we designed a novel methodology by which to induce selective GSK-3β overexpression exclusively in newborn granule neurons. To this end, we injected an rtTA-IRES-EGFP-expressing retrovirus into the hippocampus of tTO-GSK-3β mice. Using this novel retroviral strategy, we found that GSK-3β caused a cell-autonomous impairment of the morphological and synaptic maturation of newborn neurons. In addition, we examined whether GSK-3β overexpression in newborn neurons limits the effects of physical activity. While physical exercise increased the number of dendritic spines, the percentage of mushroom spines, and the head diameter of the same in tet-OFF cells, these effects were not triggered in tet-ON cells. This observation suggests that GSK-3β blocks the stimulatory actions of exercise. Given that the activity of GSK-3β is increased in the brains of individuals with AD, these data may be relevant for non-pharmacological therapies for AD.

GSK3β Overexpression in Dentate Gyrus Neural Precursor Cells Expands the Progenitor Pool and Enhances Memory Skills.

Jurado-Arjona J, Llorens-Martín M, Ávila J, Hernández F.

Journal of Biological Chemistry. 
doi: 10.1074/jbc.M115.674531.

In restricted areas of the adult brain, like the subgranular zone of the dentate gyrus (DG), there is continuous production of new neurons. This process, named adult neurogenesis, is involved in important cognitive functions such as memory and learning. It requires the presence of newborn neurons that arise from neuronal stem cells, which divide and differentiate through successive stages in adulthood. In this work, we demonstrate that overexpression of glycogen synthase kinase (GSK) 3β in neural precursor cells (NPCs) using the glial fibrillary acidic protein promoter during DG development produces an increase in the neurogenic process, increasing NPCs numbers. Moreover, the transgenic mice show higher DG volume and increased number of mature granule neurons. In an attempt to compensate for these alterations, glial fibrillary acidic protein/GSK3β-overexpressing mice show increased levels of Dkk1 and sFRP3, two inhibitors of the Wnt-frizzled complex. We have also found behavioral differences between wild type and transgenic mice, indicating a higher rating in memory tasks for GSK3β-overexpressing mice compared with wild type mice. These data indicate that GSK3β is a crucial kinase in NPC physiology and suggest that this molecule plays a key role in the correct development of DG and adult neurogenesis in this region.

The Ever-Changing Morphology of Hippocampal Granule Neurons in Physiology and Pathology.

Llorens-Martín M, Rábano A, Ávila J.

Frontiers in Neuroscience.
doi: 10.3389/fnins.2015.00526.

Newborn neurons are continuously added to the hippocampal dentate gyrus throughout adulthood. In this review, we analyze the maturational stages that newborn granule neurons go through, with a focus on their unique morphological features during each stage under both physiological and pathological circumstances. In addition, the influence of deleterious (such as schizophrenia, stress, Alzheimer's disease, seizures, stroke, inflammation, dietary deficiencies, or the consumption of drugs of abuse or toxic substances) and neuroprotective (physical exercise and environmental enrichment) stimuli on the maturation of these cells will be examined. Finally, the regulation of this process by proteins involved in neurodegenerative and neurological disorders such as Glycogen synthase kinase 3β, Disrupted in Schizophrenia 1 (DISC-1), Glucocorticoid receptor, pro-inflammatory mediators, Presenilin-1, Amyloid precursor protein, Cyclin-dependent kinase 5 (CDK5), among others, will be evaluated. Given the recently acquired relevance of the dendritic branch as a functional synaptic unit required for memory storage, a full understanding of the morphological alterations observed in newborn neurons may have important consequences for the prevention and treatment of the cognitive and affective alterations that evolve in conjunction with impaired adult hippocampal neurogenesis.

Forced swimming sabotages the morphological and synaptic maturation of newborn granule neurons and triggers a unique pro-inflammatory milieu in the hippocampus.

Llorens-Martín M, Jurado-Arjona J, Bolós M, Pallas-Bazarra N, Ávila J.

Brain Behavior and Immunity.
doi: 10.1016/j.bbi.2015.12.019.

Recent experimental data suggest that mood disorders are related to inflammatory phenomena and have led to the "inflammatory hypothesis of depression". Given that the hippocampus is one of the most affected areas in these disorders, we used a model of acute stress (the Porsolt test) to evaluate the consequences of forced swimming on two crucial events related to the pathophysiology of major depression: the functional maturation of newborn granule neurons; and the hippocampal inflammatory milieu. Using PSD95:GFP-expressing retroviruses, we found that forced swimming selectively alters the dendritic morphology of newborn neurons and impairs their connectivity by reducing the number and volume of their postsynaptic densities. In addition, acute stress triggered a series of morphological changes in microglial cells, together with an increase in microglial CD68 expression, thus suggesting the functional and morphological activation of this cell population. Furthermore, we observed an intriguing change in the hippocampal inflammatory milieu in response to forced swimming. Importantly, the levels of several molecules affected by acute stress (such as Interleukin-6 and eotaxin) have been described to also be altered in patients with depression and other mood disorders.

Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo.

Bolós M, Llorens-Martín M, Jurado-Arjona J, Hernández F, Rábano A, Avila J.

Journal of Alzheimer's Disease.
doi: 10.3233/JAD-150704.

The microtubule-associated protein (MAP) tau plays a critical role in the pathogenesis of tauopathies. Excess tau can be released into the extracellular medium in a physiological or pathological manner to be internalized by surrounding neurons-a process that contributes to the spread of this protein throughout the brain. Such spreading may correlate with the progression of the abovementioned diseases. In addition to neurons, tau can be internalized into other cells. Here we demonstrate that microglia take up tau in vitro and in vivo. In this regard, microglia from primary cultures internalized soluble (human recombinant tau42) and insoluble (homogenates derived from human AD brain) tau in vitro. Furthermore, using stereotaxic injection of tau in mice in vivo, we show that murine microglia internalize human tau. In addition, we demonstrate, for the first time, that microglia colocalize with various forms of tau in postmortem brain tissue of patients with Alzheimer's disease and non-demented control subjects. Our data reveal a potential role of microglia in the internalization of tau that might be relevant for the design of strategies to enhance the clearance of extracellular tau in neurodegenerative diseases characterized by the accumulation of this protein.


Centro de Biología Molecular Severo Ochoa (CBMSO) Universidad Autónoma de Madrid (Campus de Cantoblanco)
C/ Nicolás Cabrera 1 - 28049 Madrid (Spain)

María Llorens-Martín (PI)
+34 911964632