Publications by authors named "Jorge Valero"

43 Publications

Mitochondrial SIRT3 confers neuroprotection in Huntington's disease by regulation of oxidative challenges and mitochondrial dynamics.

Free Radic Biol Med 2021 Feb 4;163:163-179. Epub 2020 Dec 4.

CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address:

SIRT3 is a major regulator of mitochondrial acetylome. Here we show that SIRT3 is neuroprotective in Huntington's disease (HD), a motor neurodegenerative disorder caused by an abnormal expansion of polyglutamines in the huntingtin protein (HTT). Protein and enzymatic analysis revealed that increased SIRT3 is a signature in several HD models, including human HD brain, which is regulated by oxidative species. While loss of SIRT3 further aggravated the oxidative phenotype, antioxidant treatment regularized SIRT3 levels. SIRT3 overexpression promoted the antioxidant effect in cells expressing mutant HTT, leading to enhanced mitochondrial function and balanced dynamics. Decreased Fis1 and Drp1 accumulation in mitochondria induced by SIRT3 expression favored mitochondrial elongation, while the SIRT3 activator ε-viniferin improved anterograde mitochondrial neurite transport, sustaining cell survival. Notably, SIRT3 fly-ortholog dSirt2 overexpression in HD flies ameliorated neurodegeneration and extended lifespan. These findings provide a link between oxidative stress and mitochondrial dysfunction hypotheses in HD and offer an opportunity for therapeutic development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.freeradbiomed.2020.11.031DOI Listing
February 2021

Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy.

Epilepsia 2020 11 17;61(11):2593-2608. Epub 2020 Sep 17.

Achucarro Basque Center for Neuroscience, Science Park University of the Basque Country EHU/UPV, Leioa, Spain.

Objective: Microglial phagocytosis of apoptotic cells is an essential component of the brain regenerative response during neurodegeneration. Whereas it is very efficient in physiological conditions, it is impaired in mouse and human mesial temporal lobe epilepsy, and now we extend our studies to a model of progressive myoclonus epilepsy type 1 in mice lacking cystatin B (CSTB).

Methods: We used confocal imaging and stereology-based quantification of apoptosis and phagocytosis of the hippocampus of Cstb knockout (KO) mice, an in vitro model of phagocytosis and siRNAs to acutely reduce Cstb expression, and a virtual three-dimensional (3D) model to analyze the physical relationship between apoptosis, phagocytosis, and active hippocampal neurons.

Results: Microglial phagocytosis was impaired in the hippocampus of Cstb KO mice at 1 month of age, when seizures arise and hippocampal atrophy begins. This impairment was not related to the lack of Cstb in microglia alone, as shown by in vitro experiments with microglial Cstb depletion. The phagocytosis impairment was also unrelated to seizures, as it was also present in Cstb KO mice at postnatal day 14, before seizures begin. Importantly, phagocytosis impairment was restricted to the granule cell layer and spared the subgranular zone, where there are no active neurons. Furthermore, apoptotic cells (both phagocytosed and not phagocytosed) in Cstb-deficient mice were at close proximity to active cFos neurons, and a virtual 3D model demonstrated that the physical relationship between apoptotic cells and cFos neurons was specific for Cstb KO mice.

Significance: These results suggest a complex crosstalk between apoptosis, phagocytosis, and neuronal activity, hinting that local neuronal activity could be related to phagocytosis dysfunction in Cstb KO mice. Overall, these data suggest that phagocytosis impairment is an early feature of hippocampal damage in epilepsy and opens novel therapeutic approaches for epileptic patients based on targeting microglial phagocytosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756777PMC
November 2020

Chronic hyperglycemia impairs hippocampal neurogenesis and memory in an Alzheimer's disease mouse model.

Neurobiol Aging 2020 08 15;92:98-113. Epub 2020 Apr 15.

CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine of the University of Coimbra (FMUC), Coimbra, Portugal. Electronic address:

During aging, lifestyle-related factors shape the brain's response to insults and modulate the progression of neurodegenerative pathologies such as Alzheimer's disease (AD). This is the case for chronic hyperglycemia associated with type 2 diabetes, which reduces the brain's ability to handle the neurodegenerative burden associated with AD. However, the mechanisms behind the effects of chronic hyperglycemia in the context of AD are not fully understood. Here, we show that newly generated neurons in the hippocampal dentate gyrus of triple transgenic AD (3xTg-AD) mice present increased dendritic arborization and a number of synaptic puncta, which may constitute a compensatory mechanism allowing the animals to cope with a lower neurogenesis rate. Contrariwise, chronic hyperglycemia decreases the complexity and differentiation of 3xTg-AD newborn neurons and reduces the levels of β-catenin, a key intrinsic modulator of neuronal maturation. Moreover, synaptic facilitation is depressed in hyperglycemic 3xTg-AD mice, accompanying the defective hippocampal-dependent memory. Our data suggest that hyperglycemia evokes cellular and functional alterations that accelerate the onset of AD-related symptoms, namely memory impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.003DOI Listing
August 2020

Early Effects of Aβ Oligomers on Dendritic Spine Dynamics and Arborization in Hippocampal Neurons.

Front Synaptic Neurosci 2020 12;12. Epub 2020 Feb 12.

Department of Neuroscience, University of Basque Country (UPV/EHU) and CIBERNED, Leioa, Spain.

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to impaired memory and cognitive deficits. Spine loss as well as changes in spine morphology correlates with cognitive impairment in this neurological disorder. Many studies in animal models and cultures indicate that amyloid β-peptide (Aβ) oligomers induce synaptic damage early during the progression of the disease. Here, in order to determine the events that initiate synaptic alterations, we acutely applied oligomeric Aβ to primary hippocampal neurons and an model of organotypic hippocampal cultures from a mouse after targeted expression of EGFP to allow high-resolution imaging and algorithm-based evaluation of spine changes. Dendritic spines were classified as thin, stubby or mushroom, based on morphology. , time-lapse imaging showed that the three spine types were relatively stable, although their stability significantly decreased after treatment with Aβ oligomers. Unexpectedly, we observed that the density of total dendritic spines increased in organotypic hippocampal slices treated with Aβ compared to control cultures. Specifically, the fraction of stubby spines significantly increased, while mushroom and thin spines remained unaltered. Pharmacological tools revealed that acute Aβ oligomers induced spine changes through mechanisms involving CaMKII and integrin β1 activities. Additionally, analysis of dendritic complexity based on a 3D reconstruction of the whole neuron morphology showed an increase in the apical dendrite length and branching points in CA1 organotypic hippocampal slices treated with Aβ. In contrast to spines, the morphological changes were affected by integrin β1 but not by CaMKII inhibition. Altogether, these data indicate that the Aβ oligomers exhibit early dual effects by acutely enhancing dendritic complexity and spine density.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnsyn.2020.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029715PMC
February 2020

Neuropeptide Y Enhances Progerin Clearance and Ameliorates the Senescent Phenotype of Human Hutchinson-Gilford Progeria Syndrome Cells.

J Gerontol A Biol Sci Med Sci 2020 05;75(6):1073-1078

CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Hutchinson-Gilford progeria syndrome (HGPS, or classical progeria) is a rare genetic disorder, characterized by premature aging, and caused by a de novo point mutation (C608G) within the lamin A/C gene (LMNA), producing an abnormal lamin A protein, termed progerin. Accumulation of progerin causes nuclear abnormalities and cell cycle arrest ultimately leading to cellular senescence. Autophagy impairment is a hallmark of cellular aging, and the rescue of this proteostasis mechanism delays aging progression in HGPS cells. We have previously shown that the endogenous Neuropeptide Y (NPY) increases autophagy in hypothalamus, a brain area already identified as a central regulator of whole-body aging. We also showed that NPY mediates caloric restriction-induced autophagy. These results are in accordance with other studies suggesting that NPY may act as a caloric restriction mimetic and plays a role as a lifespan and aging regulator. The aim of the present study was, therefore, to investigate if NPY could delay HGPS premature aging phenotype. Herein, we report that NPY increases autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from HGPS patients. NPY also rescues nuclear morphology and decreases the number of dysmorphic nuclei, a hallmark of HGPS cells. In addition, NPY decreases other hallmarks of aging as DNA damage and cellular senescence. Altogether, these results show that NPY rescues several hallmarks of cellular aging in HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glz280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243588PMC
May 2020

Microglia Actively Remodel Adult Hippocampal Neurogenesis through the Phagocytosis Secretome.

J Neurosci 2020 02 2;40(7):1453-1482. Epub 2020 Jan 2.

Achucarro Basque Center for Neuroscience, Leioa, Bizkaia 48940, Spain,

During adult hippocampal neurogenesis, most newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of intracellular contents. Here, we propose that phagocytosis is not merely passive corpse removal but has an active role in maintaining neurogenesis. First, we found that neurogenesis was disrupted in male and female mice chronically deficient for two phagocytosis pathways: the purinergic receptor P2Y12, and the tyrosine kinases of the TAM family Mer tyrosine kinase (MerTK)/Axl. In contrast, neurogenesis was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we performed a transcriptomic analysis of the changes induced by phagocytosis in microglia and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both and Our data suggest that microglia act as a sensor of local cell death, modulating the balance between proliferation and survival in the neurogenic niche through the phagocytosis secretome, thereby supporting the long-term maintenance of adult hippocampal neurogenesis. Microglia are the brain professional phagocytes and, in the adult hippocampal neurogenic niche, they remove newborn cells naturally undergoing apoptosis. Here we show that phagocytosis of apoptotic cells triggers a coordinated transcriptional program that alters their secretome, limiting neurogenesis both and In addition, chronic phagocytosis disruption in mice deficient for receptors P2Y12 and MerTK/Axl reduces adult hippocampal neurogenesis. In contrast, inducible MerTK downregulation transiently increases neurogenesis, suggesting that microglial phagocytosis provides a negative feedback loop that is necessary for the long-term maintenance of adult hippocampal neurogenesis. Therefore, we speculate that the effects of promoting engulfment/degradation of cell debris may go beyond merely removing corpses to actively promoting regeneration in development, aging, and neurodegenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0993-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044727PMC
February 2020

Aβ oligomers promote oligodendrocyte differentiation and maturation via integrin β1 and Fyn kinase signaling.

Cell Death Dis 2019 06 6;10(6):445. Epub 2019 Jun 6.

Department of Neuroscience, University of Basque Country (UPV/EHU), Leioa, 48940, Spain.

Alzheimer´s disease (AD) is characterized by a progressive cognitive decline that correlates with the levels of amyloid β-peptide (Aβ) oligomers. Strong evidences connect changes of oligodendrocyte function with the onset of neurodegeneration in AD. However, the mechanisms controlling oligodendrocyte responses to Aβ are still elusive. Here, we tested the role of Aβ in oligodendrocyte differentiation, maturation, and survival in isolated oligodendrocytes and in organotypic cerebellar slices. We found that Aβ peptides specifically induced local translation of 18.5-kDa myelin basic protein (MBP) isoform in distal cell processes concomitant with an increase of process complexity of MBP-expressing oligodendrocytes. Aβ oligomers required integrin β1 receptor, Src-family kinase Fyn and Ca/CaMKII as effectors to modulate MBP protein expression. The pharmacological inhibition of Fyn kinase also attenuated oligodendrocyte differentiation and survival induced by Aβ oligomers. Similarly, using ex vivo organotypic cerebellar slices Aβ promoted MBP upregulation through Fyn kinase, and modulated oligodendrocyte population dynamics by inducing cell proliferation and differentiation. Importantly, application of Aβ to cerebellar organotypic slices enhanced remyelination and oligodendrocyte lineage recovery in lysolecithin (LPC)-induced demyelination. These data reveal an important role of Aβ in oligodendrocyte lineage function and maturation, which may be relevant to AD pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-019-1636-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554322PMC
June 2019

Phenotypical and functional heterogeneity of neural stem cells in the aged hippocampus.

Aging Cell 2019 08 15;18(4):e12958. Epub 2019 Apr 15.

Achucarro Basque Center for Neuroscience, Leioa, Spain.

Adult neurogenesis persists in the hippocampus of most mammal species during postnatal and adult life, including humans, although it declines markedly with age. The mechanisms driving the age-dependent decline of hippocampal neurogenesis are yet not fully understood. The progressive loss of neural stem cells (NSCs) is a main factor, but the true neurogenic output depends initially on the actual number of activated NSCs in each given time point. Because the fraction of activated NSCs remains constant relative to the total population, the real number of activated NSCs declines in parallel to the total NSC pool. We investigated aging-associated changes in NSCs and found that there are at least two distinct populations of NSCs. An alpha type, which maintains the classic type-1 radial morphology and accounts for most of the overall NSC mitotic activity; and an omega type characterized by increased reactive-like morphological complexity and much lower probability of division even under a pro-activation challenge. Finally, our results suggest that alpha-type NSCs are able to transform into omega-type cells overtime and that this phenotypic and functional change might be facilitated by the chronic inflammation associated with aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.12958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612636PMC
August 2019

Rewiring of Memory Circuits: Connecting Adult Newborn Neurons With the Help of Microglia.

Front Cell Dev Biol 2019 5;7:24. Epub 2019 Mar 5.

Laboratory of Glial Cell Biology, Achucarro Basque Center for Neuroscience, Leioa, Spain.

New neurons are continuously generated from stem cells and integrated into the adult hippocampal circuitry, contributing to memory function. Several environmental, cellular, and molecular factors regulate the formation of new neurons, but the mechanisms that govern their incorporation into memory circuits are less explored. Herein we will focus on microglia, the resident immune cells of the CNS, which modulate the production of new neurons in the adult hippocampus and are also well suited to participate in their circuit integration. Microglia may contribute to the refinement of brain circuits during development and exert a role in physiological and pathological conditions by regulating axonal and dendritic growth; promoting the formation, elimination, and relocation of synapses; modulating excitatory synaptic maturation; and participating in functional synaptic plasticity. Importantly, microglia are able to sense subtle changes in their environment and may use this information to differently modulate hippocampal wiring, ultimately impacting on memory function. Deciphering the role of microglia in hippocampal circuitry constant rewiring will help to better understand the influence of microglia on memory function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2019.00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411767PMC
March 2019

biomass increases dendritic arborization of newly-generated neurons in mouse hippocampal dentate gyrus.

Oncotarget 2018 Aug 31;9(68):32929-32942. Epub 2018 Aug 31.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Brain cognitive reserve refers to the ability of the brain to manage different challenges that arise throughout life, making it resilient to neuropathology. Hippocampal adult neurogenesis has been considered to be a relevant contributor for brain cognitive reserve and brain plasticity. (CV), a common healthful mushroom, has been receiving increasing attention by its antitumoral, anti-inflammatory, antioxidant, antibacterial, and immunomodulatory properties, including in the hippocampus. Herein, we evaluated whether CV biomass oral administration for 2.5 months enhances hippocampal neurogenic reserve under normal/physiological conditions, by quantifying hippocampal dentate gyrus (DG) granular cell layer (GCL) and subgranular zone (SGZ) volumes, proliferation, number and dendritic complexity features of hippocampal newly-generated neurons. We also analyzed β-catenin levels in DG newly-generated immature neurons, because it plays a major role in neurogenesis. Although no differences were observed in the volume of GCL and SGZ layers, in proliferation and in the number of newly-generated neurons of controls and CV-administered mice, we found that CV administration promotes a significant increase in dendritic length and branching and total dendritic volume of immature neurons, suggesting a positive effect of oral CV administration in the hippocampal neurogenic reserve. We also observed that β-catenin levels are increased both in the nucleus and cytoplasm of DG immature neurons, suggesting that Wnt/β-catenin signalling may play an important role in the CV positive effect on the differentiation of these cells. These data unveil a so far unexplored neurogenic potential of CV supplementation, which emerges as a possible preventive strategy for different neurological conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.25978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152478PMC
August 2018

ProMoIJ: A new tool for automatic three-dimensional analysis of microglial process motility.

Glia 2018 04 30;66(4):828-845. Epub 2017 Dec 30.

Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Leioa, Bizkaia, Spain.

Microglia, the immune cells of the central nervous system, continuously survey the brain to detect alterations and maintain tissue homeostasis. The motility of microglial processes is indicative of their surveying capacity in normal and pathological conditions. The gold standard technique to study motility involves the use of two-photon microscopy to obtain time-lapse images from brain slices or the cortex of living animals. This technique generates four dimensionally-coded images which are analyzed manually using time-consuming, non-standardized protocols. Microglial process motility analysis is frequently performed using Z-stack projections with the consequent loss of three-dimensional (3D) information. To overcome these limitations, we developed ProMoIJ, a pack of ImageJ macros that perform automatic motility analysis of cellular processes in 3D. The main core of ProMoIJ is formed by two macros that assist the selection of processes, automatically reconstruct their 3D skeleton, and analyze their motility (process and tip velocity). Our results show that ProMoIJ presents several key advantages compared with conventional manual analysis: (1) reduces the time required for analysis, (2) is less sensitive to experimenter bias, and (3) is more robust to varying numbers of processes analyzed. In addition, we used ProMoIJ to demonstrate that commonly performed 2D analysis underestimates microglial process motility, to reveal that only cells adjacent to a laser injured area extend their processes toward the lesion site, and to demonstrate that systemic inflammation reduces microglial process motility. ProMoIJ is a novel, open-source, freely-available tool which standardizes and accelerates the time-consuming labor of 3D analysis of microglial process motility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/glia.23287DOI Listing
April 2018

A simulation model of neuroprogenitor proliferation dynamics predicts age-related loss of hippocampal neurogenesis but not astrogenesis.

Sci Rep 2017 11 28;7(1):16528. Epub 2017 Nov 28.

Achucarro Basque Center for Neuroscience, Leioa, Bizkaia, Spain.

Adult hippocampal neuroprogenitors give rise to both neurons and astrocytes. As neuroprogenitors are lost with increased age, neurogenesis concomitantly decreases. However, the dynamics of neuron and astrocyte generation throughout adulthood has not been systematically examined. Here, we analyzed the hippocampal niche both longitudinally (from 2 h to 30d of cell life) and transversally (from 1 m to 12 m of age) and generated a Marsaglia polar random simulation model to predict newborn cell dynamics. The sharp decrease in newborn neuron production throughout adulthood was largely predicted by the number of proliferating neuroprogenitors at each age. In contrast, newborn astrocyte decay was slower and associated with their increased yield in mature mice. As a result, the niche shifted from neurogenic to neuro/astrogenic with increased age. Our data provide a simple "end-point" model to understand the hippocampal niche changes across adulthood and suggest yet unexplored functions of newborn astrocytes for the aging hippocampal circuitry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-16466-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705784PMC
November 2017

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy.

Purinergic Signal 2017 Dec 13;13(4):467-478. Epub 2017 Jul 13.

Departamento de Neurologia e Neurocirurgia, Disciplina de Neurociência, Universidade Federal de São Paulo, Rua Pedro de Toledo 669, 2° andar, São Paulo, SP, CEP 04039-032, Brazil.

Cell signaling mediated by P2X7 receptors (P2X7R) has been suggested to be involved in epileptogenesis, via modulation of intracellular calcium levels, excitotoxicity, activation of inflammatory cascades, and cell death, among other mechanisms. These processes have been described to be involved in pilocarpine-induced status epilepticus (SE) and contribute to hyperexcitability, resulting in spontaneous and recurrent seizures. Here, we aimed to investigate the role of P2X7R in epileptogenesis in vivo using RNA interference (RNAi) to inhibit the expression of this receptor. Small interfering RNA (siRNA) targeting P2X7R mRNA was injected into the lateral ventricles (icv) 6 h after SE. Four groups were studied: Saline-Vehicle, Saline-siRNA, Pilo-Vehicle, and Pilo-siRNA. P2X7R was quantified by western blotting and neuronal death assessed by Fluoro-Jade B histochemistry. The hippocampal volume (edema) was determined 48 h following RNAi. Behavioral parameters as latency to the appearance of spontaneous seizures and the number of seizures were determined until 60 days after the SE onset. The Saline-siRNA and Pilo-siRNA groups showed a 43 and 37% reduction, respectively, in P2X7R protein levels compared to respective vehicle groups. Neuroprotection was observed in CA1 and CA3 of the Pilo-siRNA group compared to Pilo-Vehicle. P2X7R silencing in pilocarpine group reversed the increase in the edema detected in the hilus, suprapyramidal dentate gyrus, CA1, and CA3; reduced mortality rate following SE; increased the time to onset of spontaneous seizure; and reduced the number of seizures, when compared to the Pilo-Vehicle group. Therefore, our data highlights the potential of P2X7R as a therapeutic target for the adjunct treatment of epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11302-017-9573-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714836PMC
December 2017

Impact of Neuroinflammation on Hippocampal Neurogenesis: Relevance to Aging and Alzheimer's Disease.

J Alzheimers Dis 2017 ;60(s1):S161-S168

Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

The cognitive reserve is associated with the capacity of the brain to maintain cognitive performance in spite of being challenged by stressful degenerative insults related to aging. Hippocampal neurogenesis is a life-long process of continuous addition of functional new neurons in the memory processing circuits. Accordingly, adult hippocampal neurogenesis is increasingly seen as a key determinant of cognitive reserve robustness. On the other side, neuroinflammation, by releasing a plethora of proinflammatory cytokines and other inflammatory molecules, is increasingly shown to be one of the key determinant pathophysiological factors that negatively impact on neurogenesis and on the cognitive reserve, playing a detrimental role in hippocampal neurogenic niche dynamics and in the progression of neurodegenerative diseases, such as Alzheimer's disease. In the present manuscript, we highlight the functional interplay between neuroinflammation, dynamics of the neurogenic niche, and spatial memory performance in healthy and age-related pathological processes, including progression of Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-170239DOI Listing
April 2018

Coxsackievirus Adenovirus Receptor Loss Impairs Adult Neurogenesis, Synapse Content, and Hippocampus Plasticity.

J Neurosci 2016 09;36(37):9558-71

Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique 5535, 34293 Montpellier, France, Université de Montpellier, 34000 Montpellier, France,

Unlabelled: Although we are beginning to understand the late stage of neurodegenerative diseases, the molecular defects associated with the initiation of impaired cognition are poorly characterized. Here, we demonstrate that in the adult brain, the coxsackievirus and adenovirus receptor (CAR) is located on neuron projections, at the presynapse in mature neurons, and on the soma of immature neurons in the hippocampus. In a proinflammatory or diseased environment, CAR is lost from immature neurons in the hippocampus. Strikingly, in hippocampi of patients at early stages of late-onset Alzheimer's disease (AD), CAR levels are significantly reduced. Similarly, in triple-transgenic AD mice, CAR levels in hippocampi are low and further reduced after systemic inflammation. Genetic deletion of CAR from the mouse brain triggers deficits in adult neurogenesis and synapse homeostasis that lead to impaired hippocampal plasticity and cognitive deficits. We propose that post-translational CAR loss of function contributes to cognitive defects in healthy and diseased-primed brains.

Significance Statement: This study addressed the role of the coxsackievirus and adenovirus receptor (CAR), a single-pass cell adhesion molecule, in the adult brain. Our results demonstrate that CAR is expressed by mature neurons throughout the brain. In addition, we propose divergent roles for CAR in immature neurons, during neurogenesis, and at the mature synapse. Notably, CAR loss of function also affects hippocampal plasticity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0132-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601941PMC
September 2016

Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation.

J Neuroinflammation 2016 06 4;13(1):137. Epub 2016 Jun 4.

Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.

Background: Histamine is an amine widely known as a peripheral inflammatory mediator and as a neurotransmitter in the central nervous system. Recently, it has been suggested that histamine acts as an innate modulator of microglial activity. Herein, we aimed to disclose the role of histamine in microglial phagocytic activity and reactive oxygen species (ROS) production and to explore the consequences of histamine-induced neuroinflammation in dopaminergic (DA) neuronal survival.

Methods: The effect of histamine on phagocytosis was assessed both in vitro by using a murine N9 microglial cell line and primary microglial cell cultures and in vivo. Cells were exposed to IgG-opsonized latex beads or phosphatidylserine (PS) liposomes to evaluate Fcγ or PS receptor-mediated microglial phagocytosis, respectively. ROS production and protein levels of NADPH oxidases and Rac1 were assessed as a measure of oxidative stress. DA neuronal survival was evaluated in vivo by counting the number of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) of mice.

Results: We found that histamine triggers microglial phagocytosis via histamine receptor 1 (H1R) activation and ROS production via H1R and H4R activation. By using apocynin, a broad NADPH oxidase (Nox) inhibitor, and Nox1 knockout mice, we found that the Nox1 signaling pathway is involved in both phagocytosis and ROS production induced by histamine in vitro. Interestingly, both apocynin and annexin V (used as inhibitor of PS-induced phagocytosis) fully abolished the DA neurotoxicity induced by the injection of histamine in the SN of adult mice in vivo. Blockade of H1R protected against histamine-induced Nox1 expression and death of DA neurons in vivo.

Conclusions: Overall, our results highlight the relevance of histamine in the modulation of microglial activity that ultimately may interfere with neuronal survival in the context of Parkinson's disease (PD) and, eventually, other neurodegenerative diseases which are accompanied by microglia-induced neuroinflammation. Importantly, our results also open promising new perspectives for the therapeutic use of H1R antagonists to treat or ameliorate neurodegenerative processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-016-0600-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893260PMC
June 2016

Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.

PLoS Biol 2016 05 26;14(5):e1002466. Epub 2016 May 26.

Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pbio.1002466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881984PMC
May 2016

Regulation of striatal astrocytic receptor for advanced glycation end-products variants in an early stage of experimental Parkinson's disease.

J Neurochem 2016 08 13;138(4):598-609. Epub 2016 Jun 13.

Laboratory of Pharmacology and Experimental Therapeutics/IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Convincing evidence indicates that advanced glycation end-products and danger-associated protein S100B play a role in Parkinson's disease (PD). These agents operate through the receptor for advanced glycation end-products (RAGE), which displays distinct isoforms playing protective/deleterious effects. However, the nature of RAGE variants has been overlooked in PD studies. Hence, we attempted to characterize RAGE regulation in early stages of PD striatal pathology. A neurotoxin-based rodent model of PD was used in this study, through administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6 mice. Animals were killed 6 h post-MPTP to assess S100B/RAGE contents (RT-qPCR, ELISA) and RAGE isoform density (WB) and cellular distribution (immunohistochemistry). Dopaminergic and gliotic status were also mapped (HPLC-ED, WB, immunohistochemistry). At this preliminary stage of MPTP-induced PD in mice, RAGE inhibitory isoforms were increased whereas full-length RAGE was not affected. This putative cytoprotective RAGE phenotype paired an inflammatory and pro-oxidant setting fueling DAergic denervation. Increased RAGE inhibitory variants occur in astrocytes showing higher S100B density but no overt signs of hypertrophy or NF-κB activation, a canonical effector of RAGE. These findings expand our understanding of the toxic effect of MPTP on striatum and offer first in vivo evidence of RAGE being a responder in early stages of astrogliosis dynamics, supporting a protective rather tissue-destructive phenotype of RAGE in the initial phase of PD degeneration. These data lay the groundwork for future studies on the relevance of astrocytic RAGE in DAergic neuroprotection strategies. We report increased antagonistic RAGE variants paralleling S100B up-regulation in early stages of MPTP-induced astrogliosis dynamics . We propose that selective RAGE regulation reflects a self-protective mechanism to maintain low levels of RAGE ligands , preventing long-term inflammation and oxidative stress arising from sustained ligands/flRAGE activation . Understanding loss of RAGE protective response to stress may provide new therapeutic options to halt or slow down dopaminergic axonopathy and, ultimately, neuronal death .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jnc.13682DOI Listing
August 2016

Lifestyle Shapes the Dialogue between Environment, Microglia, and Adult Neurogenesis.

ACS Chem Neurosci 2016 Apr 22;7(4):442-53. Epub 2016 Mar 22.

Achucarro Basque Center for Neuroscience , E-48170 Zamudio, Bizkaia Spain.

Lifestyle modulates brain function. Diet, stress levels, and physical exercise among other factors influence the "brain cognitive reserve", that is, the capacity of the brain to maintain a normal function when confronting neurodegenerative diseases, injury, and/or aging. This cognitive reserve relays on several cellular and molecular elements that contribute to brain plasticity allowing adaptive responses to cognitive demands, and one of its key components is the hippocampal neurogenic reserve. Hippocampal neural stem cells give rise to new neurons that integrate into the local circuitry and contribute to hippocampal functions such as memory and learning. Importantly, adult hippocampal neurogenesis is well-known to be modulated by the demands of the environment and lifestyle factors. Diet, stress, and physical exercise directly act on neural stem cells and/or their progeny, but, in addition, they may also indirectly affect neurogenesis by acting on microglia. Microglia, the guardians of the brain, rapidly sense changes in the brain milieu, and it has been recently shown that their function is affected by lifestyle factors. However, few studies have analyzed the modulatory effect of microglia on adult neurogenesis in these conditions. Here, we review the current knowledge about the dialogue maintained between microglia and the hippocampal neurogenic cascade. Understanding how the communication between microglia and hippocampal neurogenesis is affected by lifestyle choices is crucial to maintain the brain cognitive reserve and prevent the maladaptive responses that emerge during disease or injury through adulthood and aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschemneuro.6b00009DOI Listing
April 2016

Ataxin-3 phosphorylation decreases neuronal defects in spinocerebellar ataxia type 3 models.

J Cell Biol 2016 Feb;212(4):465-80

CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3004-517 Coimbra, Portugal

Different neurodegenerative diseases are caused by aberrant elongation of repeated glutamine sequences normally found in particular human proteins. Although the proteins involved are ubiquitously distributed in human tissues, toxicity targets only defined neuronal populations. Changes caused by an expanded polyglutamine protein are possibly influenced by endogenous cellular mechanisms, which may be harnessed to produce neuroprotection. Here, we show that ataxin-3, the protein involved in spinocerebellar ataxia type 3, also known as Machado-Joseph disease, causes dendritic and synapse loss in cultured neurons when expanded. We report that S12 of ataxin-3 is phosphorylated in neurons and that mutating this residue so as to mimic a constitutive phosphorylated state counters the neuromorphologic defects observed. In rats stereotaxically injected with expanded ataxin-3-encoding lentiviral vectors, mutation of serine 12 reduces aggregation, neuronal loss, and synapse loss. Our results suggest that S12 plays a role in the pathogenic pathways mediated by polyglutamine-expanded ataxin-3 and that phosphorylation of this residue protects against toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1083/jcb.201506025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754714PMC
February 2016

An automated image analysis method to measure regularity in biological patterns: a case study in a Drosophila neurodegenerative model.

Mol Neurodegener 2015 Mar 12;10. Epub 2015 Mar 12.

Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid-CSIC, c/ Sanz y Forés 3, Valladolid, Spain.

The fruitfly compound eye has been broadly used as a model for neurodegenerative diseases. Classical quantitative techniques to estimate the degeneration level of an eye under certain experimental conditions rely either on time consuming histological techniques to measure retinal thickness, or pseudopupil visualization and manual counting. Alternatively, visual examination of the eye surface appearance gives only a qualitative approximation provided the observer is well-trained. Therefore, there is a need for a simplified and standardized analysis of fruitfly eye degeneration extent for both routine laboratory use and for automated high-throughput analysis. We have designed the freely available ImageJ plugin FLEYE, a novel and user-friendly method for quantitative unbiased evaluation of neurodegeneration levels based on the acquisition of fly eye surface pictures. The incorporation of automated image analysis tools and a classification algorithm sustained on a built-in statistical model allow the user to quickly analyze large sample size data with reliability and robustness. Pharmacological screenings or genetic studies using the Drosophila retina as a model system may benefit from our method, because it can be easily implemented in a fully automated environment. In addition, FLEYE can be trained to optimize the image detection capabilities, resulting in a versatile approach to evaluate the pattern regularity of other biological or non-biological samples and their experimental or pathological disruption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13024-015-0005-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367968PMC
March 2015

Neuropeptide Y stimulates autophagy in hypothalamic neurons.

Proc Natl Acad Sci U S A 2015 Mar 16;112(13):E1642-51. Epub 2015 Mar 16.

CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; and

Aging is characterized by autophagy impairment that contributes to age-related disease aggravation. Moreover, it was described that the hypothalamus is a critical brain area for whole-body aging development and has impact on lifespan. Neuropeptide Y (NPY) is one of the major neuropeptides present in the hypothalamus, and it has been shown that, in aged animals, the hypothalamic NPY levels decrease. Because caloric restriction (CR) delays aging, at least in part, by stimulating autophagy, and also increases hypothalamic NPY levels, we hypothesized that NPY could have a relevant role on autophagy modulation in the hypothalamus. Therefore, the aim of this study was to investigate the role of NPY on autophagy in the hypothalamus. Using both hypothalamic neuronal in vitro models and mice overexpressing NPY in the hypothalamus, we observed that NPY stimulates autophagy in the hypothalamus. Mechanistically, in rodent hypothalamic neurons, NPY increases autophagy through the activation of NPY Y1 and Y5 receptors, and this effect is tightly associated with the concerted activation of PI3K, MEK/ERK, and PKA signaling pathways. Modulation of hypothalamic NPY levels may be considered a potential strategy to produce protective effects against hypothalamic impairments associated with age and to delay aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1416609112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386327PMC
March 2015

Nuclear signs of pre-neurodegeneration.

Methods Mol Biol 2015 ;1254:43-54

Institute for Molecular and Cell Biology of the Cancer, CSIC - Universidad de Salamanca, Salamanca, Spain.

Nuclear architecture is highly concerted including the organization of chromosome territories and distinct nuclear bodies, such as nucleoli, Cajal bodies, nuclear speckles of splicing factors, and promyelocytic leukemia nuclear bodies, among others. The organization of such nuclear compartments is very dynamic and may represent a sensitive indicator of the functional status of the cell. Here, we describe methodologies that allow isolating discrete cell populations from the brain and the fine observation of nuclear signs that could be insightful predictors of an early neuronal injury in a wide range of neurodegenerative disorders. The tools here described may be of use for the early detection of pre-degenerative processes in neurodegenerative diseases and for validating novel rescue strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-2152-2_4DOI Listing
July 2015

Impaired Src signaling and post-synaptic actin polymerization in Alzheimer's disease mice hippocampus--linking NMDA receptors and the reelin pathway.

Exp Neurol 2014 Nov 13;261:698-709. Epub 2014 Aug 13.

Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address:

Early cognitive deficits in Alzheimer's disease (AD) have been related to deregulation of N-methyl-d-aspartate receptors (NMDARs) and synaptic dysfunction in response to amyloid-beta peptide. NMDAR anchorage to post-synaptic membrane depends in part on Src kinase, which is also implicated in NMDAR activation and actin cytoskeleton stabilization, two processes relevant for normal synaptic function. In this study we analyzed the changes in GluN2B subunit phosphorylation and the levels of proteins involved in Src related signaling pathways linking the Tyr kinase to actin cytoskeleton polymerization, namely reelin, disabled-1 (Dab1) and cortactin, in hippocampal and cortical homogenates obtained from the triple transgenic mouse model of AD (3xTg-AD) that shows progression of pathology as a function of age versus age-matched wild-type mice. Moreover, we evaluated regional post-synaptic actin polymerization using phalloidin labeling in hippocampal slices. Young (3month-old) 3xTg-AD male mice hippocampus exhibited decreased GluN2B Tyr1472 phosphorylation and reduced Src activity. In the cortex, decreased Src activity correlated with reduced levels of reelin and Dab1, implicating changes in the reelin pathway. We also observed diminished phosphorylated Dab1 and cortactin protein levels in the hippocampus and cortex of young 3xTg-AD male mice. Concordantly with the recognized role of these proteins in actin stabilization, we detected a significant decrease in post-synaptic F-actin in 3month-old 3xTg-AD male CA1 and CA3 hippocampal regions. These data suggest deregulated Src-dependent signaling pathways involving GluN2B-composed NMDARs and post-synaptic actin cytoskeleton depolymerization in the hippocampus in early stages of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.expneurol.2014.07.023DOI Listing
November 2014

Pax6 is essential for the maintenance and multi-lineage differentiation of neural stem cells, and for neuronal incorporation into the adult olfactory bulb.

Stem Cells Dev 2014 Dec 17;23(23):2813-30. Epub 2014 Sep 17.

1 Instituto de Neurociencias de Castilla y León (INCyL), Universidad de Salamanca , Salamanca, Spain .

The paired type homeobox 6 (Pax6) transcription factor (TF) regulates multiple aspects of neural stem cell (NSC) and neuron development in the embryonic central nervous system. However, less is known about the role of Pax6 in the maintenance and differentiation of adult NSCs and in adult neurogenesis. Using the +/Sey(Dey) mouse, we have analyzed how Pax6 heterozygosis influences the self-renewal and proliferation of adult olfactory bulb stem cells (aOBSCs). In addition, we assessed its influence on neural differentiation, neuronal incorporation, and cell death in the adult OB, both in vivo and in vitro. Our results indicate that the Pax6 mutation alters Nestin(+)-cell proliferation in vivo, as well as self-renewal, proliferation, and survival of aOBSCs in vitro although a subpopulation of +/Sey(Dey) progenitors is able to expand partially similar to wild-type progenitors. This mutation also impairs aOBSC differentiation into neurons and oligodendrocytes, whereas it increases cell death while preserving astrocyte survival and differentiation. Furthermore, Pax6 heterozygosis causes a reduction in the variety of neurochemical interneuron subtypes generated from aOBSCs in vitro and in the incorporation of newly generated neurons into the OB in vivo. Our findings support an important role of Pax6 in the maintenance of aOBSCs by regulating cell death, self-renewal, and cell fate, as well as in neuronal incorporation into the adult OB. They also suggest that deregulation of the cell cycle machinery and TF expression in aOBSCs which are deficient in Pax6 may be at the origin of the phenotypes observed in this adult NSC population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/scd.2014.0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235597PMC
December 2014

Can we talk about microglia without neurons? A discussion of microglial cell autonomous properties in culture.

Front Cell Neurosci 2014 24;8:202. Epub 2014 Jul 24.

Neuroprotection and Neurogenesis in Brain Repair Group, Center for Neuroscience and Cell Biology, University of Coimbra Coimbra, Portugal ; Institute for Interdisciplinary Research, University of Coimbra Coimbra, Portugal.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncel.2014.00202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109436PMC
August 2014

New insights into the role of histamine in subventricular zone-olfactory bulb neurogenesis.

Front Neurosci 2014 16;8:142. Epub 2014 Jun 16.

Faculty of Health Sciences, Health Sciences Research Center, University of Beira Interior Covilhã, Portugal.

The subventricular zone (SVZ) contains neural stem cells (NSCs) that generate new neurons throughout life. Many brain diseases stimulate NSCs proliferation, neuronal differentiation and homing of these newborns cells into damaged regions. However, complete cell replacement has never been fully achieved. Hence, the identification of proneurogenic factors crucial for stem cell-based therapies will have an impact in brain repair. Histamine, a neurotransmitter and immune mediator, has been recently described to modulate proliferation and commitment of NSCs. Histamine levels are increased in the brain parenchyma and at the cerebrospinal fluid (CSF) upon inflammation and brain injury, thus being able to modulate neurogenesis. Herein, we add new data showing that in vivo administration of histamine in the lateral ventricles has a potent proneurogenic effect, increasing the production of new neuroblasts in the SVZ that ultimately reach the olfactory bulb (OB). This report emphasizes the multidimensional effects of histamine in the modulation of NSCs dynamics and sheds light into the promising therapeutic role of histamine for brain regenerative medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2014.00142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058902PMC
July 2014

Long-term effects of an acute and systemic administration of LPS on adult neurogenesis and spatial memory.

Front Neurosci 2014 21;8:83. Epub 2014 Apr 21.

Faculty of Medicine, Institute for Biomedical Imaging and Life Sciences, University of Coimbra Coimbra, Portugal.

The cognitive reserve is the capacity of the brain to maintain normal performance while exposed to insults or ageing. Increasing evidences point to a role for the interaction between inflammatory conditions and cognitive reserve status during Alzheimer's disease (AD) progression. The production of new neurons along adult life can be considered as one of the components of the cognitive reserve. Interestingly, adult neurogenesis is decreased in mouse models of AD and following inflammatory processes. The aim of this work is to reveal the long-term impact of a systemic inflammatory event on memory and adult neurogenesis in wild type (WT) and triple transgenic mouse model of AD (3xTg-AD). Four month-old mice were intraperitoneally injected once with saline or lipopolysaccharide (LPS) and their performance on spatial memory analyzed with the Morris water maze (MWM) test 7 weeks later. Our data showed that a single intraperitoneal injection with LPS has a long-term impact in the production of hippocampal neurons. Consistently, LPS-treated WT mice showed less doublecortin-positive neurons, less synaptic contacts in newborn neurons, and decreased dendritic volume and complexity. These surprising observations were accompanied with memory deficits. 3xTg-AD mice showed a decrease in new neurons in the dentate gyrus compatible with, although exacerbated, the pattern observed in WT LPS-treated mice. In 3xTg-AD mice, LPS injection did not significantly affected the production of new neurons but reduced their number of synaptic puncta and impaired memory performance, when compared to the observations made in saline-treated 3xTg-AD mice. These data indicate that LPS treatment induces a long-term impairment on hippocampal neurogenesis and memory. Our results show that acute neuroinflammatory events influence the production of new hippocampal neurons, affecting the cognitive reserve and leading to the development of memory deficits associated to AD pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2014.00083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001049PMC
May 2014