The Essential Role of Astrocytes in Neurodegeneration and Neuroprotection.

Astrocytes are glial cells that perform several fundamental physiological functions within the brain. They can control neuronal activity and levels of ions and neurotransmitters, and release several factors that modulate the brain environment. Over the past few decades, our knowledge of astrocytes and their functions has rapidly evolved. Neurodegenerative diseases are characterized by selective degeneration of neurons, increased glial activation, and glial dysfunction. Given the significant role played by astrocytes, there is growing interest in their potential therapeutic role. However, defining their contribution to neurodegeneration is more complex than was previously thought. This review summarizes the main functions of astrocytes and their involvement in neurodegenerative diseases, highlighting their neurotoxic and neuroprotective ability.

Role of Hydroxytyrosol and Oleuropein in the Prevention of Aging and Related Disorders: Focus on Neurodegeneration, Skeletal Muscle Dysfunction and Gut Microbiota.

Aging is a multi-faceted process caused by the accumulation of cellular damage over time, associated with a gradual reduction of physiological activities in cells and organs. This degeneration results in a reduced ability to adapt to homeostasis perturbations and an increased incidence of illnesses such as cognitive decline, neurodegenerative and cardiovascular diseases, cancer, diabetes, and skeletal muscle pathologies. Key features of aging include a chronic low-grade inflammation state and a decrease of the autophagic process. The Mediterranean diet has been associated with longevity and ability to counteract the onset of age-related disorders. Extra virgin olive oil, a fundamental component of this diet, contains bioactive polyphenolic compounds as hydroxytyrosol (HTyr) and oleuropein (OLE), known for their antioxidant, anti-inflammatory, and neuroprotective properties. This review is focused on brain, skeletal muscle, and gut microbiota, as these systems are known to interact at several levels. After the description of the chemistry and pharmacokinetics of HTyr and OLE, we summarize studies reporting their effects in in vivo and in vitro models of neurodegenerative diseases of the central/peripheral nervous system, adult neurogenesis and depression, senescence and lifespan, and age-related skeletal muscle disorders, as well as their impact on the composition of the gut microbiota.

Beauveria bassiana rewires molecular mechanisms related to growth and defense in tomato.

Plant roots can exploit beneficial associations with soil-inhabiting microbes, promoting growth and expanding the immune capacity of the host plant. In this work, we aimed to provide new information on changes occurring in tomato interacting with the beneficial fungus Beauveria bassiana. The tomato leaf proteome revealed perturbed molecular pathways during the establishment of the plant-fungus relationship. In the early stages of colonization (5-7 d), proteins related to defense responses to the fungus were down-regulated and proteins related to calcium transport were up-regulated. At later time points (12-19 d after colonization), up-regulation of molecular pathways linked to protein/amino acid turnover and to biosynthesis of energy compounds suggests beneficial interaction enhancing plant growth and development. At the later stage, the profile of leaf hormones and related compounds was also investigated, highlighting up-regulation of those related to plant growth and defense. Finally, B. bassiana colonization was found to improve plant resistance to Botrytis cinerea, impacting plant oxidative damage. Overall, our findings further expand current knowledge on the possible mechanisms underlying the beneficial role of B. bassiana in tomato plants.

Evaluation of Baculoviruses as Gene Therapy Vectors for Brain Cancer.

We aimed to assess the potential of baculoviral vectors (BV) for brain cancer gene therapy. We compared them with adenoviral vectors (AdV), which are used in neuro-oncology, but for which there is pre-existing immunity. We constructed BVs and AdVs encoding fluorescent reporter proteins and evaluated their transduction efficiency in glioma cells and astrocytes. Naïve and glioma-bearing mice were intracranially injected with BVs to assess transduction and neuropathology. Transgene expression was also assessed in the brain of BV-preimmunized mice. While the expression of BVs was weaker than AdVs in murine and human glioma cell lines, BV-mediated transgene expression in patient-derived glioma cells was similar to AdV-mediated transduction and showed strong correlation with clathrin expression, a protein that interacts with the baculovirus glycoprotein GP64, mediating BV endocytosis. BVs efficiently transduced normal and neoplastic astrocytes in vivo, without apparent neurotoxicity. BV-mediated transgene expression was stable for at least 21 days in the brain of naïve mice, but it was significantly reduced after 7 days in mice systemically preimmunized with BVs. Our findings indicate that BVs efficiently transduce glioma cells and astrocytes without apparent neurotoxicity. Since humans do not present pre-existing immunity against BVs, these vectors may constitute a valuable tool for the delivery of therapeutic genes into the brain.

Alzheimer's disease risk after COVID-19: a view from the perspective of the infectious hypothesis of neurodegeneration.

In light of the rising evidence of the association between viral and bacterial infections and neurodegeneration, we aimed at revisiting the infectious hypothesis of Alzheimer's disease and analyzing the possible implications of COVID-19 neurological sequelae in long-term neurodegeneration. We wondered how SARS-CoV-2 could be related to the amyloid-ß cascade and how it could lead to the pathological hallmarks of the disease. We also predict a paradigm change in clinical medicine, which now has a great opportunity to conduct prospective surveillance of cognitive sequelae and progression to dementia in people who suffered severe infections together with other risk factors for Alzheimer's disease.

Molecular diagnostics of infectious disease: Detection and characterization of microbial agents in cytology samples.

BACKGROUND: Cytology samples are widely used to diagnose various infectious diseases by detection and identification of causative infectious agents, including bacteria, fungi, and viruses. The role of cytopathology in infectious disease has expanded tremendously in the past decades with the advances in molecular techniques. Molecular diagnostic methods, compared to conventional methods, have shown improved patient outcome, reduction in cost, and shortened hospital stay times. The aim of this article is to review molecular testing in cytology samples for diagnosis of infectious diseases. METHODS: The literature search for molecular testing in common cytology samples for diagnosis of infectious diseases was performed. The findings of the studies were summarized. The common cytology samples included in this article were gynecologic specimens, cerebrospinal fluid, bronchoalveolar lavage, and urine samples. CONCLUSIONS: There are a number of molecular diagnostic tests that are available to be used in common cytology samples to detect infectious agents. Each test has its own advantages and limitations. It is our hope that upon reading this review article, the readers will have better understanding of molecular diagnostic testing of infectious diseases utilizing commonly sampled cytology specimens in daily practice.

Environmental Signals Act as a Driving Force for Metabolic and Defense Responses in the Antarctic Plant Colobanthus quitensis.

During evolution, plants have faced countless stresses of both biotic and abiotic nature developing very effective mechanisms able to perceive and counteract adverse signals. The biggest challenge is the ability to fine-tune the trade-off between plant growth and stress resistance. The Antarctic plant Colobanthus quitensis has managed to survive the adverse environmental conditions of the white continent and can be considered a wonderful example of adaptation to prohibitive conditions for millions of other plant species. Due to the progressive environmental change that the Antarctic Peninsula has undergone over time, a more comprehensive overview of the metabolic features of C. quitensis becomes particularly interesting to assess its ability to respond to environmental stresses. To this end, a differential proteomic approach was used to study the response of C. quitensis to different environmental cues. Many differentially expressed proteins were identified highlighting the rewiring of metabolic pathways as well as defense responses. Finally, a different modulation of oxidative stress response between different environmental sites was observed. The data collected in this paper add knowledge on the impact of environmental stimuli on plant metabolism and stress response by providing useful information on the trade-off between plant growth and defense mechanisms.

Simulated global warming affects endophytic bacterial and fungal communities of Antarctic pearlwort leaves and some bacterial isolates support plant growth at low temperatures.

Antarctica is one of the most stressful environments for plant life and the Antarctic pearlwort (Colobanthus quitensis) is adapted to the hostile conditions. Plant-associated microorganisms can contribute to plant survival in cold environments, but scarce information is available on the taxonomic structure and functional roles of C. quitensis-associated microbial communities. This study aimed at evaluating the possible impacts of climate warming on the taxonomic structure of C. quitensis endophytes and at investigating the contribution of culturable bacterial endophytes to plant growth at low temperatures. The culture-independent analysis revealed changes in the taxonomic structure of bacterial and fungal communities according to plant growth conditions, such as the collection site and the presence of open-top chambers (OTCs), which can simulate global warming. Plants grown inside OTCs showed lower microbial richness and higher relative abundances of biomarker bacterial genera (Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium, Aeromicrobium, Aureimonas, Hymenobacter, Novosphingobium, Pedobacter, Pseudomonas and Sphingomonas) and fungal genera (Alternaria, Cistella, and Vishniacozyma) compared to plants collected from open areas (OA), as a possible response to global warming simulated by OTCs. Culturable psychrotolerant bacteria of C. quitensis were able to endophytically colonize tomato seedlings and promote shoot growth at low temperatures, suggesting their potential contribution to plant tolerance to cold conditions.

Plant defense: ARR11 response regulator as a potential player in Arabidopsis.

Plant growth and response to environmental cues are largely driven by hormones. Salicylic acid (SA)- and jasmonic acid (JA)-mediated defenses have been shown to be effective against different types of attackers. SA-mediated defense is mainly effective against biotrophic pathogens and phloem-feeding insects, whereas JA-mediated defense is effective against necrotrophic pathogens and tissue-damaging insects. Cytokinins (CKs) are classic growth hormones that have also emerged as plant immunity modulators. Evidence pointed out that CKs contribute to the defense responses mediated by SA and JA, acting as hormone modulators of the SA/JA signaling backbone. Recently, we identified in Arabidopsis a type-B response regulator 11 (ARR 11) involved in cytokinin-mediated responses as a novel regulator of the SA/JA cross-talk. Here we investigated plant fitness and resistance against the fungal necrotrophic pathogen Botrytis cinerea in Arabidopsis wild-type Col-8 and defective arr11 mutant following SA, JA, CK single or combined treatment. Our results demonstrated that the CK and SA/JA/CK combination has a positive outcome on plant fitness in both Arabidopsis Col-8 and arr11 mutant,. The triple hormone treatment is efficient in increasing resistance to B. cinerea in Col-8 and this effect is stronger in arr11 mutant. The results will provide not only new background knowledge, corroborating the role of ARR11 in plant-defense related processes, but also new potential opportunities for alternative ways of protecting plants from fungal diseases.

Biodiversity and Bioprospecting of Fungal Endophytes from the Antarctic Plant Colobanthus quitensis.

Microorganisms from extreme environments are considered as a new and valuable reservoir of bioactive molecules of biotechnological interest and are also utilized as tools for enhancing tolerance to (a)biotic stresses in crops. In this study, the fungal endophytic community associated with the leaves of the Antarctic angiosperm Colobanthus quitensis was investigated as a new source of bioactive molecules. We isolated 132 fungal strains and taxonomically annotated 26 representative isolates, which mainly belonged to the Basidiomycota division. Selected isolates of Trametes sp., Lenzites sp., Sistotrema sp., and Peniophora sp. displayed broad extracellular enzymatic profiles; fungal extracts from some of them showed dose-dependent antitumor activity and inhibited the formation of amyloid fibrils of α-synuclein and its pathological mutant E46K. Selected fungal isolates were also able to promote secondary root development and fresh weight increase in Arabidopsis and tomato and antagonize the growth of pathogenic fungi harmful to crops. This study emphasizes the ecological and biotechnological relevance of fungi from the Antarctic ecosystem and provides clues to the bioprospecting of Antarctic Basidiomycetes fungi for industrial, agricultural, and medical applications.

The role of matrixmetalloproteinase-2 expression by fibroblasts in perineural invasion by oral cavity squamous cell carcinoma.

OBJECTIVES: The mechanisms of perineural invasion (PNI) in oral cavity squamous cell carcinoma are only partially understood, and no studies have specifically investigated the role of perineural fibroblasts in PNI. Here, we identified fibroblasts within the microenvironment of perineural invasion and assessed their expression of matrix metalloproteinase-2 (MMP-2). MATERIALS AND METHODS: Tumor specimens from 12 patients with oral cavity squamous cell carcinoma and pathologically-confirmed perineural invasion were stained by immunohistochemistry (IHC) for vimentin (positive control) and MMP-2. Scoring was quantified and compared at nerves involved with PNI and nerves uninvolved with PNI. RESULTS: All 12 patients had perineural fibroblasts around involved and uninvolved nerves as marked by vimentin IHC staining. Perineural fibroblasts had detectable MMP-2 expression at areas of perineural invasion in all 12 patients, but no patients had MMP-2 expression by fibroblasts at nerves without PNI. CONCLUSION: MMP-2 is expressed by fibroblasts within the microenvironment of perineural invasion, and MMP-2 expression by fibroblasts is a possible mechanism of perineural invasion by oral cavity squamous cell carcinoma. MMP-2 may be an anti-cancer target among oral cavity squamous cell carcinoma patients with PNI.

Atypical pulmonary presentation of Strongyloides stercoralis hyperinfection in a patient with philadelphia chromosome-positive acute lymphoblastic leukemia: Case report.

Strongyloides stercoralis is a soil-transmitted helminth endemic to tropical and subtropical regions and can be acquired due to parasite penetration through the skin. It can remain dormant in the gastrointestinal system for decades after the primary infection. In immunocompromised patients, this parasite can cause autoinfection with progression to hyperinfection syndrome. Here we report a unique case of pulmonary strongyloidiasis in a 32-year-old female, originally from Guatemala, with a significant clinical history of Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia diagnosed in 2019. The patient is status post chemotherapy with tyrosine kinase inhibitor plus hyper-CVAD regimen (Cyclophosphamide, Vincristine sulfate, Doxorubicin hydrochloride (Adriamycin), and Dexamethasone). History of drug-induced hyperglycemia and obesity was also noted. Her current chief complaint included dyspnea, tachycardia, and chest pain. Chest computerized tomography (CT) scan showed diffuse interstitial pulmonary edema with septal thickening, scattered ground-glass opacities, and small pericardial effusion. Due to normal ejection fraction, the differential diagnosis included non-cardiogenic pulmonary edema, pneumonitis secondary to chemotoxicity, and infection. She rapidly progressed to acute hypoxic respiratory failure, and a bronchoalveolar lavage study revealed numerous larvae consistent with Strongyloides hyperinfection. Further workup revealed eosinophilia with negative Strongyloides IgG antibody. Given the rarity of this infection in the United States and the patient's place of birth, acquired latent Strongyloides infection is favored as the initial source of infection. The reactivation of the infection process was most likely secondary to her chemotherapy treatment. Strongyloides hyperinfection diagnosis can be challenging to establish and entails a high level of suspicion. Cytology evaluation is an essential factor for diagnosis.

A metabotropic glutamate receptor 3 (mGlu3R) isoform playing neurodegenerative roles in astrocytes is prematurely up-regulated in an Alzheimer's model.

Subtype 3 metabotropic glutamate receptor (mGlu3R) displays a broad range of neuroprotective effects. We previously demonstrated that mGlu3R activation in astrocytes protects hippocampal neurons from Aß neurotoxicity through stimulation of both neurotrophin release and Aß uptake. Alternative-spliced variants of mGlu3R were found in human brains. The most prevalent variant, mGlu3Δ4, lacks exon 4 encoding the transmembrane domain and can inhibit ligand binding to mGlu3R. To date, neither its role in neurodegenerative disorders nor its endogenous expression in CNS cells has been addressed. The present paper describes for the first time an association between altered hippocampal expression of mGlu3Δ4 and Alzheimer's disease (AD) in the preclinical murine model PDAPP-J20, as well as a deleterious effect of mGlu3Δ4 in astrocytes. As assessed by western blot, hippocampal mGlu3R levels progressively decreased with age in PDAPP-J20 mice. On the contrary, mGlu3Δ4 levels were drastically increased with aging in nontransgenic mice, but prematurely over-expressed in 5-month-old PDAPP-J20-derived hippocampi, prior to massive senile plaque deposition. Also, we found that mGlu3Δ4 co-precipitated with mGlu3R mainly in 5-month-old PDAPP-J20 mice. We further showed by western blot that primary cultured astrocytes and neurons expressed mGlu3Δ4, whose levels were reduced by Aß, thereby discouraging a causal effect of Aß on mGlu3Δ4 induction. However, heterologous expression of mGlu3Δ4 in astrocytes induced cell death, inhibited mGlu3R expression, and prevented mGlu3R-dependent Aß glial uptake. Indeed, mGlu3Δ4 promoted neurodegeneration in neuron-glia co-cultures. These results provide evidence of an inhibitory role of mGlu3Δ4 in mGlu3R-mediated glial neuroprotective pathways, which may lie behind AD onset.

CNS Histoplasmosis as a Gliosarcoma mimicker: The diagnostic dilemma of solitary brain lesions.

Histoplasmosis is usually a benign, self-limited disease with lungs predilection. However, it might manifest as a disseminated disease in immunocompromised individuals. The involvement of the central nervous system (CNS) accounts for about 5-10% of cases with disseminated disease. Isolated histoplasmosis of the CNS is rare, and the literature shows only a few reported cases. By imaging studies, it usually presents as an isolated ring-enhancing lesion. Its spectrum of symptoms ranges from acute severe infection to progressive chronic meningitis, which delays the initial diagnosis, correct work-up and initiation of appropriate therapy. We present a case of a 57-year-old man from the Midwest of the United States who misdiagnosed with Gliosarcoma in 2019, for which he underwent appropriate management for Gliosarcoma. Presented for follow-up after new neurological symptoms; worsening in ring-enhancing brain lesions was found on magnetic resonance image MRI. After a re-examination of surgical pathological cases, histoplasmosis of the CNS was diagnosed. Failure of diagnosis CNS histoplasmosis early can lead to poor outcome and decrease chances of recovery.

Neuroinflammation in Huntington's Disease: A Starring Role for Astrocyte and Microglia.

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by a CAG repeat expansion in the huntingtin gene. HD causes motor, cognitive, and behavioral dysfunction. Since no existing treatment affects the course of this disease, new treatments are needed. Inflammation is frequently observed in HD patients before symptom onset. Neuroinflammation, characterized by the presence of reactive microglia, astrocytes and inflammatory factors within the brain, is also detected early. However, in comparison to other neurodegenerative diseases, the role of neuroinflammation in HD is much less known. Work has been dedicated to altered microglial and astrocytic functions in the context of HD, but less attention has been given to glial participation in neuroinflammation. This review describes evidence of inflammation in HD patients and animal models. It also discusses recent knowledge on neuroinflammation in HD, highlighting astrocyte and microglia involvement in the disease and considering anti-inflammatory therapeutic approaches.

A Metabolic Profiling Analysis Revealed a Primary Metabolism Reprogramming in Arabidopsis glyI4 Loss-of-Function Mutant.

Methylglyoxal (MG) is a cytotoxic compound often produced as a side product of metabolic processes such as glycolysis, lipid peroxidation, and photosynthesis. MG is mainly scavenged by the glyoxalase system, a two-step pathway, in which the coordinate activity of GLYI and GLYII transforms it into D-lactate, releasing GSH. In Arabidopsis thaliana, a member of the GLYI family named GLYI4 has been recently characterized. In glyI4 mutant plants, a general stress phenotype characterized by compromised MG scavenging, accumulation of reactive oxygen species (ROS), stomatal closure, and reduced fitness was observed. In order to shed some light on the impact of gly4 loss-of-function on plant metabolism, we applied a high resolution mass spectrometry-based metabolomic approach to Arabidopsis Col-8 wild type and glyI4 mutant plants. A compound library containing a total of 70 metabolites, differentially synthesized in glyI4 compared to Col-8, was obtained. Pathway analysis of the identified compounds showed that the upregulated pathways are mainly involved in redox reactions and cellular energy maintenance, and those downregulated in plant defense and growth. These results improved our understanding of the impacts of glyI4 loss-of-function on the general reprogramming of the plant's metabolic landscape as a strategy for surviving under adverse physiological conditions.

What Antarctic Plants Can Tell Us about Climate Changes: Temperature as a Driver for Metabolic Reprogramming.

Global warming is strongly affecting the maritime Antarctica climate and the consequent melting of perennial snow and ice covers resulted in increased colonization by plants. Colobanthus quitensis is a vascular plant highly adapted to the harsh environmental conditions of Antarctic Peninsula and understanding how the plant is responding to global warming is a new challenging target for modern cell physiology. To this aim, we performed differential proteomic analysis on C. quitensis plants grown in natural conditions compared to plants grown for one year inside open top chambers (OTCs) which determine an increase of about 4 °C at midday, mimicking the effect of global warming. A thorough analysis of the up- and downregulated proteins highlighted an extensive metabolism reprogramming leading to enhanced photoprotection and oxidative stress control as well as reduced content of cell wall components. Overall, OTCs growth seems to be advantageous for C. quitensis plants which could benefit from a better CO2 diffusion into the mesophyll and a reduced ROS-mediated photodamage.

Effect of EDTA decalcification on estrogen receptor and progesterone receptor immunohistochemistry and HER2/neu fluorescence in situ hybridization in breast carcinoma.

Bone is the most common site of metastasis in breast carcinoma (BC). Treatments for metastatic BC depend on various factors, including the tumor's estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Bone biopsies require decalcification which may affect the accuracy of ER and PR immunohistochemistry (IHC) and HER2 situ hybridization (FISH) studies. Ethylenediaminetetraacetic acid (EDTA) decalcifying solutions have been theorized to have no significant impact on ER and PR IHC or HER2 FISH analyses. We completed a prospective study of the effect of EDTA decalcification on ER and PR IHC and HER2 FISH in 29 cases of BC. Samples from 29 BC resections were collected and formalin fixed between 12 and 24 h. Control samples were routinely processed, whereas test samples were placed in EDTA for 48 h. ER and PR slides were blinded, randomized, and evaluated. Blinded samples underwent HER2 FISH assays where an average HER2 copy number and HER2/CEP17 ratio were calculated. Paired differences between EDTA and control samples were compared for ER and PR positivity, average HER2 copy number, and HER2/CEP17 ratios using paired-samples t-tests (PST) and Wilcoxon signed-rank test (WSR). PST and WSR tests yielded no significant difference between EDTA and control tissue for ER% (PST: P = 1; WSR: P = 0.916), PR% (PST: P = 0.973; WSR: P = 0.984), HER2 copy number (PST: P = 0.124; WSR: P = 0.103), and HER2/CEP17 ratio (PST: P = 0.25; WSR: P = 0.105). The use of EDTA in bony tissue is therefore a valid decalcification method to ensure accurate assessment of ER and PR IHC and HER2 FISH in metastatic BC.

Regulation and role of Acyl-CoA synthetase 4 in glial cells.

Acyl-CoA synthetase 4 (Acsl4), an enzyme involved in arachidonic acid (AA) metabolism, participates in physiological and pathological processes such as steroidogenesis and cancer. The role of Acsl4 in neurons and in nervous system development has also been documented but little is known regarding its functionality in glial cells. In turn, several processes in glial cells, including neurosteroidogenesis, stellation and AA uptake, are regulated by cyclic adenosine monophosphate (cAMP) signal. In this context, the aim of this work was to analyze the expression and functional role of Acsl4 in primary rat astrocyte cultures and in the C6 glioma cell line by chemical inhibition and stable silencing, respectively. Results show that Acsl4 expression was regulated by cAMP in both models and that cAMP stimulation of steroidogenic acute regulatory protein mRNA levels was reduced by Acsl4 inhibition or silencing. Also, Acsl4 inhibition reduced progesterone synthesis stimulated by cAMP and also affected cAMP-induced astrocyte stellation, decreasing process elongation and increasing branching complexity. Similar effects were observed for Acsl4 silencing on cAMP-induced C6 cell morphological shift. Moreover, Acsl4 inhibition and silencing reduced proliferation and migration of both cell types. Acsl4 silencing in C6 cells reduced the capacity for colony proliferation and neurosphere formation, the latter ability also being abolished by Acsl4 inhibition. In sum, this work presents novel evidence of Acsl4 involvement in neurosteroidogenesis and the morphological changes of glial cells promoted by cAMP. Furthermore, Acsl4 participates in migration and proliferation, also affecting cell self-renewal. Altogether, these findings provide insights into Acsl4 functions in glial cells.

Astrocytes from cortex and striatum show differential responses to mitochondrial toxin and BDNF: implications for protection of striatal neurons expressing mutant huntingtin.

BACKGROUND: Evidence shows significant heterogeneity in astrocyte gene expression and function. We previously demonstrated that brain-derived neurotrophic factor (BDNF) exerts protective effects on whole brain primary cultured rat astrocytes treated with 3-nitropropionic acid (3NP), a mitochondrial toxin widely used as an in vitro model of Huntington's disease (HD). Therefore, we now investigated 3NP and BDNF effects on astrocytes from two areas involved in HD: the striatum and the entire cortex, and their involvement in neuron survival. METHODS: We prepared primary cultured rat cortical or striatal astrocytes and treated them with BDNF and/or 3NP for 24 h. In these cells, we assessed expression of astrocyte markers, BDNF receptor, and glutamate transporters, and cytokine release. We prepared astrocyte-conditioned medium (ACM) from cortical and striatal astrocytes and tested its effect on a cellular model of HD. RESULTS: BDNF protected astrocytes from 3NP-induced death, increased expression of its own receptor, and activation of ERK in both cortical and striatal astrocytes. However, BDNF modulated glutamate transporter expression differently by increasing GLT1 and GLAST expression in cortical astrocytes but only GLT1 expression in striatal astrocytes. Striatal astrocytes released higher amounts of tumor necrosis factor-α than cortical astrocytes in response to 3NP but BDNF decreased this effect in both populations. 3NP decreased transforming growth factor-ß release only in cortical astrocytes, whereas BDNF treatment increased its release only in striatal astrocytes. Finally, we evaluated ACM effect on a cellular model of HD: the rat striatal neuron cell line ST14A expressing mutant human huntingtin (Q120) or in ST14A cells expressing normal human huntingtin (Q15). Neither striatal nor cortical ACM modified the viability of Q15 cells. Only ACM from striatal astrocytes treated with BDNF and ACM from 3NP + BDNF-treated striatal astrocytes protected Q120 cells, whereas ACM from cortical astrocytes did not. CONCLUSIONS: Data suggest that cortical and striatal astrocytes respond differently to mitochondrial toxin 3NP and BDNF. Moreover, striatal astrocytes secrete soluble neuroprotective factors in response to BDNF that selectively protect neurons expressing mutant huntingtin implicating that BDNF modulation of striatal astrocyte function has therapeutic potential against neurodegeneration.