Blend of Baru (Dipteryx alata Vog.) By-Products as Nutritive and Healthy Food Ingredients: Chemical Composition, Functional Properties and Application in Plant-Based Burger.

The chemical composition, antioxidant capacity and functional properties of mixtures of baru by-products, named baru food ingredients (BFI), were investigated and applied in a plant-based burger formulation. BFI were prepared from wasted baru by-products - partially defatted baru nut cake and baru pulp plus peel. A plant-based burger was developed and its chemical composition, antioxidant capacity, cooking and texture parameters were determined. BFI1 (50% partially defatted baru nut cake + 50% baru pulp plus peel) had the highest content of carbohydrate (31.9%), and dietary fibre (28.3%). BFI2 (75% partially defatted baru nut cake + 25% baru pulp plus peel) and BFI3 (90% partially defatted baru nut cake + 10% baru pulp plus peel) showed high concentration of protein and dietary fibre, and BFI3 had the highest protein content (29.5%). All BFI showed high concentration of total phenolics (402-443 mg GAE/100 g). Replacing textured pea protein of control burger (PPB) with 35% of BFI3 in the formulation of baru protein burger (BPB) resulted in a low-fat product (2.9%), with protein content (19.2%) comparable to the PPB (15.9%) and the commercial burger (mixed plant proteins - 16.3%). The BPB also showed a higher concentration of dietary fibre (4.9%) and phenolic compounds (128 mg GAE/100 g) than the control burger. BPB's cooking yield was the highest among the tested burgers. BPB had a softer texture when compared to other burgers. Baru food ingredients can be used as nutritive ingredients of health-promoting foods, especially in plant-based products, such as burger and meat analogues, or in hybrid meat products. BPB showed a healthy and nutritious profile.

Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IP3R2) Fails to Modify Disease Progression in a Mouse Model of Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disease caused by an abnormal polyglutamine expansion within the ataxin-3 protein (ATXN3). This leads to neurodegeneration of specific brain and spinal cord regions, resulting in a progressive loss of motor function. Despite neuronal death, non-neuronal cells, including astrocytes, are also involved in SCA3 pathogenesis. Astrogliosis is a common pathological feature in SCA3 patients and animal models of the disease. However, the contribution of astrocytes to SCA3 is not clearly defined. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant IP3R in mediating astrocyte somatic calcium signals, and genetically ablation of IP3R2 has been widely used to study astrocyte function. Here, we aimed to investigate the relevance of IP3R2 in the onset and progression of SCA3. For this, we tested whether IP3R2 depletion and the consecutive suppression of global astrocytic calcium signalling would lead to marked changes in the behavioral phenotype of a SCA3 mouse model, the CMVMJD135 transgenic line. This was achieved by crossing IP3R2 null mice with the CMVMJD135 mouse model and performing a longitudinal behavioral characterization of these mice using well-established motor-related function tests. Our results demonstrate that IP3R2 deletion in astrocytes does not modify SCA3 progression.

Development of a new non invasive prognostic stroke scale (NIPSS) including triage elements for sleep apnea and peripheral artery disease.

BACKGROUND: Although sleep apnea and peripheral artery disease are prognostic factors for stroke, their added benefit in the acute stage to further prognosticate strokes has not been evaluated. OBJECTIVES: We tested the accuracy in the acute stroke stage of a novel score called the Non-Invasive Prognostic Stroke Scale (NIPSS). PATIENTS AND METHODS: Prospective cohort with imaging-confirmed ischemic stroke. Clinical data, sleep apnea risk score (STOPBANG) and blood pressure measures were collected at baseline. Primary outcome was the 90-day modified Rankin Scale (mRS), with poor outcome defined as mRS 3-6. Area under the ROC curve (AUC) was calculated for NIPSS and compared to six other stroke prognostic scores in our cohort: SPAN-100 index, S-SMART, SOAR, ASTRAL, THRIVE, and Dutch Stroke scores. RESULTS: We enrolled 386 participants. After 90 days, there were 56% with poor outcome, more frequently older, female predominant and with higher admission National Institute of Health Stroke Scale (NIHSS). Four variables remained significantly associated with primary endpoint in the multivariable model: age (OR 1.87), NIHSS (OR 7.08), STOPBANG category (OR 1.61), and ankle-braquial index (OR 2.11). NIPSS AUC was 0.86 (0.82-0.89); 0.83 (0.79-0.87) with bootstrapping. When compared to the other scores, NIPSS, ASTRAL, S-SMART and DUTCH scores had good abilities in predicting poor outcome, with AUC of 0.86, 0.86, 0.83 and 0.82, respectively. THRIVE, SOAR and SPAN-100 scores were fairly predictive. DISCUSSION AND CONCLUSIONS: Non-invasive and easily acquired emergency room data can predict clinical outcome after stroke. NIPSS performed equal to or better than other prognostic stroke scales.

Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aß-evoked hippocampal pathology.

Despite considerable progress in the understanding of its neuropathology, Alzheimer's disease (AD) remains a complex disorder with no effective treatment that counteracts the memory deficits and the underlying synaptic malfunction triggered by the accumulation of amyloid beta (Aß) and Tau protein. Mounting evidence supports a precipitating role for chronic environmental stress and glutamatergic excitotoxicity in AD, suggesting that targeting of glutamate receptor signaling may be a promising approach against both stress and AD pathologies. In light of the limited cognitive benefit of the direct antagonism of NMDA receptors in AD, we here focus on an alternative way to modify glutamatergic signaling through positive allosteric modulation of AMPA receptors, by the use of a PAM-AMPA compound. Using non-transgenic animal model of Aß oligomer injection as well as the combined stress and Aß i.c.v. infusion, we demonstrate that positive allosteric modulation of AMPA receptors by PAM-AMPA treatment reverted memory, but not mood, deficits. Furthermore, PAM-AMPA treatment reverted stress/Aß-driven synaptic missorting of Tau and associated Fyn/GluN2B-driven excitotoxic synaptic signaling accompanied by recovery of neurotransmitter levels in the hippocampus. Our findings suggest that positive allosteric modulation of AMPA receptors restores synaptic integrity and cognitive performance in stress- and Aß-evoked hippocampal pathology. As the prevalence of AD is increasing at an alarming rate, novel therapeutic targeting of glutamatergic signaling should be further explored against the early stages of AD synaptic malfunction with the goal of attenuating further synaptic damage before it becomes irreversible.

Potential Anti-Inflammatory Effect of Rosmarinus officinalis in Preclinical In Vivo Models of Inflammation.

This systematic review aimed to evaluate the potential anti-inflammatory effect of Rosmarinus officinalis in preclinical in vivo models of inflammation. A search was conducted in the databases PubMed, Scopus, and Web of Science, with related keywords. The inclusion criteria were inflammation, plant, and studies on rats or mice; while, the exclusion criteria were reviews, studies with in vitro models, and associated plants. The predominant animal models were paw edema, acute liver injury, and asthma. Rosemary was more commonly used in its entirety than in compounds, and the prevalent methods of extraction were maceration and hydrodistillation. The most common routes of administration reported were gavage, intraperitoneal, and oral, on a route-dependent dosage. Treatment took place daily, or was single-dose, on average for 21 days, and it more often started before the induction. The most evaluated biomarkers were tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-10, myeloperoxidase (MPO), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), malondialdehyde (MDA), and superoxide dismutase (SOD). The best results emerged at a dose of 60 mg/kg, via IP of carnosic acid, a dose of 400 mg/kg via gavage of Rosmarinus officinalis, and a dose of 10 mg/kg via IP of rosmarinic acid. Rosmarinus officinalis L. showed anti-inflammatory activity before and after induction of treatments.

Self-compassion and mindful parenting among postpartum mothers during the COVID-19 pandemic: The role of depressive and anxious symptoms.

Self-compassion is an important psychological skill that may facilitate the adoption of a mindful way of parenting, especially during the COVID-19 pandemic. However, the association between these constructs may be explained by several variables, such as maternal psychopathological symptoms, with a well-established interference in parenting. This study aimed to compare mothers who experienced and mothers who did not experience a negative emotional impact of the COVID-19 pandemic on self-compassion, mindful parenting, postpartum depressive symptoms (PPDS) and postpartum anxious symptoms (PPAS). We also explored whether mothers' self-compassion was associated with mindful parenting and whether this relationship may be mediated by PPDS and PPAS. A sample of 977 Portuguese mothers of infants aged between zero and six months completed an online survey between December 2020 and January 2021, a period of major pandemic-related restrictions. The survey included several self-report questionnaires that assessed sociodemographic, clinical, and COVID-19 information, self-compassion, mindful parenting, PPDS and PPAS. Mothers who reported having felt that the pandemic had a negative emotional impact during their postpartum period (79.5%) presented lower levels of self-compassion and mindful parenting, and higher levels of PPDS and PPAS. Regarding the mediation model, higher levels of self-compassion were related to higher levels of mindful parenting, and this association was mediated by lower levels of PPAS. These results highlight the relevance of mothers' self-compassion for helping them feel less anxious and to adopt a mindful way of parenting in the postpartum period, particularly during the pandemic. Compassion-based interventions may be particularly important in reducing PPAS and promoting mindful parenting and should be available to postpartum mothers, especially during, but also beyond the pandemic.

Unilateral Intrastriatal 6-Hydroxydopamine Lesion in Mice: A Closer Look into Non-Motor Phenotype and Glial Response.

Parkinson's disease (PD) is a prevalent movement disorder characterized by the progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). The 6-hydroxydopamine (6-OHDA) lesion is still one of the most widely used techniques for modeling Parkinson's disease (PD) in rodents. Despite commonly used in rats, it can be challenging to reproduce a similar lesion in mice. Moreover, there is a lack of characterization of the extent of behavioral deficits and of the neuronal loss/neurotransmitter system in unilateral lesion mouse models. In this study, we present an extensive behavioral and histological characterization of a unilateral intrastriatal 6-OHDA mouse model. Our results indicate significant alterations in balance and fine motor coordination, voluntary locomotion, and in the asymmetry's degree of forelimb use in 6-OHDA lesioned animals, accompanied by a decrease in self-care and motivational behavior, common features of depressive-like symptomatology. These results were accompanied by a decrease in tyrosine hydroxylase (TH)-labelling and dopamine levels within the nigrostriatal pathway. Additionally, we also identify a marked astrocytic reaction, as well as proliferative and reactive microglia in lesioned areas. These results confirm the use of unilateral intrastriatal 6-OHDA mice for the generation of a mild model of nigrostriatal degeneration and further evidences the recapitulation of key aspects of PD, thereby being suitable for future studies beholding new therapeutical interventions for this disease.

Postpartum during COVID-19 pandemic: Portuguese mothers' mental health, mindful parenting, and mother-infant bonding.

BACKGROUND: Millions of people worldwide have been diagnosed with coronavirus disease 2019 (COVID-19), which has impacted maternal mental health and mother-infant relationships during the postpartum period. OBJECTIVES: To explore how mothers' anxious and depressive symptoms, parenting stress, mindful parenting, and mother-infant bonding vary as a function of the moment of the baby's birth (pre-COVID-19 or post-COVID-19) and to examine the contribution of those variables to mother-infant bonding. METHODS: The sample was recruited online and comprises 567 mothers (18-46 years) with an infant aged between 0 and 12 months old. RESULTS: Approximately 27.5% of the mothers presented clinically significant levels of anxious and depressive symptoms. Mothers who gave birth during the COVID-19 pandemic presented lower levels of Emotional Awareness of the Child and a more impaired mother-infant bonding than mothers who gave birth before the pandemic started. Approximately 49% of the mother-infant bonding variance was explained by parenting stress and by several dimensions of mindful parenting. CONCLUSION: Our findings provide important insights into the impact of COVID-19 on maternal mental health and parenting.

The role of mothers' self-compassion on mother-infant bonding during the COVID-19 pandemic: A longitudinal study exploring the mediating role of mindful parenting and parenting stress in the postpartum period.

The current COVID-19 pandemic is a challenging time for postpartum mothers, and associated challenges may have a negative impact on their parenting and, consequently, on mother-infant bonding. This study aimed to longitudinally explore whether mothers' self-compassion was associated with mother-infant bonding and whether this relationship was mediated by mindful parenting and parenting stress. A total of 125 Portuguese mothers of infants aged between 0 and 12 months completed an online survey at two assessment points during the first wave of the COVID-19 pandemic (T1: April-May 2020; T2: June-July 2020). The survey included several questionnaires assessing sociodemographic, clinical, and COVID-19 information; self-compassion; mindful parenting; parenting stress; and mother-infant bonding. Mothers presented significantly higher levels of self-compassion, less impaired mother-infant bonding, and lower levels of depressive symptoms at T2 than T1. Higher levels of self-compassion at T1 predicted less impaired mother-infant bonding at T2, and this relationship was mediated by higher levels of mindful parenting and lower levels of parenting stress (both assessed at T1). These results highlight the relevance of mothers' self-compassion to establishing mother-infant bonding in the postpartum period, particularly during the COVID-19 pandemic, and the important role of mindful parenting and parenting stress in determining this relationship.

Long-term postoperative atrophy of contralateral hippocampus and cognitive function in unilateral refractory MTLE with unilateral hippocampal sclerosis.

OBJECTIVE: This study aimed to evaluate long-term atrophy in contralateral hippocampal volume after surgery for unilateral MTLE, as well as the cognitive outcome for patients submitted to either selective transsylvian amygdalohippocampectomy (SelAH) or anterior temporal lobe resection (ATL). METHODS: We performed a longitudinal study of 47 patients with MRI signs of unilateral hippocampal sclerosis (23 patients with right-sided hippocampal sclerosis) who underwent surgical treatment for MTLE. They underwent preoperative/postoperative high-resolution MRI as well as neuropsychological assessment for memory and estimated IQ. To investigate possible changes in the contralateral hippocampus of patients, we included 28 controls who underwent two MRIs at long-term intervals. RESULTS: The volumetry using preoperative MRI showed significant hippocampal atrophy ipsilateral to the side of surgery when compared with controls (p<0.0001) but no differences in contralateral hippocampal volumes. The mean postoperative follow-up was 8.7 years (± 2.5 SD; median=8.0). Our patients were classified as Engel I (80%), Engel II (18.2%), and Engel III (1.8%). We observed a small but significant reduction in the contralateral hippocampus of patients but no volume changes in controls. Most of the patients presented small declines in both estimated IQ and memory, which were more pronounced in patients with left TLE and in those with persistent seizures. Different surgical approaches did not impose differences in seizure control or in cognitive outcome. CONCLUSIONS: We observed small declines in cognitive scores with most of these patients, which were worse in patients with left-sided resection and in those who continued to suffer from postoperative seizures. We also demonstrated that manual volumetry can reveal a reduction in volume in the contralateral hippocampus, although this change was mild and could not be detected by visual analysis. These new findings suggest that dynamic processes continue to act after the removal of the hippocampus, and further studies with larger groups may help in understanding the underlying mechanisms.

Electrochemical immunosensor for point-of-care detection of soybean Gly m TI allergen in foods.

Soybean is a legume with high technological functionality, commonly used by the food industry as an ingredient in different products. However, soybean is an allergenic food whose undeclared presence in processed foods may represent a public health risk. In this work, it was developed an efficient electrochemical immunosensor, targeting the soybean trypsin inhibitor (Gly m TI) allergen using commercial anti-Gly m TI IgG, aiming at detecting/quantifying minute amounts of soybean in different food formulations. For this purpose, model mixtures of different foods (sausages, cooked-hams, biscuits) were prepared to contain known amounts of soybean protein isolate (100,000-0.1 mg kg-1) and submitted to specific thermal treatments (autoclaving, oven-cooking, baking). The electrochemical immunosensor allowed quantifying down to 0.1 mg kg-1 of soybean in the three food matrices, raw and processed (0.0012 mg of Gly m TI/kg of matrix). Accordingly, the immunosensor is suitable for detecting traces of soybean in raw, processed, and complex foods, thus protecting 99 % of soybean-allergic patients.

Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the farnesoid X receptor (FXR). TUDCA was predicted to bind to the GR, in a similar fashion to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset in presymptomatic subjects and FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3 and propose this readily available drug for clinical trials in SCA3 patients.

Exploring factors associated with complete mental health of pregnant women during the COVID-19 pandemic.

OBJECTIVE: To explore a wide range of factors associated with complete mental health (i.e., positive mental health - the presence of flourishing, and the absence of mental illness - depressive and anxious symptoms) among Portuguese pregnant women, during the COVID-19 pandemic. DESIGN: Quantitative cross-sectional study. SETTING: Data were collected through an online survey placed on social media websites targeting pregnant Portuguese adult women between October 2020 and April 2021. PARTICIPANTS: The sample comprised 207 pregnant women. RESULTS: A multivariate logistic regression model showed that higher levels of self-compassion and higher engagement in mindful self-care practices increased the likelihood of reporting complete mental health during pregnancy. CONCLUSIONS: Promoting self-compassion and mindful self-care may be particularly important in pregnant women, as these psychological factors appear to contribute to complete mental health during COVID-19 pandemic. IMPLICATIONS FOR PRACTICE: The COVID-19 pandemic represented a demanding period for pregnant women. Our findings highlight that targeting the promotion of self-compassion and mindful self-care practices during stressful periods could significantly contribute to their overall mental health.

A Web-Based, Mindful, and Compassionate Parenting Training for Mothers Experiencing Parenting Stress: Results from a Pilot Randomized Controlled Trial of the Mindful Moment Program.

Objectives: Mindful Moment is a self-guided, web-based, mindful, and compassionate parenting training for postpartum mothers who experience parenting stress. We aimed to assess Mindful Moment's feasibility, acceptability, and usability, and to gather preliminary evidence of its effectiveness in reducing parenting stress and outcomes such as mindful parenting, self-compassion, depressive symptoms, anxious symptoms, dispositional mindfulness, mother's perception of infant temperament, and mother-infant bonding. Methods: This pilot randomized controlled trial (RCT) was a two-arm trial and followed the CONSORT 2010, CONSORT-EHEALTH, and CONSORT-SPI 2018 extension guidelines. A total of 292 Portuguese mothers were randomly assigned to the intervention group (n = 146) or to the waiting list control group (n = 146) and completed baseline (T1) and postintervention (T2) self-reported assessments. Results: A total of 31 mothers (21.23%) completed the Mindful Moment intervention. Most mothers evaluated the program as good or excellent (90%), considered that Mindful Moment provided them the kind of help they expected or wanted (61%), were satisfied with the help provided by the program (74.6%), would recommend it to a friend in a similar situation (86.4%), and would use it again if needed (81.4%). Regarding the program's preliminary effectiveness, mothers in the intervention group presented a greater decrease in parenting stress, a greater increase in dispositional mindfulness, and a greater decrease in their perception of the difficult temperament of their infants from T1 to T2. Conclusions: This study provides preliminary evidence of the Mindful Moment's effectiveness and suggests that it is a feasible and acceptable program for postpartum mothers experiencing parenting stress. Further research is needed to confirm these results in a larger RCT. Trial Registration: ClinicalTrials.gov (NCT04892082).

DNA polymer films used as drug delivery systems to early-stage diagnose and treatment of breast cancer using 3D tumor spheroids as a model.

The present study examines the design of DNA polymeric films (DNA-PFs) associated with aluminum chloride phthalocyanine (AlClPc) (DNA-PFs-AlClPc), as a promising drug delivery system (DDS), applicable for breast cancer treatment and early-stage diagnosis using photodynamic therapy (PDT). This study starts evaluating (MCF7) as a model for breast cancer cell behavior associated with DNA-PFs. Analyses of the morphological behaviors, biochemical reaction, and MCF7 cell adhesion profile on DNA-PFs were evaluated. SEM and AFM analysis allowed the morphological characterization of the DNA-PFs. Cell viability and cell cycle kinetics studies indicate highly biocompatible material capable of anchoring MCF7 cells, allowing the attachment and support of cell in the same structure where the insertion of AlClPc (DNA-PFs-AlClPc). The application of visible light photoactivation based on classical PDT protocol over the DNA-PFs-AlClPc showed a reduction in cell viability with increased cell death proportional to the fluency energy range from 600, 900, and 1800 mJ cm-2. The 3D organoid system mimics the tumor microenvironment which was precisely observed in human breast cancer in early-stage progression in the body. The results observed indicate that the viability was reduced by more than 80% in monolayer culture and around 50% in the 3D organoid cell culture at the highest energy fluency (1800 mJ cm-2). With low energy fluency (100 mJ cm-2,), the DNA-PFs-AlClPc did not show a cytotoxic effect on MCF7 cells, enabling the potential for photodiagnosis of early-stage human breast cancer detection in the initial stage of progression.

Target selectivity of cholesterol-phosphatidylcholine liposome loaded with phthalocyanine for breast cancer diagnosis and treatment by photodynamic therapy.

This study investigated the ability of cholesterol-phosphatidylcholine liposomes loaded with chloride aluminum phthalocyanine (CL-AlClPc) to discriminate between healthy (MCF-10A) and neoplastic (MCF-7 and MDA-MB-231) breast cells for breast cancer diagnosis and treatment by photodynamic therapy (PDT) using a new drug delivery system consisting of CL-AlClPc. When PDT treatment was applied at an energy fluence of 700 mJ/cm², CL-AlClPc was more cytotoxic to neoplastic cells than to healthy breast cells because CL-AlClPc was better internalized by the tumor cells. An even higher fluorescence signal is expected for neoplastic cells during clinical treatment than for healthy cells, which will be useful for precise and targeted tumor cell detection. CL-AlClPc also facilitated better drug distribution and targeting of essential organelles inside the cells. This selectivity is critical for future in vivo diagnosis and treatment; it prevents side effects because it prioritizes tumor cells and tissues instead of healthy ones. The CL-AlClPc system designed herein had a small size (150 nm), low zeta potential (-6 mV), low polydispersity (0.16), high encapsulation rate efficiency (82.83%), and high shelf stability (12 months).

Cerebellar neuronal dysfunction accompanies early motor symptoms in spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset, progressive ataxia. SCA3 presents with ataxia before any gross neuropathology. A feature of many cerebellar ataxias is aberrant cerebellar output that contributes to motor dysfunction. We examined whether abnormal cerebellar output was present in the CMVMJD135 SCA3 mouse model and, if so, whether it correlated with the disease onset and progression. In vivo recordings showed that the activity of deep cerebellar nuclei neurons, the main output of the cerebellum, was altered. The aberrant activity correlated with the onset of ataxia. However, although the severity of ataxia increased with age, the severity of the aberrant cerebellar output was not progressive. The abnormal cerebellar output, however, was accompanied by non-progressive abnormal activity of their upstream synaptic inputs, the Purkinje cells. In vitro recordings indicated that alterations in intrinsic Purkinje cell pacemaking and in their synaptic inputs contributed to abnormal Purkinje cell activity. These findings implicate abnormal cerebellar physiology as an early, consistent contributor to pathophysiology in SCA3, and suggest that the aberrant cerebellar output could be an appropriate therapeutic target in SCA3.

Microglial Depletion Has No Impact on Disease Progression in a Mouse Model of Machado-Joseph Disease.

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder (ND). While most research in NDs has been following a neuron-centric point of view, microglia are now recognized as crucial in the brain. Previous work revealed alterations that point to an increased activation state of microglia in the brain of CMVMJD135 mice, a MJD mouse model that replicates the motor symptoms and neuropathology of the human condition. Here, we investigated the extent to which microglia are actively contributing to MJD pathogenesis and symptom progression. For this, we used PLX3397 to reduce the number of microglia in the brain of CMVMJD135 mice. In addition, a set of statistical and machine learning models were further implemented to analyze the impact of PLX3397 on the morphology of the surviving microglia. Then, a battery of behavioral tests was used to evaluate the impact of microglial depletion on the motor phenotype of CMVMJD135 mice. Although PLX3397 treatment substantially reduced microglia density in the affected brain regions, it did not affect the motor deficits seen in CMVMJD135 mice. In addition to reducing the number of microglia, the treatment with PLX3397 induced morphological changes suggestive of activation in the surviving microglia, the microglia of wild-type animals becoming similar to those of CMVMJD135 animals. These results suggest that microglial cells are not key contributors for MJD progression. Furthermore, the impact of PLX3397 on microglial activation should be taken into account in the interpretation of findings of ND modification seen upon treatment with this CSF1R inhibitor.

Profiling Microglia in a Mouse Model of Machado-Joseph Disease.

Microglia have been increasingly implicated in neurodegenerative diseases (NDs), and specific disease associated microglia (DAM) profiles have been defined for several of these NDs. Yet, the microglial profile in Machado-Joseph disease (MJD) remains unexplored. Here, we characterized the profile of microglia in the CMVMJD135 mouse model of MJD. This characterization was performed using primary microglial cultures and microglial cells obtained from disease-relevant brain regions of neonatal and adult CMVMJD135 mice, respectively. Machine learning models were implemented to identify potential clusters of microglia based on their morphological features, and an RNA-sequencing analysis was performed to identify molecular perturbations and potential therapeutic targets. Our findings reveal morphological alterations that point to an increased activation state of microglia in CMVMJD135 mice and a disease-specific transcriptional profile of MJD microglia, encompassing a total of 101 differentially expressed genes, with enrichment in molecular pathways related to oxidative stress, immune response, cell proliferation, cell death, and lipid metabolism. Overall, these results allowed us to define the cellular and molecular profile of MJD-associated microglia and to identify genes and pathways that might represent potential therapeutic targets for this disorder.