Neurotoxic Microglial Activation via IFNγ-Induced Nrf2 Reduction Exacerbating Alzheimer's Disease.

Microglial neuroinflammation appears to be neuroprotective in the early pathological stage, yet neurotoxic, which often precedes neurodegeneration in Alzheimer's disease (AD). However, it remains unclear how the microglial activities transit to the neurotoxic state during AD progression, due to complex neuron-glia interactions. Here, the mechanism of detrimental microgliosis in AD by employing 3D human AD mini-brains, brain tissues of AD patients, and 5XFAD mice is explored. In the human and animal AD models, amyloid-beta (Aß)-overexpressing neurons and reactive astrocytes produce interferon-gamma (IFNγ) and excessive oxidative stress. IFNγ results in the downregulation of mitogen-activated protein kinase (MAPK) and the upregulation of Kelch-like ECH-associated Protein 1 (Keap1) in microglia, which inactivate nuclear factor erythroid-2-related factor 2 (Nrf2) and sensitize microglia to the oxidative stress and induces a proinflammatory microglia via nuclear factor kappa B (NFκB)-axis. The proinflammatory microglia in turn produce neurotoxic nitric oxide and proinflammatory mediators exacerbating synaptic impairment, phosphorylated-tau accumulation, and discernable neuronal loss. Interestingly, recovering Nrf2 in the microglia prevents the activation of proinflammatory microglia and significantly blocks the tauopathy in AD minibrains. Taken together, it is envisioned that IFNγ-driven Nrf2 downregulation in microglia as a key target to ameliorate AD pathology.

KDS2010, a reversible MAO-B inhibitor, extends the lifetime of neural probes by preventing glial scar formation.

Implantable neural probes have been extensively utilized in the fields of neurocircuitry, systems neuroscience, and brain-computer interface. However, the long-term functionality of these devices is hampered by the formation of glial scar and astrogliosis at the surface of electrodes. In this study, we administered KDS2010, a recently developed reversible MAO-B inhibitor, to mice through ad libitum drinking in order to prevent glial scar formation and astrogliosis. The administration of KDS2010 allowed long-term recordings of neural signals with implantable devices, which remained stable over a period of 6 months and even restored diminished neural signals after probe implantation. KDS2010 effectively prevented the formation of glial scar, which consists of reactive astrocytes and activated microglia around the implant. Furthermore, it restored neural activity by disinhibiting astrocytic MAO-B dependent tonic GABA inhibition induced by astrogliosis. We suggest that the use of KDS2010 is a promising approach to prevent glial scar formation around the implant, thereby enabling long-term functionality of neural devices.

The Effect of Leg Length Discrepancy on Paraspinal Muscles Activation Using Surface Electromyography.

OBJECTIVE: The aim of the study is to assess the effects of leg length discrepancy on paraspinal muscle activity and kinematic variables during gait. DESIGN: Thirty-nine healthy participants aged 5-12 yrs performed the 10-m walk test using the surface electromyography and G-walk sensor for the following conditions: (1) non-leg length discrepancy condition (leg length discrepancy 0 cm) and (2) leg length discrepancy condition with an insole on the right leg at three different heights (leg length discrepancy 0.5 cm, 1.0 cm, and 1.5 cm). The root mean square was normalized using maximal voluntary contraction and reference voluntary contraction methods (RMS_MVC and RMS_ref) and compared between the sides. RESULTS: The mean RMS_MVC of the 12th thoracic erector spinae on the right side was significantly higher at a leg length discrepancy 0.5 cm and 1 cm. Regarding the 3rd lumbar multifidus, the mean RMS_MVC on the right side was significantly higher at a leg length discrepancy 1.5 cm. The mean RMS_ref exhibited similar patterns. Pelvic obliquity and rotation showed asymmetry at a leg length discrepancy 1.5 cm compared with a leg length discrepancy 0 cm. CONCLUSIONS: A small leg length discrepancy significantly affected the asymmetric hyperactivation of the 3rd lumbar multifidus and 12th thoracic erector spinae muscles during gait. Considering the action of these muscles, asymmetric hyperactivation might result in rotation and bending of the lumbar spine and the bending of the thoracolumbar spine.

Application of 3D scanner to measure physical size and improvement of hip brace manufacturing technology in severe cerebral palsy patients.

This prospective pilot study aimed to develop a personalized hip brace for treating hip subluxation in children with cerebral palsy. Nineteen children, aged 1-15, with severe cerebral palsy participated in the study. Customized hip braces were created based on 3D scanner measurements and worn for 7 days. The primary outcome, Hip Migration Index (MI), and secondary outcomes, including range of motion (ROM) in the hip and knee joints, pain intensity, satisfaction, discomfort scores, CPCHILD, and wearability test, were assessed. The MI and ROM were assessed at screening and at Visit 1 (when the new hip brace was first worn), while other indicators were evaluated at screening, Visit 1, and Visit 2 (7 days after wearing the new hip brace). The study demonstrated significant improvements in the MI for the right hip, left hip, and both sides. However, there were no statistically significant differences in hip and knee joint ROM. Other indicators showed significant changes between screening, Visit 1, and Visit 2. The study suggests that customized hip braces effectively achieved immediate correction, positively impacting the quality of life and satisfaction in children with cerebral palsy. Furthermore, the hip braces have the potential to enhance compliance and prevent hip subluxation.Clinical Trial Registration number: NCT05388422.

Effects of hip brace on coxa valga in nonambulatory children with cerebral palsy: A randomized controlled trial.

BACKGROUND: Coxa valga, measured as the neck-shaft angle (NSA) or head-shaft angle (HSA), is regarded as a potential risk factor for hip dislocation in patients with cerebral palsy. We investigated the effects of a novel hip brace on coxa valga. METHODS: A prospective, multicenter, assessor-blinded, randomized controlled trial was conducted from July 2019 to November 2021. Children with cerebral palsy aged 1 to 10 years with Gross Motor Function Classification System levels IV and V were recruited. The study group wore a hip brace for at least 12 hour a day. A lower strap of the hip brace was designed to prevent coxa valga biomechanically. The effectiveness of the hip brace on coxa valga was assessed by measurement of the NSA and head-shaft angle at enrollment and 6 and 12 months after enrollment. RESULTS: Sixty-six participants were enrolled, and 33 patients were assigned to each group. Changes in the mean NSA of both sides and the NSA of left side showed significant differences between the 2 groups over 12 months (mean NSA of both sides, -1.12 ± 3.64 in the study group and 1.43 ± 3.75 in the control group, P = .023; NSA of the left side, -1.72 ± 5.38 in the study group and 2.01 ± 5.22 in the control group, P = .008). CONCLUSIONS: The hip brace was effective in preventing the progression of coxa valga and hip displacement, suggesting that the prevention of coxa valga using hip brace is a contributing factor in prevention of hip displacement.

Analysis of the mechanism and clinical classification of thoracolumbar scoliosis using three-dimensional EOS and surface electromyography.

To analyze a thoracolumbar scoliosis group, we analyzed data from the acquired database by groups: the sEMG group (n = 16) and 3D-EOS group (n = 55). The asymmetric hyper/hypoactivation ratio of muscle and LLD (>3 mm) were measured in the sEMG group. In the 3D-EOS group, we recorded the values of parameters including LLD, pelvis rotation, and kyphosis/lordosis. In the sEMG study, sEMG examinations were conducted individually in patients with idiopathic scoliosis to analyze hyper/hypoactivation of the paraspinal muscle. In the three-dimensional EOS study, the Cobb angle, femoral height difference, and thoracic kyphosis and lumbar lordosis angles were measured using 2D images and 3D reconstructed images. Sixteen patients with thoracolumbar scoliosis were classified into asymmetric hyperactivation (A-Hyper) and asymmetric hypoactivation (A-Hypo) groups. The Cobb angle of the A-Hyper subtype was significantly higher than that of the A-Hypo subtype (22.41 versus 15.2, p = 0.023). Coronal deviation (p = 0.028) and the pelvis rotation angle (p = 0.001) were significantly higher in the LLD (+) subtype than in the LLD (-) subtype. When we classified patients cross-sectionally along with A-Hyper/Hypo and LLD (±), A-Hyper elevated the Cobb angle, and LLD (+) was significantly correlated with coronal deviation and pelvis rotation. In the 3D-EOS evaluation, the pelvic height difference (p = 0.043) and coronal deviation (p = 0.001) were significantly higher in the LLD (+) subtype than in the LLD (-) subtype. In conclusions, paraspinal muscular asymmetry and LLD can be strong factors in inducing or progressing thoracolumbar scoliosis.

Kinematic mechanism of the rehabilitative effect of 4-channel NMES: post-hoc analysis of a prospective randomized controlled study.

The sequential 4-channel neuromuscular electrical stimulation (NMES), based on the normal contractile sequences of swallowing-related muscles, is a new rehabilitative treatment. The objective of this study was to explore the mechanism of the rehabilitative effect of the 4-channel NMES using kinematic analysis of videofluoroscopic swallowing study (VFSS) data. For this post-hoc analysis, we included a subset of participants from the prospective randomized controlled study on the clinical effectiveness of the sequential 4-channel NMES compared with that of the conventional 2-channel NMES. Seventeen subjects (11 and six in the 4- and 2-channel NMES groups, respectively) were eligible for the kinematic analysis of VFSS data. The hyoid bone movement was analyzed by evaluating the distance and time parameters with four peak points (A, B, C, D). The 4-channel NMES group showed significant improvement in vertical distances (A-C), horizontal distance (A-B, A-C), time interval (A-B-C) and total time, compared with their pretreatment data. The 2-channel NMES group showed significant improvements in time interval (A-B); however, the Euclidean distance (A-D) and mean velocity of the Euclidean distance (A-C) were significantly decreased. When the two groups were directly compared, the 4-channel group showed significantly greater improvement in horizontal distance (A-B), Euclidean distance (A-D), time interval (A-B-C), and mean velocity the Euclidean distance (A-D). The results in this study suggest that the sequential 4-channel NMES might lead to the physiologic circular movement of the hyoid bone during swallowing, and therefore be an effective treatment for dysphagia.Trial registration: Clinicaltrials.gov, registration number: NCT03670498.

Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA.

The lateral hypothalamic area (LHA) regulates food intake and energy balance. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we show that GABRA5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity mouse models in males. Chemogenetic inhibition of GABRA5LHA suppresses fat thermogenesis and increases weight gain, whereas gene silencing of GABRA5 in LHA decreases weight gain. In the diet-induced obesity mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by monoamine oxidase B (Maob). Gene silencing of astrocytic Maob in LHA facilitates fat thermogenesis and reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a Maob inhibitor, KDS2010. We propose that firing of GABRA5LHA suppresses fat accumulation and selective inhibition of astrocytic GABA is a molecular target for treating obesity.

Analysis of abnormal muscle activities in patients with loss of cervical lordosis: a cross-sectional study.

BACKGROUND: This study aimed to detect the differences in cervical muscle activation patterns in people with versus without cervical lordosis and explore the possible mechanism of cervical pain originating therein. METHODS: This cross-sectional design included 39 participants without and 18 with normal cervical lordosis. Muscular activation was measured for 5 s in both groups using surface electromyography. Subsequently, the root mean square (RMS) of muscle amplitude was obtained at the bilateral splenius capitis, upper and lower parts of the splenius cervicis, upper and lower parts of the semispinalis cervicis, sternocleidomastoid, upper trapezius, and rhomboid muscles in five cervical positions: 0° (resting), 30° of flexion, 30° of extension, 60° of extension, and upon a 1-kg load on the head in a resting posture. RESULTS: The RMS values of the upper trapezius muscle at all postures and the rhomboid muscles at 60° of extension were significantly lower in the loss of lordosis than control group. Comparing the RMS ratio of each posture to the resting position, the ratio of the upper trapezius at flexion was significantly higher and that of the rhomboids at 60° of extension and upon loading was significantly lower in the loss of lordosis than control group. Moreover, the pattern changes in the RMS values according to posture showed a similar shape in these two muscles, and lower in the loss of lordosis than the normal group. CONCLUSIONS: The loss of normal cervical alignment may correlate with predisposed conditions such as reduced muscle activation of the trapezius and rhomboid muscle, and may also provoke over-firing of the upper trapezius muscle, possibly increasing neck musculoskeletal pain. CLINICALTRIALS: gov, registration number: NCT03710785.

Efficacy of a Hip Brace for Hip Displacement in Children With Cerebral Palsy: A Randomized Clinical Trial.

Importance: There is no consensus on interventions to slow the progress of hip displacement in patients with cerebral palsy. Objective: To investigate the efficacy of a novel hip brace in preventing progressive hip displacement in patients with cerebral palsy. Design, Setting, and Participants: This 2-group randomized clinical trial was conducted at 4 tertiary hospitals in South Korea from July 2019 to November 2021. Participants included children aged 1 to 10 years with nonambulatory cerebral palsy (Gross Motor Function Classification System level IV or V). Block randomization was used to assign an equal number of patients to the study and control groups via computerized random allocation sequences. Data were analyzed from November to December 2021. Interventions: The intervention group wore the hip brace for at least 12 hours a day for the study duration (ie, 12 months). Follow-up evaluations were performed after 6 and 12 months of wearing the brace. Both groups proceeded with conventional rehabilitation therapy during the trial. Main Outcomes and Measures: The primary outcome was the Reimers migration index (MI) on radiography, as assessed by 3 blinded investigators. Primary outcome variables were analyzed using linear mixed models. Secondary outcomes include change in the Caregiver Priorities & Child Health Index of Life with Disabilities, on which lower scores indicate better quality of life. Results: A total of 66 patients were included, with 33 patients (mean [SD] age, 68.7 [31.6] months; 25 [75.8%] boys) randomized to the intervention group and 33 patients (mean [SD] age, 60.7 [24.9] months; 20 [60.6%] boys) randomized to the control group. The baseline mean (SD) MI was 37.4% (19.3%) in the intervention group and 30.6% (16.3%) in the control group. The mean difference of the MI between the intervention group and control group was -8.7 (95% CI, -10.2 to -7.1) percentage points at 6 months and -12.7 (95% CI, -14.7 to -10.7) percentage points at 12 months. The changes in the Caregiver Priorities & Child Health Index of Life with Disabilities were favorable in the study group and reached statistical significance at the 6-month follow-up compared with the control group (difference, -14.2; 95% CI, -25.2 to -3.3). Conclusions and Relevance: In this randomized clinical trial, the novel hip brace was significantly effective in preventing the progression of hip displacement, compared with the control group. It effectively improved quality of life in patients with nonambulatory cerebral palsy. Therefore, hip brace use could be a promising treatment method to delay hip surgery and improve the quality of life of patients with nonambulatory cerebral palsy. Trial Registration: ClinicalTrials.gov Identifier: NCT04033289.

The facilitation of trunk muscles by abdominal bracing during walking in chronic low back pain patients.

Walking is known to be beneficial for chronic low back pain (LBP) patients and fast walking recruits more trunk muscles. Abdominal bracing has also been shown to improve LBP and facilitate several trunk muscles. We aimed to investigate the effects of walking velocity and abdominal bracing on the activation of trunk muscles in chronic LBP patients during walking. Forty-six volunteers with chronic LBP underwent walking exercise on the treadmill without ("non-braced walking") and with abdominal bracing ("braced walking") at speeds of 4, 5, and 6 km/h, with the surface electrodes placed on their trunk muscles to measure muscle activity. The root mean square values of the surface electromyography amplitude data were obtained at the multifidus of lower (ML) and upper lumbar (MU), erector spinae of lower lumbar (EL) and thoracic (ET), rectus abdominis (RA), and external oblique (EO). All muscles activated significantly more at faster walking. The "braced walking" facilitated the ET and RA significantly more than the "non-braced walking". The interaction between the walking speed and abdominal bracing was significant at ML, MU, and RA. The increase in muscle activation observed at lower speed diminished as speed increased. Since "braced walking" seems to additionally facilitate the trunk muscles especially at slower gait speeds, patients who cannot walk fast may still be able to train their muscles by "braced walking."

Unaltered Tonic Inhibition in the Arcuate Nucleus of Diet-induced Obese Mice.

The principal inhibitory transmitter, γ-aminobutyric acid (GABA), is critical for maintaining hypothalamic homeostasis and released from neurons phasically, as well as from astrocytes tonically. Although astrocytes in the arcuate nucleus (ARC) of the hypothalamus are shown to transform into reactive astrocytes, the tonic inhibition by astrocytic GABA has not been adequately investigated in diet-induced obesity (DIO). Here, we investigated the expression of monoamine oxidase-B (MAOB), a GABA-synthesizing enzyme, in reactive astrocytes in obese mice. We observed that a chronic high-fat diet (HFD) significantly increased astrocytic MAOB and cellular GABA content, along with enhanced hypertrophy of astrocytes in the ARC. Unexpectedly, we found that the level of tonic GABA was unaltered in chronic HFD mice using whole-cell patch-clamp recordings in the ARC. Furthermore, the GABA-induced current was increased with elevated GABAA receptor α5 (GABRA5) expression. Surprisingly, we found that a nonselective GABA transporter (GAT) inhibitor, nipecotic acid (NPA)-induced current was significantly increased in chronic HFD mice. We observed that GAT1 inhibitor, NO711-induced current was significantly increased, whereas GAT3 inhibitor, SNAP5114-induced current was not altered. The unexpected unaltered tonic inhibition was due to an increase of GABA clearance in the ARC by neuronal GAT1 rather than astrocytic GAT3. These results imply that increased astrocytic GABA synthesis and neuronal GABAA receptor were compensated by GABA clearance, resulting in unaltered tonic GABA inhibition in the ARC of the hypothalamus in obese mice. Taken together, GABA-related molecular pathways in the ARC dynamically regulate the tonic inhibition to maintain hypothalamic homeostasis against the HFD challenge.

Astrocytic urea cycle detoxifies Aß-derived ammonia while impairing memory in Alzheimer's disease.

Alzheimer's disease (AD) is one of the foremost neurodegenerative diseases, characterized by beta-amyloid (Aß) plaques and significant progressive memory loss. In AD, astrocytes are proposed to take up and clear Aß plaques. However, how Aß induces pathogenesis and memory impairment in AD remains elusive. We report that normal astrocytes show non-cyclic urea metabolism, whereas Aß-treated astrocytes show switched-on urea cycle with upregulated enzymes and accumulated entering-metabolite aspartate, starting-substrate ammonia, end-product urea, and side-product putrescine. Gene silencing of astrocytic ornithine decarboxylase-1 (ODC1), facilitating ornithine-to-putrescine conversion, boosts urea cycle and eliminates aberrant putrescine and its toxic byproducts ammonia and H2O2 and its end product GABA to recover from reactive astrogliosis and memory impairment in AD. Our findings implicate that astrocytic urea cycle exerts opposing roles of beneficial Aß detoxification and detrimental memory impairment in AD. We propose ODC1 inhibition as a promising therapeutic strategy for AD to facilitate removal of toxic molecules and prevent memory loss.

Active role of glia-like supporting cells in the organ of Corti: Membrane proteins and their roles in hearing.

The organ of Corti, located in the cochlea in the inner ear, is one of the major sensory organs involved in hearing. The organ of Corti consists of hair cells, glia-like supporting cells, and the cochlear nerve, which work in harmony to receive sound from the outer ear and transmit auditory signals to the cochlear nucleus in the auditory ascending pathway. In this process, maintenance of the endocochlear potential, with a high potassium gradient and clearance of electrolytes and biochemicals in the inner ear, is critical for normal sound transduction. There is an emerging need for a thorough understanding of each cell type involved in this process to understand the sophisticated mechanisms of the organ of Corti. Hair cells have long been thought to be active, playing a primary role in the cochlea in actively detecting and transmitting signals. In contrast, supporting cells are thought to be silent and function to support hair cells. However, growing lines of evidence regarding the membrane proteins that mediate ionic movement in supporting cells have demonstrated that supporting cells are not silent, but actively play important roles in normal signal transduction. In this review, we summarize studies that characterize diverse membrane proteins according to the supporting cell subtypes involved in cochlear physiology and hearing. This review contributes to a better understanding of supporting cell functions and facilitates the development of potential therapeutic tools for hearing loss.

Inhibition of monoamine oxidase B prevents reactive astrogliosis and scar formation in stab wound injury model.

Reactive astrocytes manifest molecular, structural, and functional alterations under various pathological conditions. We have previously demonstrated that the reactive astrocytes of the stab wound injury model (STAB) display aberrant cellular gamma-aminobutyric acid (GABA) content and tonic GABA release, whereas the active astrocytes under enriched environment (EE) express high levels of proBDNF. However, the role of monoamine oxidase B (MAO-B) in reactive astrogliosis and hypertrophy still remains unknown. Here, we investigate the role of MAO-B, a GABA-producing enzyme, in reactive astrogliosis in STAB. We observed that the genetic removal of MAO-B significantly reduced the hypertrophy, scar formation, and GABA production of reactive astrocytes, whereas the MAO-B overexpression under glial fibrillary acidic protein (GFAP) promoter enhanced the levels of GFAP and GABA. Furthermore, we found that one of the by-products of the MAO-B action, H2 O2 , but not GABA, was sufficient and necessary for the hypertrophy of reactive astrocytes. Notably, we identified two potent pharmacological tools to attenuate scar-forming astrogliosis-the recently developed reversible MAO-B inhibitor, KDS2010, and an H2 O2 scavenger, crisdesalazine (AAD-2004). Our results implicate that inhibiting MAO-B activity has dual beneficial effects in preventing astrogliosis and scar-formation under brain injury, and that the MAO-B/H2 O2 pathway can be a useful therapeutic target with a high clinical potential.

Effect of Botulinum Toxin Injection on the Progression of Hip Dislocation in Patients with Spastic Cerebral Palsy: A Pilot Study.

Hip adductor spasticity is a contributing factor to hip dislocation in patients with cerebral palsy (CP). We hypothesized that botulinum toxin injected into the hip adductor muscles would reduce spasticity and help prevent hip dislocation. Twenty patients with bilateral spastic CP aged 2 to 10 years with gross motor function classification system level IV or V were included. Botulinum toxin was injected into the hip adductor muscles at baseline and at 6-month follow-up. Muscle tone was measured with an eight-channel surface electromyography (EMG) recorder. A hip X-ray was performed, and Reimer's hip migration index (MI) was measured. The Wilcoxon signed-rank test was used to compare the surface EMG values of the hip muscles at baseline and follow-up. The mean root mean square surface EMG value of the hip adductor muscles was significantly reduced at 1, 2, 3, and 7 months after the first injection, up to approximately 53% of the baseline. The 1-year progression of the hip MI was -0.04%. Repeated sessions of botulinum toxin injections at the hip adductor muscles significantly reduced muscle tone and hip displacement. A botulinum toxin injection may be used as an adjunctive treatment in the prevention of hip dislocation.

The effect of a flexible thoracolumbar brace on neuromuscular scoliosis: A prospective observational study.

ABSTRACT: Neuromuscular scoliosis is a common deformity seen in patients with neuromuscular diseases. Although rigid thoracolumbosacral orthosis is the most frequently used brace, it has low compliance rates and can lead to complications including skin ulcers. Thus, alternative methods for treating neuromuscular scoliosis are needed. The purpose of this study is to evaluate the clinical effects of a novel flexible brace to prevent the progression of neuromuscular scoliosis.This study is a prospective observational study. Twenty-three patients with neuromuscular scoliosis were enrolled in the study. Among patients diagnosed with neuromuscular disease, spine radiographs were checked for a neuromuscular scoliosis diagnosis. The participants were treated with a novel flexible brace for 6 months. The control group (n = 46) was selected using propensity score matching method from a clinical data warehouse. The Cobb angle was measured and compared between the study and control groups.In the study group, the average Cobb's angle significantly decreased from 47.22 ±â€Š18.9° to 31.8 ±â€Š20.0 when wearing the flexible brace (P < .001). Thus, the correction rate was 36.9%. The annual progression rate was significantly lower in the study group than in the control group (P  < .05).The flexible brace showed a significant correction rate of scoliosis in patients with severe neuromuscular diseases. The flexible brace is an alternative treatment modality for patients with neuromuscular scoliosis. Daily application of the flexible brace during the growing period can reduce the degree of fixed deformity in the long term.

Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer's disease via H2O2- production.

Although the pathological contributions of reactive astrocytes have been implicated in Alzheimer's disease (AD), their in vivo functions remain elusive due to the lack of appropriate experimental models and precise molecular mechanisms. Here, we show the importance of astrocytic reactivity on the pathogenesis of AD using GiD, a newly developed animal model of reactive astrocytes, where the reactivity of astrocytes can be manipulated as mild (GiDm) or severe (GiDs). Mechanistically, excessive hydrogen peroxide (H2O2) originated from monoamine oxidase B in severe reactive astrocytes causes glial activation, tauopathy, neuronal death, brain atrophy, cognitive impairment and eventual death, which are significantly prevented by AAD-2004, a potent H2O2 scavenger. These H2O2--induced pathological features of AD in GiDs are consistently recapitulated in a three-dimensional culture AD model, virus-infected APP/PS1 mice and the brains of patients with AD. Our study identifies H2O2 from severe but not mild reactive astrocytes as a key determinant of neurodegeneration in AD.

Astrocytic proBDNF and Tonic GABA Distinguish Active versus Reactive Astrocytes in Hippocampus.

Astrocytes are the most abundant cell type in the brain and they make close contacts with neurons and blood vessels. They respond dynamically to various environmental stimuli and change their morphological and functional properties. Both physiological and pathological stimuli can induce versatile changes in astrocytes, as this phenomenon is referred to as 'astrocytic plasticity'. However, the molecular and cellular mechanisms of astrocytic plasticity in response to various stimuli remain elusive, except for the presence of hypertrophy, a conspicuous structural change which is frequently observed in activated or reactive astrocytes. Here, we investigated differential characteristics of astrocytic plasticity in a stimulus-dependent manner. Strikingly, a stab wound brain injury lead to hypertrophy of astrocytes accompanied by increased GABA expression and tonic GABA release in mouse CA1 hippocampus. In contrast, the mice experiencing enriched environment exhibited astrocytic hypertrophy with enhanced proBDNF immunoreactivity but without GABA signal. Based on the results, we define proBDNF-positive/GABA-negative hypertrophic astrocytes as 'active' astrocytes and GABA-positive hypertrophic astrocytes as 'reactive' astrocytes, respectively. We propose for the first time that astrocytic proBDNF can be a bona fide molecular marker of the active astrocytes, which are distinct from the reactive astrocytes which show hypertrophy but with aberrant GABA.