Denser brain capillary network with preserved pericytes in Alzheimer's disease

Pericytes are vascular mural cells that surround capillaries of the central nervous system (CNS). They are crucial for brain development and contribute to CNS homeostasis by regulating blood–brain barrier function and cerebral blood flow. It has been suggested that pericytes are lost in Alzheimer''s disease (AD), implicating this cell type in disease pathology. Here, we have employed state‐of‐the‐art stereological morphometry techniques as well as tissue clearing and two‐photon imaging to assess the distribution of pericytes in two independent cohorts of AD (n = 16 and 13) and non‐demented controls (n = 16 and 4). Stereological quantification revealed increased capillary density with a normal pericyte population in the frontal cortex of AD brains, a region with early amyloid β deposition. Two‐photon analysis of cleared frontal cortex tissue confirmed the preservation of pericytes in AD cases. These results suggest that pericyte demise is not a general hallmark of AD pathology.     

Loss of capillary pericytes and the blood–brain barrier in white matter in poststroke and vascular dementias and Alzheimer’s disease

White matter (WM) disease is associated with disruption of the gliovascular unit, which involves breach of the blood–brain barrier (BBB). We quantified pericytes as components of the gliovascular unit and assessed their status in vascular and other common dementias. Immunohistochemical and immunofluorescent methods were developed to assess the distribution and quantification of pericytes connected to the frontal lobe WM capillaries. Pericytes with a nucleus were identified by collagen 4 (COL4) and platelet‐derived growth factor receptor‐β (PDGFR‐β) antibodies with further verification using PDGFR‐β‐specific ELISA. We evaluated a total of 124 post‐mortem brains from subjects with post‐stroke dementia (PSD), vascular dementia (VaD), Alzheimer’s disease (AD), AD‐VaD (Mixed) and post‐stroke non‐demented (PSND) stroke survivors as well as normal aging controls. COL4 and PDGFR‐β reactive pericytes adopted the characteristic “crescent” or nodule‐like shapes around capillary walls. We estimated densities of pericyte somata to be 225 ±38 and 200 ±13 (SEM) per COL4 mm² area or 2.0 ± 0.1 and 1.7 ± 0.1 per mm capillary length in young and older aging controls. Remarkably, WM pericytes were reduced by ~35%–45% in the frontal lobe of PSD, VaD, Mixed and AD subjects compared to PSND and controls subjects (P < 0.001). We also found pericyte numbers were correlated with PDGFR‐β reactivity in the WM. Our results first demonstrate a reliable method to quantify COL4‐positive pericytes and then, indicate that deep WM pericytes are decreased across different dementias including PSD, VaD, Mixed and AD. Our findings suggest that downregulation of pericytes is associated with the disruption of the BBB in the deep WM in several aging‐related dementias.     

Brain alpha‐amylase: a novel energy regulator important in Alzheimer disease?

Reduced glucose metabolism and formation of polyglucosan bodies (PGB) are, beside amyloid beta plaques and neurofibrillary tangles, well‐known pathological findings associated with Alzheimer''s disease (AD). Since both glucose availability and PGB are regulated by enzymatic degradation of glycogen, we hypothesize that dysfunctional glycogen degradation is a critical event in AD progression. We therefore investigated whether alpha (α)‐amylase, an enzyme known to efficiently degrade polysaccharides in the gastrointestinal tract, is expressed in the hippocampal CA1/subiculum and if the expression is altered in AD patients. Using immunohistochemical staining techniques, we show the presence of the α‐amylase isotypes AMY1A and AMY2A in neuronal dendritic spines, pericytes and astrocytes. Moreover, AD patients showed reduced gene expression of α‐amylase, but conversely increased protein levels of α‐amylase as well as increased activity of the enzyme compared with non‐demented controls. Lastly, we observed increased, albeit not significant, load of periodic acid‐Schiff positive PGB in the brain of AD patients, which correlated with increased α‐amylase activity. These findings show that α‐amylase is expressed and active in the human brain, and suggest the enzyme to be affected, alternatively play a role, in the neurodegenerative Alzheimer''s disease pathology.     

Non‐organ‐specific autoimmunity in adult 47,XXY Klinefelter patients and higher‐grade X‐chromosome aneuploidies

Current literature regarding systemic autoimmune diseases in X‐chromosome aneuploidies is scarce and limited to case reports. Our aim was to evaluate the frequency of anti‐nuclear (ANAs), extractable nuclear (ENA), anti‐double‐stranded DNA (dsDNAs), anti‐smooth muscle (ASMAs) and anti‐mitochondrial (AMAs) antibodies in a large cohort of adults with Klinefelter’s syndrome (KS, 47,XXY) and rare higher‐grade sex chromosome aneuploidies (HGAs) for the first time. Sera from 138 X‐chromosome aneuploid patients [124 adult patients with 47,XXY KS and 14 patients with HGA (six children, eight adults)] and 50 age‐matched 46,XY controls were recruited from the Sapienza University of Rome (2007–17) and tested for ANAs, ENAs, anti‐dsDNAs, ASMAs and AMAs. Non‐organ‐specific immunoreactivity was found to be significantly higher in patients with 47,XXY KS (14%) than in the controls (2%, p = 0.002). Among all the antibodies investigated, only ANAs were observed significantly more frequently in patients with 47,XXY KS (12.1%) than in the controls (2%, p = 0.004). No anti‐dsDNA immunoreactivity was found. Stratifying by testosterone replacement therapy (TRT), non‐organ‐specific autoantibody frequencies were higher in TRT‐naive (p = 0.01) and TRT‐treated groups than in controls. No patients with HGA were found positive for the various autoantibodies. Non‐organ‐specific autoantibodies were significantly present in 47,XXY adult patients. Conversely, HGAs did not appear to be target of non‐organ‐specific immunoreactivity, suggesting that KS and HGAs should be considered as two distinct conditions. The classification and diagnosis of systemic autoimmune diseases is frequently difficult. To support a correct clinical evaluation of KS disease and to prevent eventual secondary irreversible immune‐mediated damages, we highlight the importance of screening for non‐organ‐specific autoimmunity in Klinefelter’s syndrome.     

Development of a high‐sensitivity ELISA detecting IgG,IgA and IgM antibodies to the SARS‐CoV‐2 spike glycoprotein in serum and saliva

Detecting antibody responses during and after SARS‐CoV‐2 infection is essential in determining the seroepidemiology of the virus and the potential role of antibody in disease. Scalable, sensitive and specific serological assays are essential to this process. The detection of antibody in hospitalized patients with severe disease has proven relatively straightforward; detecting responses in subjects with mild disease and asymptomatic infections has proven less reliable. We hypothesized that the suboptimal sensitivity of antibody assays and the compartmentalization of the antibody response may contribute to this effect. We systematically developed an ELISA, optimizing different antigens and amplification steps, in serum and saliva from non‐hospitalized SARS‐CoV‐2‐infected subjects. Using trimeric spike glycoprotein, rather than nucleocapsid, enabled detection of responses in individuals with low antibody responses. IgG1 and IgG3 predominate to both antigens, but more anti‐spike IgG1 than IgG3 was detectable. All antigens were effective for detecting responses in hospitalized patients. Anti‐spike IgG, IgA and IgM antibody responses were readily detectable in saliva from a minority of RT‐PCR confirmed, non‐hospitalized symptomatic individuals, and these were mostly subjects who had the highest levels of anti‐spike serum antibodies. Therefore, detecting antibody responses in both saliva and serum can contribute to determining virus exposure and understanding immune responses after SARS‐CoV‐2 infection.     

lncRNA MEG3 restrained the M1 polarization of microglia in acute spinal cord injury through the HuR/A20/NF‐κB axis

The M1 polarization of microglia and neuroinflammation restrict the treatment of acute spinal cord injury (ASCI), and long non‐coding ribonucleic acid (lncRNA) maternally expressed gene 3 (MEG3) expression is lessened in ASCI. However, the function and mechanism of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI are unclear. The expressions of lncRNA MEG3 in ASCI mouse spinal cord tissues and lipopolysaccharide (LPS)‐treated primary microglia and BV2 cells were quantified through a quantitative real‐time polymerase chain reaction. In‐vitro assays were conducted to explore the function of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI. RNA degradation, RNA immunoprecipitation, RNA pull‐down, cycloheximide‐chase, and ubiquitination analyses were carried out to probe into the mechanism of lncRNA MEG3 in the M1 polarization of microglia and neuroinflammation in ASCI. The lncRNA MEG3 expression was lessened in the ASCI mouse spinal cord tissues and LPS‐treated primary microglia and BV2 cells, and the overexpression of lncRNA MEG3 restrained the M1 polarization of microglia and the neuroinflammation by regulating the NF‐κB signaling pathway. For the investigation of the potential mechanism of such, the overexpression of lncRNA MEG3 restrained the M1 polarization of microglia through the HuR/A20/NF‐κB axis and boosted the motor function recovery and neuroinflammation relief in the mice with SCI. The overexpression of lncRNA MEG3 restrained the M1 polarization of microglia through the HuR/A20/NF‐κB axis.     

Potential anti neuro‐inflammatory effect of BioCen‐128 in animal models of dementia

BackgroundBioCen‐128 is a new active pharmaceutical ingredient composed of a specific bovine thymic fraction of a polypeptide nature. Positive results of similar thymus extracts have been shown to be effective in delaying the processes associated with aging, immunosenescence and Alzheimer''s disease (AD), where the inflammation plays an important role. Because of the anti‐inflammatory potential of BioCen‐128, the aim of this study was to evaluate the granuloma model induced by a cotton wool implantation and the model induced by intracerebroventricular (ICV) administration of streptozotocin (STZ).MethodThe experiment was carried out using male OF‐1_cenp mice weighing 20 ± 2 g.ResultsMice administered BioCen‐128 in via the IP route at 5, 10 and 20 mg/kg of corporal weigh showed a decrease in the wet and dry weights of the granuloma, providing evidence of a systemic anti‐inflammatory effect. In the ICV model of STZ, the administration of BioCen‐128 improved cognitive function.ConclusionThese responses suggested an anti‐neuroinflammatory effect explainable by the action of thymosin β4 and thymosin alfa proteins. The results suggested that BioCen‐128 could be used in the prevention and treatment of some diseases, for example AD, where neuroinflammation is one of the biological events that take place.     

Towards PET imaging of the dynamic phenotypes of microglia

There is increasing evidence showing the heterogeneity of microglia activation in neuroinflammatory and neurodegenerative diseases. It has been hypothesized that pro‐inflammatory microglia are detrimental and contribute to disease progression, while anti‐inflammatory microglia play a role in damage repair and remission. The development of therapeutics targeting the deleterious glial activity and modulating it into a regenerative phenotype relies heavily upon a clearer understanding of the microglia dynamics during disease progression and the ability to monitor therapeutic outcome in vivo. To that end, molecular imaging techniques are required to assess microglia dynamics and study their role in disease progression as well as to evaluate the outcome of therapeutic interventions. Positron emission tomography (PET) is such a molecular imaging technique, and provides unique capabilities for non‐invasive quantification of neuroinflammation and has the potential to discriminate between microglia phenotypes and define their role in the disease process. However, several obstacles limit the possibility for selective in vivo imaging of microglia phenotypes mainly related to the poor characterization of specific targets that distinguish the two ends of the microglia activation spectrum and lack of suitable tracers. PET tracers targeting translocator protein 18 kDa (TSPO) have been extensively explored, but despite the success in evaluating neuroinflammation they failed to discriminate between microglia activation statuses. In this review, we highlight the current knowledge on the microglia phenotypes in the major neuroinflammatory and neurodegenerative diseases. We also discuss the current and emerging PET imaging targets, the tracers and their potential in discriminating between the pro‐ and anti‐inflammatory microglia activation states.     

Reconstituting neurovascular unit with primary neural stem cells and brain microvascular endothelial cells in three‐dimensional matrix

Neurovascular dysfunction is a primary or secondary cause in the pathogenesis of several cerebrovascular and neurodegenerative disorders, including stroke. Therefore, the overall protection of the neurovascular unit (NVU) is a promising therapeutic strategy for various neurovascular diseases. However, the complexity of the NVU limits the study of the pathological mechanisms of neurovascular dysfunction. Reconstituting the in vitro NVU is important for the pathological study and drug screening of neurovascular diseases. In this study, we generated a spontaneously assembled three‐dimensional NVU (3D NVU) by employing the primary neural stem cells and brain microvascular endothelial cells in a Matrigel extracellular matrix platform. This novel model exhibits the fundamental structures and features of the NVU, including neurons, astrocytes, oligodendrocytes, vascular‐like structures, and blood–brain barrier‐like characteristics. Additionally, under oxygen‐glucose deprivation, the 3D NVU exhibits the neurovascular‐ or oxidative stress‐related pathological characteristics of cerebral ischemia and the injuries can be mitigated, respectively, by supplementing with the vascular endothelial growth factor or edaravone, which demonstrated that the availability of 3D NVU in ischemic stroke modeling. Finally, the 3D NVU promoted the angiogenesis and neurogenesis in the brain of cerebral ischemia rats. We expect that the proposed in vitro 3D NVU model will be widely used to investigate the relationships between angiogenesis and neurogenesis and to study the pathology and pharmacology of neurovascular diseases.     

Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer's disease

The neurovascular unit (NVU) comprises cerebral blood vessels and surrounding astrocytes, neurons, perivascular microglia and pericytes. Astrocytes associated with the NVU are responsible for maintaining cerebral blood flow and ionic and osmotic balances in the brain. A significant proportion of individuals with Alzheimer's disease (AD) have vascular amyloid deposits (cerebral amyloid angiopathy, CAA) that contribute to the heterogeneous nature of the disease. To determine whether NVU astrocytes are affected by the accumulation of amyloid at cerebral blood vessels we examined astrocytic markers in four transgenic mouse models of amyloid deposition. These mouse models represent mild CAA, moderate CAA with disease progression to tau pathology and neuron loss, severe CAA and severe CAA with disease progression to tau pathology and neuron loss. We found that CAA and disease progression both resulted in distinct NVU astrocytic changes. CAA causes a loss of apparent glial fibrillary acidic protein (GFAP)–positive astrocytic end-feet and loss of water channels (aquaporin 4) localized to astrocytic end feet. The potassium channels Kir4.1, an inward rectifying potassium channel, and BK, a calcium-sensitive large-conductance potassium channel, were also lost. The anchoring protein, dystrophin 1, is common to these channels and was reduced in association with CAA. Disease progression was associated with a phenotypic switch in astrocytes indicated by a loss of GFAP-positive cells and a gain of S100β-positive cells. Aquaporin 4, Kir4.1 and dystrophin 1 were also reduced in autopsied brain tissue from individuals with AD that also display moderate and severe CAA. Together, these data suggest that damage to the neurovascular unit may be a factor in the pathogenesis of Alzheimer's disease.     

COVID‐19‐related neuropathology and microglial activation in elderly with and without dementia

The actual role of SARS‐CoV‐2 in brain damage remains controversial due to lack of matched controls. We aim to highlight to what extent is neuropathology determined by SARS‐CoV‐2 or by pre‐existing conditions. Findings of 9 Coronavirus disease 2019 (COVID‐19) cases and 6 matched non‐COVID controls (mean age 79 y/o) were compared. Brains were analyzed through immunohistochemistry to detect SARS‐CoV‐2, lymphocytes, astrocytes, endothelium, and microglia. A semi‐quantitative scoring was applied to grade microglial activation. Thal‐Braak stages and the presence of small vessel disease were determined in all cases. COVID‐19 cases had a relatively short clinical course (0–32 days; mean: 10 days), and did not undergo mechanical ventilation. Five patients with neurocognitive disorder had delirium. All COVID‐19 cases showed non‐SARS‐CoV‐2‐specific changes including hypoxic‐agonal alterations, and a variable degree of neurodegeneration and/or pre‐existent SVD. The neuroinflammatory picture was dominated by ameboid CD68 positive microglia, while only scant lymphocytic presence and very few traces of SARS‐CoV‐2 were detected. Microglial activation in the brainstem was significantly greater in COVID‐19 cases (p = 0.046). Instead, microglial hyperactivation in the frontal cortex and hippocampus was clearly associated to AD pathology (p = 0.001), regardless of the SARS‐CoV‐2 infection. In COVID‐19 cases complicated by delirium (all with neurocognitive disorders), there was a significant enhancement of microglia in the hippocampus (p = 0.048). Although higher in cases with both Alzheimer''s pathology and COVID‐19, cortical neuroinflammation is not related to COVID‐19 per se but mostly to pre‐existing neurodegeneration. COVID‐19 brains seem to manifest a boosting of innate immunity with microglial reinforcement, and adaptive immunity suppression with low number of brain lymphocytes probably related to systemic lymphopenia. Thus, no neuropathological evidence of SARS‐CoV‐2‐specific encephalitis is detectable. The microglial hyperactivation in the brainstem, and in the hippocampus of COVID‐19 patients with delirium, appears as a specific topographical phenomenon, and probably represents the neuropathological basis of the “COVID‐19 encephalopathic syndrome” in the elderly.     

Cellular response to β‐amyloid neurotoxicity in Alzheimer's disease and implications in new therapeutics

β‐Amyloid (Aβ) is a specific pathological hallmark of Alzheimer''s disease (AD). Because of its neurotoxicity, AD patients exhibit multiple brain dysfunctions. Disease‐modifying therapy (DMT) is the central concept in the development of AD therapeutics today, and most DMT drugs that are currently in clinical trials are anti‐Aβ drugs, such as aducanumab and lecanemab. Therefore, understanding Aβ''s neurotoxic mechanism is crucial for Aβ‐targeted drug development. Despite its total length of only a few dozen amino acids, Aβ is incredibly diverse. In addition to the well‐known Aβ_1‐42, N‐terminally truncated, glutaminyl cyclase (QC) catalyzed, and pyroglutamate‐modified Aβ (pEAβ) is also highly amyloidogenic and far more cytotoxic. The extracellular monomeric Aβ_x‐42 (x = 1–11) initiates the aggregation to form fibrils and plaques and causes many abnormal cellular responses through cell membrane receptors and receptor‐coupled signal pathways. These signal cascades further influence many cellular metabolism‐related processes, such as gene expression, cell cycle, and cell fate, and ultimately cause severe neural cell damage. However, endogenous cellular anti‐Aβ defense processes always accompany the Aβ‐induced microenvironment alterations. Aβ‐cleaving endopeptidases, Aβ‐degrading ubiquitin‐proteasome system (UPS), and Aβ‐engulfing glial cell immune responses are all essential self‐defense mechanisms that we can leverage to develop new drugs. This review discusses some of the most recent advances in understanding Aβ‐centric AD mechanisms and suggests prospects for promising anti‐Aβ strategies.     

Severe histomorphological alterations in post‐mortem olfactory glomeruli in Alzheimer’s disease

Alzheimer''s disease (AD) is the most prevalent form of dementia. Key AD symptoms include memory and cognitive decline; however, comorbid symptoms such as depression and sensory‐perceptual dysfunction are often reported. Among these, a deterioration of olfactory sensation is observed in approximately 90% of AD patients. However, the precise pathophysiological basis underlying olfactory deficits because of AD remains elusive. The olfactory glomeruli in the olfactory bulb (OB) receive sensory information in the olfactory processing pathway. Maintaining the structural and functional integrity of the olfactory glomerulus is critical to olfactory signalling. Herein, we conducted an in‐depth histopathological assessment to reveal detailed structural alterations in the olfactory glomeruli in AD patients. Fresh frozen post‐mortem OB specimens obtained from six AD patients and seven healthy age‐matched individuals were examined. We used combined immunohistochemistry and stereology to assess the gross morphology and histological alterations, such as those in the expression of Aβ protein, microglia, and neurotransmitters in the OB. Electron microscopy was employed to study the ultrastructural features in the glomeruli. Significant accumulation of Aβ, morphologic damage, altered neurotransmitter levels, and microgliosis in the olfactory glomeruli of AD patients suggests that glomerular damage could affect olfactory function. Moreover, greater neurodegeneration was observed in the ventral olfactory glomeruli of AD patients. The synaptic ultrastructure revealed distorted postsynaptic densities and a decline in presynaptic vesicles in AD specimens. These findings show that the primary olfactory pathway is affected by the pathogenesis of AD, and may provide clues to identifying the mechanism involved in olfactory dysfunction in AD.     

Magnetic resonance imaging under isoflurane anesthesia alters cortical cyclooxygenase‐2 expression and glial cell morphology during sepsis‐associated neurological dysfunction in rats

BackgroundMagnetic resonance imaging (MRI) of rodents combined with histology allows to determine what mechanisms underlie functional and structural brain changes during sepsis‐associated encephalopathy. However, the effects of MRI performed in isoflurane‐anesthetized rodents on modifications of the blood‐brain barrier and the production of vasoactive prostaglandins and glia cells, which have been proposed to mediate sepsis‐associated brain dysfunction, are unknown.MethodsThis study addressed the effect of MRI under isoflurane anesthesia on blood‐brain barrier integrity, cyclooxygenase‐2 expression, and glial cell activation during cecal ligature and puncture‐induced sepsis‐associated brain dysfunction in rats.ResultsCecal ligature and puncture reduced food intake and the righting reflex. MRI under isoflurane anesthesia reduced blood‐brain barrier breakdown, decreased circularity of white matter astrocytes, and increased neuronal cyclooxygenase‐2 immunoreactivity in the cortex 24 hours after laparotomy. In addition, it annihilated cecal ligature and puncture‐induced increased circularity of white matter microglia. MRI under isoflurane anesthesia, however, did not alter sepsis‐associated perivascular cyclooxygenase‐2 induction.ConclusionThese findings indicate that MRI under isoflurane anesthesia of rodents can modify neurovascular and glial responses and should, therefore, be interpreted with caution.     

Exposure to chewing tobacco promotes primary oral squamous cell carcinoma and regional lymph node metastasis by alterations of SDF1α/CXCR4 axis

A high incidence of oral squamous cell carcinoma (OSCC) is observed in South‐East Asian countries due to addictions such as chewing tobacco. Local invasion and distant metastases are primary causes of poor prognosis in OSCC. This study aimed to understand the alterations in metastasis biomarkers, such as stromal cell–derived factor‐1α (SDF‐1 or SDF1α) and its receptor C‐X‐C chemokine receptor type 4 (CXCR4), in OSCC patient samples that were stratified based on the history of addiction to chewing tobacco. Targeted immunohistochemical staining and Western blotting were performed on primary tumour and metastatic lymph node (LN) tissues in parallel. Overexpression of hepatocyte growth factor (HGF), activated form of its cognate receptor tyrosine kinase, c‐Met (p‐Met), GRB2‐associated‐binding protein 1 (Gab1), phospho‐protein kinase B (pAkt), nuclear factor kappa B (NF‐κB) and cyclooxygenase‐2 (COX‐2) were observed in primary tumour and metastatic lymph nodes in both chewer and non‐chewer cohorts. Variance analysis showed significant positive correlation between them (P < .0001) indicating upregulation of these biomarkers upon ligand‐induced activation of c‐Met in both tobacco chewers and non‐chewers. Significantly higher expressions of SDF1α and CXCR4 were observed in both primary tumours and metastatic lymph nodes of tobacco chewers (P < .0001) and coincided with overexpressed HGF. In contrast, no significant correlation was observed between expression of HGF and that of SDF1α and CXCR4 in non‐chewers. Together, our findings provide important insights into the association of HGF/c‐Met and the SDF1α/CXCR4 axis in lymph node metastasis and to an aetiological link with the habit of chewing tobacco.     

Neutralizing peripheral circulating IL1β slows the progression of ALS in a lentivirus‐infected OPTNE478G mouse model

BackgroundAmyotrophic lateral sclerosis (ALS) is irreversible and fatal within 3–5 years, with limited options for treatment. It is imperative to develop a symptom‐based treatment that may increase the survival of ALS patients and improve their quality of life. Inflammation status, especially elevated interleukin 1β (IL1β), has been reported to play a critical role in ALS progression. Our study determined that neutralizing circulating IL1β slows down the progression of ALS in an ALS mouse model.MethodsThe ALS mouse model was developed by microinjection of lentivirus‐carrying OPTN^E478G (optineurin, a mutation from ALS patients) into the intra‐motor cortex of mice. Peripheral circulating IL1β was neutralized by injecting anti‐IL1β antibody into the tail vein. Enzyme‐linked immunosorbent assay (ELISA) and real‐time polymerase chain reaction (RT‐PCR) were carried out to determine the protein and gene expression levels of IL1β. TUNEL assay was used to assess the neural cell death. Immunofluorescent staining of MAP2 and CASP3 was accomplished to evaluate neuronal cell apoptosis. Glial fibrillary acidic protein staining was performed to analyze the number of astrocytes. Rotarod test, grip strength test, balance beam test, and footprint test were conducted to assess the locomotive function after anti‐IL1β treatment.ResultsThe model revealed that neuroinflammation contributes to ALS progression. ALS mice exhibited elevated neuroinflammation and IL1β secretion. After anti‐IL1β treatment, ALS mice revealed decreased neural cell death and astrogliosis and gained improved muscle strength and motor ability.ConclusionsBlocking IL1β is a promising strategy to slow down the progression of ALS.     

Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer's disease

Changes in microglia function are involved in Alzheimer's disease (AD) for which ageing is the major risk factor. We evaluated microglial cell process morphologies and their gray matter coverage (arborized area) during ageing and in the presence and absence of AD pathology in autopsied human neocortex. Microglial cell processes were reduced in length, showed less branching and reduced arborized area with aging (case range 52–98 years). This occurred during normal ageing and without microglia dystrophy or changes in cell density. There was a larger reduction in process length and arborized area in AD compared to aged‐matched control microglia. In AD cases, on average, 49%–64% of microglia had discontinuous and/or punctate Iba1 labeled processes instead of continuous Iba1 distribution. Up to 16% of aged‐matched control microglia displayed discontinuous or punctate features. There was no change in the density of microglial cell bodies in gray matter during ageing or AD. This demonstrates that human microglia show progressive cell process retraction without cell loss during ageing. Additional changes in microglia occur with AD including Iba1 protein puncta and discontinuity. We suggest that reduced microglial arborized area may be an aging‐related correlate of AD in humans. These variations in microglial cells during ageing and in AD could reflect changes in neural‐glial interactions which are emerging as key to mechanisms involved in ageing and neurodegenerative disease.