Low-grade systemic inflammation stimulates microglial turnover and accelerates the onset of Alzheimer's-like pathology.

Several in vivo studies have shown that systemic inflammation, mimicked by LPS, triggers an inflammatory response in the CNS, driven by microglia, characterized by an increase in inflammatory cytokines and associated sickness behavior. However, most studies induce relatively high systemic inflammation, not directly compared with the more common low-grade inflammatory events experienced in humans during the life course. Using mice, we investigated the effects of low-grade systemic inflammation during an otherwise healthy early life, and how this may precondition the onset and severity of Alzheimer's disease (AD)-like pathology. Our results indicate that low-grade systemic inflammation induces sub-threshold brain inflammation and promotes microglial proliferation driven by the CSF1R pathway, contrary to the effects caused by high systemic inflammation. In addition, repeated systemic challenges with low-grade LPS induce disease-associated microglia. Finally, using an inducible model of AD-like pathology (Line 102 mice), we observed that preconditioning with repeated doses of low-grade systemic inflammation, prior to APP induction, promotes a detrimental effect later in life, leading to an increase in Aß accumulation and disease-associated microglia. These results support the notion that episodic low-grade systemic inflammation has the potential to influence the onset and severity of age-related neurological disorders, such as AD.

Novel combination of Olesoxime/Resveratrol-encapsulated exosomes to improve cognitive function by targeting amyloid ß-induced Alzheimer's disease: investigation on in vitro and in vivo model.

Alzheimer's disease (AD) is a fatal neurological illness that worsens with time. Preventing the aggregate formation of amyloid beta protein is a promising approach to treat Alzheimer's disease. This article describes an amiable procedure for the synthesis of Olesoxime-Resveratrol (OLX-RSV) encapsulated in exosomes. By suppressing Aß1-42 aggregation and crossing the blood-brain barrier also known as BBB after intravenous treatment without resulting in any discernible damage, the nanocomposite demonstrated good biocompatibility. A variety of characterization technique including particle size, TEM, and in vitro drug release experiments, were used to characterize the exosomes. Human Neuroblastoma (SHSY5Y) cells were used to test the cytotoxicity and viability of cells of the formulation using the Cell Counting Kit-8 assay. The prepared OLX-RSV-loaded exosomes were tested for their ability to suppress Aß1-42 in SHSY5Y Cells by analyzing the amyloid samples using CD spectra. The effects of apoptosis on Human neuroblastoma cells were studied using cytofluorometry. The parameters of SOD, caspase-3 and the ability to scavenge reactive oxygen species (ROS) were also evaluated. The behavioral outcomes of Morris water maze test demonstrated that OLX-RSV-loaded exosomes significantly enhanced the APP/PS1 mice's capacity to learn and remember spatial cues. Therefore, we hypothesized that OLX-RSV-loaded exosomes could be a useful and efficient method in the treatment of AD.

Cognitive status and its risk factors in patients with hypertension and diabetes in a low-income rural area of China: A cross-sectional study.

OBJECTIVES: The proportion of older people with dementia in China is gradually increasing with the increase in the aging population over recent years. Hypertension and diabetes are common non-communicable diseases among rural populations in China. However, it remains unclear whether these conditions affect the occurrence and development of cognitive impairment as there is limited research on cognitive status and its risk factors among residents of rural areas. METHODS: A multi-stage stratified cluster random sampling method was used to select 5400 participants from rural permanent residents. A self-designed structured questionnaire was used to investigate demographic data of the participants. Cognitive function was assessed using the Montreal Cognitive Function Assessment Scale (MoCA). The results were analyzed using chi-square test, ANOVA and multiple linear regression analysis. RESULTS: A total of 5028 participants returned the survey, giving a response rate of 93.1%. Higher education (odds ratio (OR) = 3.2, 95% confidence interval (CI) 2.87-3.54, p < 0.001), higher income (OR = 1.61, 95% CI 1.16-2.07, p < 0.001), and dietary control (OR = 0.66, 95%CI 0.34-0.98, p < 0.001) were protective factors. A visual representation of the relationship between annual income and MoCA score showed an inverted U-curve, the group with an annual income of 6000-7999 RMB had a maximum OR of 1.93 (95%CI 0.12-2.74, p < 0.001). While difficulty in maintaining sleep were risk factors for cognitive impairment (OR = -2.28, 95% CI-4.18-0.39, p = 0.018). CONCLUSIONS: Participants with middle incomes had better cognitive status than those with the highest incomes. Higher education, proper diet control and good sleep are beneficial to the cognitive status of residents in rural areas.

Exercise improves cognitive dysfunction and neuroinflammation in mice through Histone H3 lactylation in microglia.

BACKGROUND: Exercise is postulated to be a promising non-pharmacological intervention for the improvement of neurodegenerative disease pathology. However, the mechanism of beneficial effects of exercise on the brain remains to be further explored. In this study, we investigated the effect of an exercise-induced metabolite, lactate, on the microglia phenotype and its association with learning and memory. RESULTS: Microglia were hyperactivated in the brains of AlCl3/D-gal-treated mice, which was associated with cognitive decline. Running exercise ameliorated the hyperactivation and increased the anti-inflammatory/reparative phenotype of microglia and improved cognition. Mice were injected intraperitoneally with sodium lactate (NaLA) had similar beneficial effects as that of exercise training. Exogenous NaLA addition to cultured BV2 cells promoted their transition from a pro-inflammatory to a reparative phenotype. CONCLUSION: The elevated lactate acted as an "accelerator" of the endogenous "lactate timer" in microglia promoting this transition of microglia polarization balance through lactylation. These findings demonstrate that exercise-induced lactate accelerates the phenotypic transition of microglia, which plays a key role in reducing neuroinflammation and improving cognitive function.

Brain-Airway Interactions in Asthma.

Asthma and brain interactions have long been appreciated and initially centered on increased anxiety and depression. Epidemiology studies have shown that early life stressors and situational disadvantages are risk factors for asthma. Conversely, the presence of asthma is a risk for mood and anxiety disorders, thus indicating a bidirectional effect between asthma and brain-related health. To substantiate asthma-brain interactions, validated instruments indicate and elucidate that communication likely exists between asthma and the brain. For example, provocation of an asthmatic response with an allergen challenge modulates how the brain responds to emotion-laden information. As detected by imaging studies, emotion-related brain activation is associated with generating airway inflammation. However, the specific mediators and processes mediating airway communication with the brain have yet to be established.Systemic inflammation is also associated with asthma and can affect other organ systems such as the cardiovascular system and the brain. Epidemiology studies have shown that asthma is a risk factor for dementia and Alzheimer's disease. In support of the importance of asthma as a risk factor for impaired cognitive function, imaging studies have shown changes to the white matter of the brain in asthma patients that resemble neuroinflammation changes seen in Alzheimer's disease and other neurodegenerative diseases. Therefore, bidirectional links between asthma and the brain exist with an important next research step to define asthma-brain interactions linked to neurodegeneration and dementia and explore whether treatments directed toward asthma-related inflammation can prevent the deleterious effects of asthma on brain health.

A kinetic scheme to examine the role of glial cells in the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder that leads to severe impairments in cognitive functions including memory and learning. An improved kinetic model is proposed here to understand the pathogenesis of AD in particular the role of glial cells in the presence of amyloid plaques and neurofibrillary tangles (NFTs). The kinetic model describes the production of activated microglia and astroglia. It involves two rate equations and incorporates the dual role of these glial cells which can function as neuroprotective and as neurotoxic cells. Examination of the steady state solutions of the model predicts an increase in population of these glial cells as (AD) progresses, and that this continues to increase linearly even after the amyloid population has reached a plateau.This is in agreement with experimental data. Limiting AD to the effect of amyloid peptides alone is incorrect and the role of neurofibrillary tangles, clearance rate of dead neurons and neuroinflammation from glial cells are vital and must be included in understanding the pathogenesis of AD. The study shows that increasing the clearance of dead neurons and use of any method to deactivate the glial cells will diminish the progression of AD.

Aß-Induced Alterations in Membrane Lipids Occur before Synaptic Loss Appears.

Loss of active synapses and alterations in membrane lipids are crucial events in physiological aging as well as in neurodegenerative disorders. Both are related to the abnormal aggregation of amyloid-beta (Aß) species, generally known as amyloidosis. There are two major known human Aß species: Aß(1-40) and Aß(1-42). However, which of these species have more influence on active synapses and membrane lipids is still poorly understood. Additionally, the time-dependent effect of Aß species on alterations in membrane lipids of hippocampal neurones and glial cells remains unknown. Therefore, our study contributes to a better understanding of the role of Aß species in the loss of active synapses and the dysregulation of membrane lipids in vitro. We showed that Aß(1-40) or Aß(1-42) treatment influences membrane lipids before synaptic loss appears and that the loss of active synapses is not dependent on the Aß species. Our lipidomic data analysis showed early changes in specific lipid classes such as sphingolipid and glycerophospholipid neurones. Our results underscore the potential role of lipids as a possible early diagnostic biomarker in amyloidosis-related disorders.

Exploring reported genes of microglia RNA-sequencing data: Uses and considerations.

The advent of RNA-sequencing techniques has made it possible to generate large, unbiased gene expression datasets of tissues and cell types. Several studies describing gene expression data of microglia from Alzheimer's disease or multiple sclerosis have been published, aiming to generate more insight into the role of microglia in these neurological diseases. Though the raw sequencing data are often deposited in open access databases, the most accessible source of data for scientists is what is reported in published manuscripts. We observed a relatively limited overlap in reported differentially expressed genes between various microglia RNA-sequencing studies from multiple sclerosis or Alzheimer's diseases. It was clear that differences in experimental set up influenced the number of overlapping reported genes. However, even when the experimental set up was very similar, we observed that overlap in reported genes could be low. We identified that papers reporting large numbers of differentially expressed microglial genes generally showed higher overlap with other papers. In addition, though the pathology present within the tissue used for sequencing can greatly influence microglia gene expression, often the pathology present in samples used for sequencing was underreported, leaving it difficult to assess the data. Whereas reanalyzing every raw dataset could reduce the variation that contributes to the observed limited overlap in reported genes, this is not feasible for labs without (access to) bioinformatic expertise. In this study, we thus provide an overview of data present in manuscripts and their supplementary files and how these data can be interpreted.

Utilizing magnetic resonance techniques to study membrane interactions of amyloid peptides.

Alzheimer's disease (AD) is a common neurodegenerative condition that involves the extracellular accumulation of amyloid plaques predominantly consisting of Aß peptide aggregates. The amyloid plaques and soluble oligomeric species of Aß are believed to be the major cause of synaptic dysfunction in AD brain and their cytotoxic mechanisms have been proposed to involve interactions with cell membranes. In this review, we discuss our solid-state nuclear magnetic resonance (ssNMR) studies of Aß interactions with model membranes.

The Box Task: A novel tool to differentiate the primary progressive aphasias.

OBJECTIVE: Differentiating the primary progressive aphasia (PPA) variants in clinical settings remains complex and challenging, especially for the logopenic (lv-PPA) and non-fluent variants (nfv-PPA). Recent studies suggest that visuospatial memory is more compromised in lv-PPA than in nfv-PPA and is relatively spared in the semantic variant (sv-PPA). Accordingly, assessment of visuospatial memory performance may assist in the differential diagnosis of PPA variants. Here, we investigated the utility of a novel computerised visuospatial working memory test-the Box Task-to differentiate the three PPA variants and typical Alzheimer's disease (AD). METHODS: Eighteen lv-PPA, 14 nfv-PPA, 23 sv-PPA, 33 AD patients, and 32 healthy controls matched for age and education were recruited. All participants completed the computerised Box Task and WMS-III Spatial Span as measures of visuospatial working memory. RESULTS: The lv-PPA group made significantly more Box Task between-search errors than nfv-PPA, sv-PPA and control groups. The AD group, however, displayed the greatest impairments on this measure relative to the PPA variants. Logistic regression analyses in lv-PPA and nfv-PPA demonstrated that the combination of Box Task between-search error variables (i.e., 4- and 6-box levels) could correctly classify 72% of lv-PPA patients and nearly 79% of nfv-PPA patients. Area under the receiver operator characteristics curve (AUC) analyses revealed the Box Task was more sensitive than Spatial Span at differentiating lv-PPA from nfv-PPA. CONCLUSIONS: Our findings suggest that a simple, computerised measure of visuospatial working memory-the Box Task-shows potential diagnostic utility in differentiating lv-PPA from the other PPA variants.

Derivatives of montanine-type alkaloids and their implication for the treatment of Alzheimer's disease: Synthesis, biological activity and in silico study.

Alzheimers disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC50 < 5 µM), and one analog, 1v, showed selective hBuChE inhibition activity (IC50 = 1.73 ± 0.05 µM). The prediction of CNS availability, as disclosed by the BBB score, suggests that the active compounds in this survey should be able pass through the blood-brain barrier (BBB). Cytotoxicity screening and docking studies were carried out for the two most pronounced cholinesterase inhibitors, 1n and 1v.

Histamine H3 receptor antagonists with peptidomimetic (keto)piperazine structures to inhibit Aß oligomerisation.

Alzheimers disease (AD) is the most prominent neurodegenerative disorder with high medical need. Protein-protein-interactions (PPI) interactions have a critical role in AD where ß-amyloid structures (Aß) build toxic oligomers. Design of disease modifying multi target directed ligand (MTDL) has been performed, which disable PPI on the one hand and on the other hand, act as procognitive antagonists at the histamine H3 receptor (H3R). The synthetized compounds are structurally based on peptidomimetic amino acid-like structures mainly as keto, diketo-, or acyl variations of a piperazine moiety connected to an H3R pharmacophore. Most of them showed low nanomolar affinities at H3R and some with promising affinity to Aß-monomers. The structure-activity relationships (SAR) described offer new possibilities for MTDL with an optimized profile combining symptomatic and potential causal therapeutic approaches in AD.

APOE alters glucose flux through central carbon pathways in astrocytes.

The Apolipoprotein E (APOE) gene is a major genetic risk factor associated with Alzheimer's disease (AD). APOE encodes for three main isoforms in humans (E2, E3, and E4). Homozygous E4 individuals have more than a 10-fold higher risk for developing late-onset AD, while E2 carriers are protected. A hallmark of AD is a reduction in cerebral glucose metabolism, alluding to a strong metabolic component in disease onset and progression. Interestingly, E4 individuals display a similar regional pattern of cerebral glucose hypometabolism decades prior to disease onset. Mapping this metabolic landscape may help elucidate the underlying biological mechanism of APOE-associated risk for AD. Efficient metabolic coupling of neurons and glia is necessary for proper neuronal function, and disruption in glial energy distribution has been proposed to contribute to neuronal cell death and AD pathology. One important function of astrocytes - canonically the primary source of apolipoprotein E in the brain - is to provide metabolic substrates (lactate, lipids, amino acids and neurotransmitters) to neurons. Here we investigate the effects of APOE on astrocyte glucose metabolism in vitro utilizing scintillation proximity assays, stable isotope tracer metabolomics, and gene expression analyses. Glucose uptake is impaired in E4 astrocytes relative to E2 or E3 with specific alterations in central carbon metabolism. Using stable isotope labeled glucose [U-13C] allowed analyses of astrocyte-specific deep metabolic networks affected by APOE, and provided insight to the effects downstream of glucose uptake. Enrichment of 13C in early steps of glycolysis was lowest in E4 astrocytes (highest in E2), while synthesis of lactate from glucose was highest in E4 astrocytes (lowest in E2). We observed an increase in glucose flux through the pentose phosphate pathway (PPP), with downstream increases in gluconeogenesis, lipid, and de novo nucleotide biosynthesis in E4 astrocytes. There was also a marked increase in 13C enrichment in the TCA cycle of E4 astrocytes - whose substrates were also incorporated into biosynthetic pathways at a higher rate. Pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH) are the two main enzymes controlling pyruvate entry to the TCA cycle. PC gene expression is increased in E4 astrocytes and the activity relative to PDH was also increased, compared to E2 or E3. Decreased enrichment in the TCA cycle of E2 and E3 astrocytes is suggestive of increased oxidation and non-glucose derived anaplerosis, which could be fueling mitochondrial ATP production. Conversely, E4 astrocytes appear to increase carbon flux into the TCA cycle to fuel cataplerosis. Together, these data demonstrate clear APOE isoform-specific effects on glucose utilization in astrocytes, including E4-associated increases in lactate synthesis, PPP flux, and de novo biosynthesis pathways.

Microglial phagocytosis in aging and Alzheimer's disease.

Microglia are the innate immune cells of the brain, which maintain homeostasis by constantly scanning and surveying the environment with their highly ramified processes. In order to exert this function, they need to phagocytose synapses as well as debris and dead cells, a process that is further amplified in pathological conditions. Importantly, it has been shown that microglia phagocytic capacity is altered in the course of neurodegenerative disease, for which aging is one of the highest risk factors. Thus, understanding how phagocytosis is impaired during aging is a priority for future research. Advances in this area are expected to significantly contribute to our understanding of normal cognition during aging, as well as changes that take place in age-associated neurodegenerative diseases. In this review, we will summarize the current knowledge on how phagocytosis is executed and affected by aging or in age-associated neurological disorders, such as Alzheimer's disease (AD). Furthermore, we will summarize both protective and deleterious consequences of altered phagocytosis in AD and where relevant in other neurodegenerative diseases.

How to diagnose difficult white matter disorders.

Genetic and acquired disorders of white matter comprise a diverse group of conditions, with often overlapping clinical and radiological findings. Patients present with a variable combination of cognitive impairment, ataxia, spasticity or movement disorders, among others. There are many genetic causes, and the route to diagnosis involves comprehensive clinical assessment, radiological expertise, metabolic investigations and finally genetic studies. It is essential not to miss the treatable acquired causes. In this review, we present a practical approach to investigating patients with acquired and genetic disorders of white matter, based on the experience of a large international referral centre. We present a guide for clinicians, including pitfalls of testing, clinical pearls and where to seek advice.

The effect of early growth response 1 on levels of Amyloid-ß 40 peptide in U87MG cells.

A recent study has shown that early growth response 1 (EGR1) plays a critical role in the ß-amyloid cascade and tau hypotheses. In addition, evidence has suggested that EGR1 can regulate levels of amyloid-beta peptides, key molecules in the pathogenesis of Alzheimer's disease (AD). However, whether EGR1 is a deleterious or protective factor in the AD is still controversial. In this present study, we constructed an overexpression plasmid, CMV-EGFP-EGR1-Kanamycin, and transfected it into U87MG cells to investigate the effects of EGR1 expression on amyloid-ß (1-40) peptide (Aß40) levels. U87MG cells transfected by CMV-EGFP-EGR1-Kanamycin and CMV-EGFP-Kanamycin were assigned, respectively, to experimental and control groups. Fluorescence microscopy was used to observe transfection efficiencies of the plasmids after 6 hours. EGR1 messenger RNA levels were measured by quantitative reverse transcription polymerase chain reaction. Aß40 secretion was analyzed by enzyme-linked immunosorbent assay. Expression of the amyloid precursor protein, beta-secretase enzyme, and presenilin 1 proteins were analyzed by Western blot analysis. The results showed that EGR1 overexpression increased Aß40 secretion in vitro, possibly through increasing BACE1 expression. Based on these results, EGR1 might be a promising therapeutic target for the AD.

Combination of schisandrin and nootkatone exerts neuroprotective effect in Alzheimer's disease mice model.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases which seriously affect the quality of life of the elderly. Schisandrin (SCH) and nootkatone (NKT) are the two marked active components in ASHP. In this study, the effects of Alpinia oxyphylla-Schisandra chinensis herb pair (ASHP) as well as its bioactive components on cognitive deficiency and dementia were revealed via Aß1-42-induced AD in mouse. Morris water maze test showed that acute administration of ASHP and SCH + NKT treatments had higher discrimination index in the object recognition task, more quadrant dwell time and shorter escape latency compared with those in the Morris water maze. The levels of TNF-α, IL-1ß and IL-6 were decreased after ASHP and SCH + NKT treatment. The inflammatory response was attenuated by inhibiting TLR4/ NF-κB/ NLRP3 pathway. In addition, ASHP and SCH + NKT treatments significantly restored the activities of superoxide dismutase (SOD), glutathione S-transferase (GST), cyclooxygenase-2 (COX-2), total antioxidant capacity (T-AOC) and inducible nitric oxide syntheses (iNOS), and the levels of glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO). The histopathological changes of hippocampus were noticeably improved after ASHP and SCH + NKT treatments. These findings demonstrate that ASHP as well as its bioactive components exerted a protective effects on cognitive disorder, inflammatory reaction and oxidative stress.

Strength and Similarity Guided Group-level Brain Functional Network Construction for MCI Diagnosis.

Sparse representation-based brain functional network modeling often results in large inter-subject variability in the network structure. This could reduce the statistical power in group comparison, or even deteriorate the generalization capability of the individualized diagnosis of brain diseases. Although group sparse representation (GSR) can alleviate such a limitation by increasing network similarity across subjects, it could, in turn, fail in providing satisfactory separability between the subjects from different groups (e.g., patients vs. controls). In this study, we propose to integrate individual functional connectivity (FC) information into the GSR-based network construction framework to achieve higher between-group separability while maintaining the merit of within-group consistency. Our method was based on an observation that the subjects from the same group have generally more similar FC patterns than those from different groups. To this end, we propose our new method, namely "strength and similarity guided GSR (SSGSR)", which exploits both BOLD signal temporal correlation-based "low-order" FC (LOFC) and inter-subject LOFC-profile similarity-based "high-order" FC (HOFC) as two priors to jointly guide the GSR-based network modeling. Extensive experimental comparisons are carried out, with the rs-fMRI data from mild cognitive impairment (MCI) subjects and healthy controls, between the proposed algorithm and other state-of-the-art brain network modeling approaches. Individualized MCI identification results show that our method could achieve a balance between the individually consistent brain functional network construction and the adequately maintained inter-group brain functional network distinctions, thus leading to a more accurate classification result. Our method also provides a promising and generalized solution for the future connectome-based individualized diagnosis of brain disease.

Selective Degeneration of Entorhinal-CA1 Synapses in Alzheimer's Disease via Activation of DAPK1.

Excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) form functional excitatory synapses with CA1 parvalbumin inhibitory neurons (CA1PV) and undergo selective degeneration in the early stages of Alzheimer's disease (AD). Here, we show that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPN of AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PV synaptic loss and improves spatial learning and memory in AD mice. This study demonstrates that activation of DAPK1 in ECIIPN contributes to a memory loss in AD and hence warrants a promising target for the treatment of AD. SIGNIFICANCE STATEMENT: Our recent study reported that excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) target to CA1 parvalbumin-type inhibitory neurons (CA1PV) at a direct pathway and are one of the most vulnerable brain cells that are selectively degenerated in the early stage of Alzheimer's disease (AD). Our present study shows that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPN of AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PV synaptic loss and improves spatial learning and memory in the early stage of AD. These data not only demonstrate a crucial molecular event for synaptic degeneration but also provide a therapeutic target for the treatment of AD.

Inhibition of glial hemichannels by boldine treatment reduces neuronal suffering in a murine model of Alzheimer's disease.

The contribution of reactive gliosis to the pathological phenotype of Alzheimer's disease (AD) opened the way for therapeutic strategies targeting glial cells instead of neurons. In such context, connexin hemichannels were proposed recently as potential targets since neuronal suffering is alleviated when connexin expression is genetically suppressed in astrocytes of a murine model of AD. Here, we show that boldine, an alkaloid from the boldo tree, inhibited hemichannel activity in astrocytes and microglia without affecting gap junctional communication in culture and acute hippocampal slices. Long-term oral administration of boldine in AD mice prevented the increase in glial hemichannel activity, astrocytic Ca2+ signal, ATP and glutamate release and alleviated hippocampal neuronal suffering. These findings highlight the important pathological role of hemichannels in AD mice. The neuroprotective effect of boldine treatment might provide the basis for future pharmacological strategies that target glial hemichannels to reduce neuronal damage in neurodegenerative diseases.