Amyloid-ß-activated microglia can induce compound proteinopathies.

Neuropathological features of Alzheimer's disease include amyloid plaques, neurofibrillary tangles and Lewy bodies, with the former preceding the latter two. However, it is not fully understood how these compound proteinopathies are interconnected. Here, we show that transplantation of amyloid-ß oligomer-activated microglia into the striatum of naïve mice was sufficient to generate all the features of Alzheimer's disease, including widespread tauopathy and synucleinopathy, gliosis, neuroinflammation, synapse loss, neuronal death, and cognitive and motor deficits. These pathological features were eliminated by microglia depletion and anti-inflammatory drug administration. Our results suggest the crucial roles of microglia-driven inflammation in development of mixed pathology. This study provides not only mechanistic insights into amyloid-ß oligomer-triggered proteinopathies but also a novel animal model recapitulating the salient features of Alzheimer's disease.

AP collagen peptides (APCPs) promote hair growth by activating the GSK-3ß/ß-catenin pathway and improve hair condition.

AP collagen peptides (APCPs) are enzymatically decomposed collagen peptides that contain tri-peptides such as glycine-proline-hydroxyproline. We found that APCPs increased the proliferation of both human dermal papilla cells (hDPCs) and human outer root sheath cells (hORSCs). APCPs also stimulated the secretion of several growth factors, including IGFBP-6, PDGF-AB, PIGF and VEGF in hDPCs. Moreover, APCPs enhanced the phosphorylation of Akt(Ser473), GSK-3ß(Ser9) and ß-catenin(Ser675), indicating the activation of the GSK-3ß/ß-catenin signalling pathway. Ex vivo culture of human hair follicles (hHFs) tissue and in vivo patch assay revealed that APCPs promoted the elongation of hHFs and the induction of new hair shafts. In a mouse model, APCPs significantly promoted the transition from telogen to anagen phase and prolonged anagen phase, resulting in increased hair growth. APCPs also improved the thickness, amino acid content (cystine and methionine) and roughness of mouse hair. Taken together, these findings demonstrate that APCPs accelerate hair growth and contribute to overall hair health. Therefore, APCPs have the potential to be utilized as a food supplement and ingredient for preventing hair loss and maintaining hair health.

Efficacy and safety of a home-use handheld multi-energy-based device for skin rejuvenation: clinical, ex vivo, and histological studies.

Alongside increases in the average lifespan and a growing interest in anti-aging remedies, the demand for at-home skincare devices is rapidly expanding in the cosmetic market. This study aimed to assess the safety and efficacy of a novel home-use handheld multi-energy-based device for skin rejuvenation that simultaneously emits low level light, low-dose radiofrequency, low-energy microcurrent, and low-intensity ultrasonic wave. This prospective, randomized, split-face clinical trial enrolled 36 healthy Korean women. After 8 weeks of device use, parameters associated with skin aging were assessed. Additionally, a preliminary ex vivo study and skin biopsy following device use were performed to confirm safety and efficiency of the device. Parameters associated with skin aging including skin hydration, elasticity, roughness, skin pore size, and eye wrinkle volume showed significant improvements after 8 weeks of the device use, relative to baseline measurements and the control side. No adverse effects were observed during the follow-up period. Results of ex vivo and in vivo skin tissue studies correlated with clinical findings, which showed an increase in the expression of type 1 collagen and a decrease in the expression of matrix metalloproteinase-1, which is related to the skin aging phenotype. The expression of loricrin and involucrin, major components of the epidermal skin barrier, also increased after the use of the device. Multi-energy-based device is effective for skin rejuvenation and tolerable, without any considerable adverse effects.

Quantitative Analysis of Hair Luster in a Novel Ultraviolet-Irradiated Mouse Model.

Hair luster is a key attribute of healthy hair and a crucial aspect of cosmetic appeal, reflecting the overall health and vitality of hair. Despite its significance, the advancement of therapeutic strategies for hair luster enhancement have been limited due to the absence of an effective experimental model. This study aimed to establish a novel animal model to assess hair gloss, employing ultraviolet (UV) irradiation on C57BL/6 mice. Specifically, UVB irradiation was meticulously applied to the shaved skin of these mice, simulating conditions that typically lead to hair luster loss in humans. The regrowth and characteristics of the hair were evaluated using a dual approach: an Investigator's Global Assessment (IGA) scale for subjective assessment and an image-based pixel-count method for objective quantification. These methods provided a comprehensive understanding of the changes in hair quality post-irradiation. To explore the potential reversibility of hair luster changes, oral minoxidil was administered, a treatment known for its effects on hair growth and texture. Further, to gain insights into the underlying biological mechanisms, bulk RNA transcriptomic analysis of skin tissue was conducted. This analysis revealed significant alterations in the expression of keratin-associated protein (KRTAP) genes, suggesting modifications in hair keratin crosslinking due to UV exposure. These changes are crucial in understanding the molecular dynamics affecting hair luster. The development of this new mouse model is a significant advancement in hair care research. It not only facilitates the evaluation of hair luster in a controlled setting but also opens avenues for the research and development of innovative therapeutic strategies. This model holds promise for the formulation of more effective hair care products and treatments, potentially revolutionizing the approach towards managing and enhancing hair luster.

Efficacy and safety of persimmon leaf formulated with green tea and sophora fruit extracts (BLH308) on hair growth: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Recent research suggests that persimmon leaf extract (PLE) has an effect on inflammatory skin diseases. Previously, PLE is revealed to inhibit not only nitric oxide production but also inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression levels in mouse macrophages in vitro. Moreover, it significantly reduced IL-6 production and 5α-reductase expression in human follicle dermal papilla cells (HFDPCs). This study aimed to determine whether the PLE-containing BLH308 complex improves hair growth in clinical trials. MATERIALS AND METHODS: A total of 88 participants were recruited, and were instructed to orally take BLH308 or the placebo twice a day for 24 weeks. The mean age of the test group was 38.52 ± 7.98 years and that of placebo group was 38.98 ± 8.80 years. The study was conducted for 24 weeks, and hair density, thickness, and gloss were evaluated. All participants completed a satisfaction survey questionnaire. RESULTS: The test group showed significantly increased hair density and hair diameter at week 24 compared with the placebo group (p = 0.0015 and p = 0.0001, respectively). Although not statistically significant, the degree of gloss also showed higher improvement in the test group compared to the placebo group. CONCLUSIONS: Our data demonstrated that oral consumption of the BLH308 complex containing PLE significantly increased hair density and thickness compared to the placebo group, showing its possible role in promoting hair growth.

Age-related changes in scalp biophysical parameters: A comparative analysis of the 20s and 50s age groups.

BACKGROUND: Age-related changes in scalp parameters affect hair quality and scalp condition. However, detailed data on biophysical parameters of the scalp across age groups remain scarce. We aimed to investigate the differences in scalp parameters between individuals in their 20s and 50s and analyze their sex-specific variations. MATERIALS AND METHODS: Two hundred participants (160 women and 40 men) were equally divided into 20s and 50s age groups. Biophysical parameters of the scalp, including elasticity, pH, trans-epidermal water loss (TEWL), sebum production, desquamation, firmness, redness, and yellowness, were measured in the vertex, occipital, and temporal regions. Hair density and thickness were measured in the temporal region. The accumulation of advanced glycation end products (AGEs) in the skin was noninvasively measured in a subset of 60 women. RESULTS: Skin firmness and redness increased with age in women, whereas yellowness increased with age in both sexes. Sebum production and pH levels were significantly lower in the 50s age group than in the 20s age group, particularly in women. TEWL was lower in men in their 50s than in those in their 20s, particularly in the occipital region. A significant reduction in hair density was observed in the 50s age group in both sexes. AGE accumulation in the skin increased with age and was correlated with scalp skin yellowness. CONCLUSION: Age-related changes in scalp parameters have important implications for hair health and scalp condition. These findings emphasize the importance of considering age and sex when developing hair care strategies.

The QPLEX™ Plus Assay Kit for the Early Clinical Diagnosis of Alzheimer's Disease.

We recently developed a multiplex diagnostic kit, QPLEX™ Alz plus assay kit, which captures amyloid-ß1-40, galectin-3 binding protein, angiotensin-converting enzyme, and periostin simultaneously using microliters of peripheral blood and utilizes an optimized algorithm for screening Alzheimer's disease (AD) by correlating with cerebral amyloid deposition. Owing to the demand for early AD detection, we investigate the potential of our kit for the early clinical diagnosis of AD. A total of 1395 participants were recruited, and their blood samples were analyzed with the QPLEX™ kit. The average of QPLEX™ algorithm values in each group increased gradually in the order of the clinical progression continuum of AD: cognitively normal (0.382 ± 0.150), subjective cognitive decline (0.452 ± 0.130), mild cognitive impairment (0.484 ± 0.129), and AD (0.513 ± 0.136). The algorithm values between each group showed statistically significant differences among groups divided by Mini-Mental State Examination and Clinical Dementia Rating. The QPLEX™ algorithm values could be used to distinguish the clinical continuum of AD or cognitive function. Because blood-based diagnosis is more accessible, convenient, and cost- and time-effective than cerebral spinal fluid or positron emission tomography imaging-based diagnosis, the QPLEX™ kit can potentially be used for health checkups and the early clinical diagnosis of AD.

An Exploratory In Vivo Study on the Effect of Annurca Apple Extract on Hair Growth in Mice.

Hair loss is an important problem affecting the quality of life in modern society. Recent studies show that Annurca apple extract (AAE), enriched in procyanidin B2 and nutraceuticals, promotes hair growth and induces keratin production. In this study, we investigated the effects of AAE by orally administering AAE in six-week-old C57BL/6 mice once a day for 21 d. We observed improvement in hair length, thickness, weight, and density. The gene expression of two growth factors related to hair growth, vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 7 (FGF-7), were measured using the quantitative reverse transcription polymerase chain reaction (qRT-PCR). The gene expression of both VEGFA and FGF-7 increased significantly in the AAE-treated group. Additionally, treatment with AAE suppressed the gene expression of type 1 5α-reductase. Histological analysis showed that protein levels of cytokeratin 5 and 10 were increased in the skin tissues of the AAE-treated group. These results suggest that AAE might be a potential therapeutic natural product that prevents hair loss by promoting the expression of hair growth-related factors.

Neurotoxicity of phenylalanine on human iPSC-derived cerebral organoids.

Phenylketonuria (PKU) is a common genetic metabolic disorder that causes phenylalanine accumulation in the blood. The most serious symptoms are related to the brain, as intellectual disability, seizure, and microcephaly are commonly found in poorly treated PKU patients and the babies of maternal PKU. However, the mechanism of hyperphenylalaninemia on human neurodevelopment is still unclear. Here we utilized human induced pluripotent stem cell (iPSC)-derived cerebral organoids to investigate the neurotoxicity of hyperphenylalaninemia. Cerebral organoids at days 40 or 100 were treated with different concentrations of phenylalanine for 5 days. After phenylalanine treatments, the cerebral organoids displayed alterations in organoid size, induction of apoptosis, and depletion of neural progenitor cells. However, phenylalanine did not have an impact on neurons and glia, including astrocytes, immature oligodendrocytes, and mature oligodendrocytes. Remarkably, a reduction in the thickness of the cortical rosettes and a decrease in myelination at the intermediate zone were inspected with the elevated phenylalanine concentrations. RNA-seq of phenylalanine-treated organoids revealed that gene sets related to apoptosis, p53 signaling pathway, and TNF signaling pathway via NF-kB were enriched in upregulated genes, while those related to cell cycle and amino acid metabolism were enriched in downregulated genes. In addition, there were several microcephaly disease genes, such as ASPM, LMNB1, and CENPE, ranked at the top of the downregulated genes. These findings indicate that phenylalanine exposure may contribute to microcephaly, abnormal cortical expansion, and myelination lesions in the developing human brain.

Effect of a Topical Collagen Tripeptide on Antiaging and Inhibition of Glycation of the Skin: A Pilot Study.

The glycation process has been recognized as one of the critical parameters that accelerate signs of skin aging, especially in skin exposed to environment factors, such as ultraviolet radiation. Although previous studies showed the anti-inflammatory and antiaging properties of the hydrolyzed collagen tripeptide (CTP), its exact mechanism is not fully understood. Therefore, in this study, we sought to investigate the effect of a topical CTP on facial skin. Our group designed a 4 week prospective, single-arm study of 22 Asian women who applied topical CTP. We observed significant improvements in skin wrinkles, elasticity, and density with a reduction in skin accumulation of advanced glycated end products (AGEs) at week 4 without any adverse effects. The in vitro study revealed a preventive effect of the topical CTP on the accumulation of AGEs, denatured collagen production, and reactive oxygen species in dermal fibroblasts. Moreover, treatment with the CTP decreased induction of matrix metalloproteinases while increasing the collagen 1 level. These results suggest that the application of a topical CTP might improve clinical aging phenotypes via the inhibition of glycation and oxidative stress, leading to a delay in cellular aging.

Stress-associated ectopic differentiation of melanocyte stem cells and ORS amelanotic melanocytes in an ex vivo human hair follicle model.

Hair greying depends on the altered presence and functionality of hair follicle melanocytes. Melanocyte stem cells (MelSCs) reside in the bulge of hair follicles and give rise to migrating and differentiating progeny during the anagen phase. Ageing, genotoxic stress, redox stress and multiple behaviour-associated acute stressors have been seen to induce hair greying by depleting the MelSC pool, a phenomenon which is accompanied by ectopic pigmentation of these cells, followed by their depletion from the stem cell niche. This aberrant differentiation produces a state from which a return to stem cell-like quiescence appears to be lost. The cellular features of stress-induced hair greying have been extensively studied in murine models. Here, we describe a method to assess and quantify human hair follicle MelSC differentiation by measuring ectopically pigmented MelSCs in isolated human hair follicles exposed to specific stress signal mediators. Ionizing radiation, hydrogen peroxide and noradrenaline have been shown to cause hair greying in mice. We demonstrate here that isolated, ex vivo cultured human hair follicles exposed to these treatments display similar ectopic pigmentation within the bulge area which is accompanied by induction of differentiated melanocytic markers. This study suggests that as in murine models, stress signalling induces closely matching phenotypic changes in human hair follicles which can be monitored and studied as a surrogate model for early steps in human hair greying.

Amyloid beta regulates ER exit sites formation through O-GlcNAcylation triggered by disrupted calcium homeostasis.

BACKGROUND INFORMATION: Aberrant production of amyloid beta (Aß) causes disruption of intracellular calcium homeostasis, a crucial factor in the pathogenesis of Alzheimer's disease. Calcium is required for the fusion and trafficking of vesicles. Previously, we demonstrated that Sec31A, a main component for coat protein complex II (COPII) vesicles at ER exit sites (ERES), is modulated by O-GlcNAcylation. O-GlcNAcylation, a unique and dynamic protein glycosylation process, modulates the formation of COPII vesicles. RESULTS: In this study, we observed that disrupted calcium levels affected the formation of COPII vesicles in ERES through calcium-triggered O-GlcNAcylation of Sec31A. Additionally, we found that Aß impaired ERES through Aß-disturbed calcium homeostasis and O-GlcNAcylation of Sec31A in neuronal cells. Furthermore, we identified that Aß disrupted the ribbon-like structure of Golgi. Golgi fragmentation by Aß was rescued by up-regulation of O-GlcNAcylaion levels using Thiamet G (ThiG), an O-GlcNAcase inhibitor. Additionally, we observed that the Golgi reassembly stacking proteins having a function in Golgi stacking showed attenuation at COPII vesicles following Aß treatment. CONCLUSIONS: This study demonstrated that Aß impaired Sec31A targeting to ERES through altered Sec31A O-GlcNAcylation triggered by disruption of intracellular calcium homeostasis. SIGNIFICANCE: The findings of this study suggested that protection of ERES or Sec31 O-GlcNAcylation may offer a promising novel avenue for development of AD therapeutics.

Proteoglycan Combined with Hyaluronic Acid and Hydrolyzed Collagen Restores the Skin Barrier in Mild Atopic Dermatitis and Dry, Eczema-Prone Skin: A Pilot Study.

Dry and eczema-prone skin conditions such as atopic dermatitis and xerotic eczema primarily indicate an impaired skin barrier function, which leads to chronic pruritus. Here, we investigated the effects of a novel emollient containing H.ECMTM liposome, which contains a soluble proteoglycan in combination with hydrolyzed collagen and hyaluronic acid. A prospective, single-arm study was conducted on 25 participants with mild atopic dermatitis or dry skin to assess the hydration and anti-inflammatory effect of the novel emollient applied daily over four weeks. All efficacy parameters, including itching severity, transepidermal water loss, and skin hydration, improved significantly after four weeks. The in vitro and ex vivo studies confirmed the restoration of the skin's barrier function. The study revealed the clinical and laboratory efficacy of H.ECMTM liposome in reducing itching and improving the skin's barrier integrity. Thus, the use of H.ECMTM liposome can be considered a therapeutic option for dry and eczema-prone skin.

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer's disease animal model.

OBJECTIVE: Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer's disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive. DESIGN: Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis. RESULTS: Composition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid ß plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice. CONCLUSION: These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

Plasma tau/amyloid-ß1-42 ratio predicts brain tau deposition and neurodegeneration in Alzheimer's disease.

One of the hallmarks of Alzheimer's disease is abnormal deposition of tau proteins in the brain. Although plasma tau has been proposed as a potential biomarker for Alzheimer's disease, a direct link to brain deposition of tau is limited. Here, we estimated the amount of in vivo tau deposition in the brain by PET imaging and measured plasma levels of total tau (t-tau), phosphorylated tau (p-tau, T181) and amyloid-ß1-42. We found significant correlations of plasma p-tau, t-tau, p-tau/amyloid-ß1-42, and t-tau/amyloid-ß1-42 with brain tau deposition in cross-sectional and longitudinal manners. In particular, t-tau/amyloid-ß1-42 in plasma was highly predictive of brain tau deposition, exhibiting 80% sensitivity and 91% specificity. Interestingly, the brain regions where plasma t-tau/amyloid-ß1-42 correlated with brain tau were similar to the typical deposition sites of neurofibrillary tangles in Alzheimer's disease. Furthermore, the longitudinal changes in cerebral amyloid deposition, brain glucose metabolism, and hippocampal volume change were also highly associated with plasma t-tau/amyloid-ß1-42. These results indicate that combination of plasma tau and amyloid-ß1-42 levels might be potential biomarkers for predicting brain tau pathology and neurodegeneration.

O-GlcNAcylation regulates endoplasmic reticulum exit sites through Sec31A modification in conventional secretory pathway.

The conventional secretory pathway is indispensable for eukaryotic cells. Newly synthesized membrane and secretory proteins are released from the endoplasmic reticulum (ER) through ER-derived vesicles to their appropriate destination. Vesicle formation is important for steady protein trafficking. O-GlcNAcylation ( O-GlcNAc) is a unique protein glycosylation signature, whose dynamic regulation by O-GlcNAc transferase and O-GlcNAcase occurs exclusively for nuclear and cytoplasmic proteins. Because of this locally limited property, the role of O-GlcNAc in the conventional protein secretory pathway is unknown. We report that Sec31A on COPII vesicles, a specific coat-protein complex for anterograde trafficking in the ER-Golgi network, is O-GlcNAcylated on S964, which accelerates COPII vesicle formation through control of its binding affinity to apoptosis-linked gene 2, a calcium-binding protein. Together, O-GlcNAc on Sec31A regulates conventional secretory vesicle trafficking in the ER-Golgi network. These modifications accelerate COPII vesicle formation and accelerated anterograde transport of vesicles within the ER-Golgi networks.-Cho, H. J., Mook-Jung, I. O-GlcNAcylation regulates endoplasmic reticulum exit sites through Sec31A modification in conventional secretory pathway.

Harnessing Intramolecular Rotation To Enhance Two-photon Imaging of Aß Plaques through Minimizing Background Fluorescence.

The aggregation of amyloid beta (Aß) proteins in senile plaques is a critical event during the development of Alzheimer's disease, and the postmortem detection of Aß-rich proteinaceous deposits through fluorescent staining remains one of the most robust diagnostic tools. In animal models, fluorescence imaging can be employed to follow the progression of the disease, and among the different imaging methods, two-photon microscopy (TPM) has emerged as one of the most powerful. To date, several near-infrared-emissive two-photon dyes with a high affinity for Aß fibrils have been developed, but there has often been a tradeoff between excellent two-photon cross-sections and large fluorescence signal-to-background ratios. In the current work, we introduced a twisted intramolecular charge state (TICT)-based de-excitation pathway, which results in a remarkable fluorescence increase of around 167-fold in the presence of Aß fibrils, while maintaining an excellent two-photon cross section, thereby enabling high-contrast ex vivo and in vivo TPM imaging. Overall, the results suggest that adopting TICT de-excitation in two-photon fluorophores may represent a general method to overcome the tradeoff between probe brightness and signal-to-background ratio.

Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease.

Glycosylation with O-linked ß-N-acetylglucosamine (O-GlcNAc) is one of the protein glycosylations affecting various intracellular events. However, the role of O-GlcNAcylation in neurodegenerative diseases such as Alzheimer's disease (AD) is poorly understood. Mitochondrial adenosine 5'-triphosphate (ATP) synthase is a multiprotein complex that synthesizes ATP from ADP and Pi. Here, we found that ATP synthase subunit α (ATP5A) was O-GlcNAcylated at Thr432 and ATP5A O-GlcNAcylation was decreased in the brains of AD patients and transgenic mouse model, as well as Aß-treated cells. Indeed, Aß bound to ATP synthase directly and reduced the O-GlcNAcylation of ATP5A by inhibition of direct interaction between ATP5A and mitochondrial O-GlcNAc transferase, resulting in decreased ATP production and ATPase activity. Furthermore, treatment of O-GlcNAcase inhibitor rescued the Aß-induced impairment in ATP production and ATPase activity. These results indicate that Aß-mediated reduction of ATP synthase activity in AD pathology results from direct binding between Aß and ATP synthase and inhibition of O-GlcNAcylation of Thr432 residue on ATP5A.

Global changes of phospholipids identified by MALDI imaging mass spectrometry in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia; however, at the present time there is no disease-modifying drug for AD. There is increasing evidence supporting the role of lipid changes in the process of normal cognitive aging and in the etiology of age-related neurodegenerative diseases. AD is characterized by the presence of intraneuronal protein clusters and extracellular aggregates of ß-amyloid (Aß). Disrupted Aß kinetics may activate intracellular signaling pathways, including tau hyperphosphorylation and proinflammatory pathways. We analyzed and visualized the lipid profiles of mouse brains using MALDI-TOF MS. Direct tissue analysis by MALDI-TOF imaging MS (IMS) can determine the relative abundance and spatial distribution of specific lipids in different tissues. We used 5XFAD mice that almost exclusively generate and rapidly accumulate massive cerebral levels of Aß-42 (1). Our data showed changes in lipid distribution in the mouse frontal cortex, hippocampus, and subiculum, where Aß plaques are first generated in AD. Our results suggest that MALDI-IMS is a powerful tool for analyzing the distribution of various phospholipids and that this application might provide novel insight into the prediction of disease.

Microglia contributes to plaque growth by cell death due to uptake of amyloid ß in the brain of Alzheimer's disease mouse model.

Pathological hallmarks of Alzheimer's disease (AD) include extracellularly accumulated amyloid ß (Aß) plaques and intracellular neurofibrillary tangles in the brain. Activated microglia, brain-resident macrophages, are also found surrounding Aß plaques. The study of the brain of AD mouse models revealed that Aß plaque formation is completed by the consolidation of newly generated plaque clusters in vicinity of existed plaques. However, the dynamics of Aß plaque formation, growth and the mechanisms by which microglia contribute to Aß plaque formation are unknown. In the present study, we confirmed how microglia are involved in Aß plaque formation and their growth in the brain of 5XFAD mice, the Aß-overexpressing AD transgenic mouse model, and performed serial intravital two-photon microscopy (TPM) imaging of the brains of 5XFAD mice crossed with macrophage/microglia-specific GFP-expressing CX3CR1GFP/GFP mice. We found that activated microglia surrounding Aß plaques take up Aß, which are clusters developed inside activated microglia in vivo and this was followed by microglial cell death. These dying microglia release the accumulated Aß into the extracellular space, which contributes to Aß plaque growth. This process was confirmed by live TPM in vivo imaging and flow cytometry. These results suggest that activated microglia can contribute to formation and growth of Aß plaques by causing microglial cell death in the brain. GLIA 2016;64:2274-2290.