1,721,007 research outputs found
Gut Microbiota as a Hidden Player in the Pathogenesis of Alzheimer's Disease
No full textAlzheimer's disease (AD), the most common neurodegenerative disorder, is accompanied by cognitive impairment and shows representative pathological features, including senile plaques and neurofibrillary tangles in the brain. Recent evidence suggests that several systemic changes outside the brain are associated with AD and may contribute to its pathogenesis. Among the factors that induce systemic changes in AD, the gut microbiota is increasingly drawing attention. Modulation of gut microbiome, along with continuous attempts to remove pathogenic proteins directly from the brain, is a viable strategy to cure AD. Seeking a holistic understanding of the pathways throughout the body that can affect the pathogenesis, rather than regarding AD solely as a brain disease, may be key to successful therapy. In this review, we focus on the role of the gut microbiota in causing systemic manifestations of AD. The review integrates recently emerging concepts and provides potential mechanisms about the involvement of the gut-brain axis in AD, ranging from gut permeability and inflammation to bacterial translocation and cross-seeding.N
Amyloid beta regulates ER exit sites formation through O‐GlcNAcylation triggered by disrupted calcium homeostasis
No full textBackground Information Aberrant production of amyloid beta (A beta) 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 A beta impaired ERES through A beta-disturbed calcium homeostasis and O-GlcNAcylation of Sec31A in neuronal cells. Furthermore, we identified that A beta disrupted the ribbon-like structure of Golgi. Golgi fragmentation by A beta 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 A beta treatment. Conclusions This study demonstrated that A beta 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.N
Amyloid-β-activated microglia can induce compound proteinopathies
No full textNeuropathological 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-beta oligomer-activated microglia into the striatum of na & iuml;ve 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-beta oligomer-triggered proteinopathies but also a novel animal model recapitulating the salient features of Alzheimer's disease. Amyloid plaques precede neurofibrillary tangles and Lewy bodies in Alzheimer's disease, but the relationship between these proteinopathies is unclear. Lee et al. show in mice that microglia activated by A beta drive neuroinflammation, which subsequently induces tau and alpha-synuclein aggregation and the associated neurodegenerative phenotypes.N
Association of B cell profile and receptor repertoire with the progression of Alzheimer's disease
No full text© 2022 The Author(s)Alzheimer's disease (AD) is the most prevalent type of dementia. Reports have revealed that the peripheral immune system is linked to neuropathology; however, little is known about the contribution of B lymphocytes in AD. For this longitudinal study, 133 participants are included at baseline and second-year follow-up. Also, we analyze B cell receptor (BCR) repertoire data generated from a public dataset of three normal and 10 AD samples and perform BCR repertoire profiling and pairwise sharing analysis. As a result, longitudinal increase in B lymphocytes is associated with increased cerebral amyloid deposition and hyperactivates induced pluripotent stem cell-derived microglia with loss-of-function for beta-amyloid clearance. Patients with AD share similar class-switched BCR sequences with identical isotypes, despite the high somatic hypermutation rate. Thus, BCR repertoire profiling can lead to the development of individualized immune-based therapeutics and treatment. We provide evidence of both quantitative and qualitative changes in B lymphocytes during AD pathogenesis.N
Mitochondria-Targeting Ceria Nanoparticles as Antioxidants for Alzheimer’s Disease
No full textMitochondrial oxidative stress is
a key pathologic factor in neurodegenerative
diseases, including Alzheimer’s disease. Abnormal generation
of reactive oxygen species (ROS), resulting from mitochondrial dysfunction,
can lead to neuronal cell death. Ceria (CeO<sub>2</sub>) nanoparticles
are known to function as strong and recyclable ROS scavengers by shuttling
between Ce<sup>3+</sup> and Ce<sup>4+</sup> oxidation states. Consequently,
targeting ceria nanoparticles selectively to mitochondria might be
a promising therapeutic approach for neurodegenerative diseases. Here,
we report the design and synthesis of triphenylphosphonium-conjugated
ceria nanoparticles that localize to mitochondria and suppress neuronal
death in a 5XFAD transgenic Alzheimer’s disease mouse model.
The triphenylphosphonium-conjugated ceria nanoparticles mitigate reactive
gliosis and morphological mitochondria damage observed in these mice.
Altogether, our data indicate that the triphenylphosphonium-conjugated
ceria nanoparticles are a potential therapeutic candidate for mitochondrial
oxidative stress in Alzheimer’s disease
Neurotoxicity of phenylalanine on human iPSC-derived cerebral organoids
No full textPhenylketonuria (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.(c) 2022 Elsevier Inc. All rights reserved.N
Prognostic plasma protein panel for Aβ deposition in the brain in Alzheimer's disease
No full text© 2019 Elsevier LtdAlzheimer's disease (AD) is the most common age-associated dementia. Many studies have sought to predict cerebral amyloid deposition, the major pathological hallmark of AD, using body fluids such as blood or cerebral spinal fluid (CSF). The use of blood in diagnostic procedures is widespread in medicine; however, existing blood biomarkers for AD remain unreliable. We sought to discover blood biomarkers that discriminate Aβ deposition status in the brain. This study used 107 individuals who were cognitively normal (CN), 107 patients with mild cognitive impairment (MCI), and 40 AD patients with Pittsburg compound B positron emission tomography (PiB-PET) amyloid imaging data available. We found five plasma biomarker candidates via mass spectrometry (MS) based-proteomic analysis and validated these proteins using enzyme-linked immunosorbent assay (ELISA). Our integrated models were highly predictive of brain amyloid deposition, exhibiting 0.871 accuracy with 79% sensitivity and 84% specificity overall, and 0.836 accuracy with 68% sensitivity and 90% specificity in patients with MCI. These results indicated that a combination of proteomic-based blood proteins might be a possible biomarker set for predicting cerebral amyloid deposition11Nsciescopu
Two-Photon Absorbing Dyes with Minimal Autofluorescence in Tissue Imaging: Application to in Vivo Imaging of Amyloid-beta Plaques with a Negligible Background Signal
No full textFluorescence imaging of tissues offer an essential means for studying biological systems. Autofluorescence becomes a serious issue in tissue imaging under excitation at UV-vis wavelengths where biological molecules compete with the fluorophore. To address this critical issue, a novel class of fluorophores that can :be excited at, similar to 900 nm under two-photon excitation conditions and emits in the red wavelength region (>= 600 nm) has been disclosed. The new pi-extended dipolar dye system, shows several advantageous features including minimal antofluorescence in tissue imaging and pronounced solvent-sensitive emission behavior, compared with a widely used two-photon absorbing dye, acedan. As an important application of the new dye system, one of the dyes was developed into a fluorescent probe for amyloicl-beta plaques, a key biomarker of Alzheimer's disease. The probe enabled in Vivo imaging of amyloid-beta plaques in a disease-model mouse, with negligible background signal. The new dye system has great potential for the development of other types of two-photon fluorescent probes and tags for imaging of tissues with minimal autofluorescence.
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No full textFluorescence imaging of tissues offer an essential means for studying biological systems. Autofluorescence becomes a serious issue in tissue imaging under excitation at UV−vis wavelengths where biological molecules compete with the fluorophore. To address this critical issue, a novel class of fluorophores that can be excited at ∼900 nm under two-photon excitation conditions and emits in the red wavelength region (≥600 nm) has been disclosed. The new π-extended dipolar dye system shows several advantageous features including minimal autofluorescence in tissue imaging and pronounced solvent-sensitive emission behavior, compared with a widely used two-photon absorbing dye, acedan. As an important application of the new dye system, one of the dyes was developed into a fluorescent probe foramyloid-β plaques, a key biomarker of Alzheimer’s disease. The probe enabled in vivo imaging of amyloid-β plaques in a disease-model mouse, with negligible background signal. The new dye system has great potential for the development of other types of two-photon fluorescent probes and tags for imaging of tissues with minimal autofluorescence.16
Brain somatic mutations observed in Alzheimer's disease associated with aging and dysregulation of tau phosphorylation
Get PDFThe role of brain somatic mutations in Alzheimer's disease (AD) is not well understood. Here, we perform deep whole-exome sequencing (average read depth 584x) in 111 postmortem hippocampal formation and matched blood samples from 52 patients with AD and 11 individuals not affected by AD. The number of somatic single nucleotide variations (SNVs) in AD brain specimens increases significantly with aging, and the rate of mutation accumulation in the brain is 4.8-fold slower than that in AD blood. The putatively pathogenic brain somatic mutations identified in 26.9% (14 of 52) of AD individuals are enriched in PI3K-AKT, MAPK, and AMPK pathway genes known to contribute to hyperphosphorylation of tau. We show that a pathogenic brain somatic mutation in PIN1 leads to a loss-of-function mutation. In vitro mimicking of haploinsufficiency of PIN1 aberrantly increases tau phosphorylation and aggregation. This study provides new insights into the genetic architecture underlying the pathogenesis of AD.
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