A5070072260- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Neuroscience and Neuropharmacology Research
- Genetics and Neurodevelopmental Disorders
- Cholinesterase and Neurodegenerative Diseases
- Glycosylation and Glycoproteins Research
- Diet and metabolism studies
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Autism Spectrum Disorder Research
- Tryptophan and brain disorders
- Immune cells in cancer
- Adenosine and Purinergic Signaling
- Computational Drug Discovery Methods
- Immune Response and Inflammation
- Lipoproteins and Cardiovascular Health
- Ion channel regulation and function
- Liver Disease Diagnosis and Treatment
- Cholesterol and Lipid Metabolism
- Neurogenesis and neuroplasticity mechanisms
- Drug Transport and Resistance Mechanisms
- Dementia and Cognitive Impairment Research
- Mitochondrial Function and Pathology
- Lysosomal Storage Disorders Research
- Advanced Glycation End Products research
- Crystallization and Solubility Studies
University of California, Davis
2016-2025
University of California Davis Medical Center
2015-2024
California State University, Sacramento
2020
Emory University Hospital
2015
Kansas State University
2015
UC Davis Health System
2005-2014
Miami University
2012
NeuroDevelopment Center
2010-2011
University of Washington
2002-2006
UC Davis Comprehensive Cancer Center
2006
MECP2 , an X-linked gene encoding the epigenetic factor methyl-CpG-binding protein-2, is mutated in Rett syndrome (RTT) and aberrantly expressed autism. Most children affected by RTT are heterozygous Mecp2 −/+ females whose brain function impaired postnatally due to MeCP2 deficiency. Recent studies suggest a role of glia causing neuronal dysfunction via non-cell-autonomous effect RTT. Here we report potent neurotoxic activity conditioned medium (CM) obtained from Mecp2- null microglia....
MECP2 , an X-linked gene encoding the epigenetic factor methyl-CpG-binding protein-2, is mutated in Rett syndrome (RTT) and aberrantly expressed autism. Most children affected by RTT are heterozygous Mecp2 −/+ females whose brain function impaired postnatally due to MeCP2 deficiency. While prior functional investigations of have focused exclusively on neurons concluded absence astrocytes, here we report that astrocytes express MeCP2, deficiency causes significant abnormalities BDNF...
Neuroinflammation and associated neuronal dysfunction mediated by activated microglia play an important role in the pathogenesis of Alzheimer disease (AD). Microglia are aggregated forms amyloid-β protein (Aβ), usually demonstrated vitro stimulating with micromolar concentrations fibrillar Aβ, a major component amyloid plaques AD brains. Here we report that oligomer (AβO), at 5-50 nm, induces unique pattern activation requires activity scavenger receptor A Ca(2+)-activated potassium channel...
Abstract Several small molecule ligands for amyloid‐β (Aβ) fibrils deposited in brain have been developed to facilitate radiological diagnosis of Alzheimer’s disease (AD). Recently, the build‐up Aβ oligomers (AβO) has recognized as an additional hallmark AD and may play a more significant role early stages. Evidence suggests that quantitative assessment AβO would provide accurate index therapeutic effect drug trials. Therefore, there is urgent need develop methods efficient identification...
New advances in polarized light microscopy were used to image Congo red-stained cerebral amyloidosis sharp relief. The rotating-polarizer method was separate the optical effects of transmission, linear birefringence, extinction, dichroism, and orientation electric dipole transition moments display them as false-color maps. These are typically convolved an ordinary microscope. In this way, we show that amyloid deposits Alzheimer's disease plaques contain structurally disordered centers,...
Microglia are highly plastic cells that can assume different phenotypes in response to microenvironmental signals. Lipopolysaccharide (LPS) and interferon‐γ (IFN‐γ) promote differentiation into classically activated M1‐like microglia, which produce high levels of pro‐inflammatory cytokines nitric oxide thought contribute neurological damage ischemic stroke Alzheimer's disease. IL‐4 contrast induces a phenotype associated with anti‐inflammatory effects tissue repair. We here investigated...
The goal of this study was to identify the intrinsic links that explain effect a Western diet (WD) on cognitive dysfunction. Specific pathogen-free, wild-type mice were fed either control (CD) or high-fat, high-sucrose WD after weaning and euthanized at 10 mo age pathways affect health. results showed long-term intake reduced hippocampal synaptic plasticity level brain-derived neurotrophic factor mRNA in brain isolated microglia. A also activated ERK1/2 postsynaptic density-95 brain,...
Development of therapeutic strategies to prevent Alzheimer's Disease (AD) is great importance. We show that mild inhibition mitochondrial complex I with small molecule CP2 reduces levels amyloid beta and phospho-Tau averts cognitive decline in three animal models familial AD. Low-mass molecular dynamics simulations biochemical studies confirmed competes flavin mononucleotide for binding the redox center leading elevated AMP/ATP ratio activation AMP-activated protein kinase neurons mouse...
Microglia significantly contribute to the pathophysiology of Alzheimer's disease but an effective microglia-targeted therapeutic approach is not yet available clinically. The potassium channels Kv1.3 and Kir2.1 play important roles in regulating immune cell functions have been implicated by vitro studies 'M1-like pro-inflammatory' or 'M2-like anti-inflammatory' state microglia, respectively. We here found that amyloid-β oligomer-induced expression cultured primary microglia. Likewise, ex...
Glycosylation has been found to be altered in the brains of individuals with Alzheimer's disease (AD). However, it is unknown which specific glycosylation-related pathways are AD dementia. Using publicly available RNA-seq datasets covering seven brain regions and including 1724 samples, we identified genes ubiquitously changed AD. Several differentially expressed glycosyltransferases by were confirmed qPCR a different set human medial temporal cortex (MTC) samples (n = 20 vs. controls)....
Abstract The Ketogenic Diet (KD) improves memory and longevity in aged C57BL/6 mice. We tested 7 months KD vs. control diet (CD) the mouse Alzheimer’s Disease (AD) model APP/PS1. significantly rescued Long-Term-Potentiation (LTP) to wild-type levels, not by changing Amyloid-β (Aβ) levels. KD’s ‘main actor’ is thought be Beta-Hydroxy-butyrate (BHB) whose levels rose CD mice, BHB itself LTP APP/PS1 hippocampi. 6 most significant pathways induced brains RNAseq all related Synaptic Plasticity....
Activated microglia/macrophages significantly contribute to the secondary inflammatory damage in ischemic stroke. Cultured neonatal microglia express K+ channels Kv1.3 and KCa3.1, both of which have been reported be involved microglia-mediated neuronal killing, oxidative burst cytokine production. However, it is questionable whether cultures accurately reflect channel expression activated adult brain. We here subjected mice middle cerebral artery occlusion with eight days reperfusion...
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging our understanding molecular pathogenesis, only limited neuropathologic information on FXS available.Neuropathologic examinations were performed post-mortem brain tissue from three older men (aged 57, 64 78 years) who had received a clinical or genetic diagnosis FXS. In each case, physical...
Mutations in MECP2 encoding methyl-CpG-binding protein 2 (MeCP2) cause the X-linked neurodevelopmental disorder Rett syndrome. syndrome patients exhibit neurological symptoms that include irregular breathing, impaired mobility, stereotypic hand movements, and loss of speech. MeCP2 epigenetically modulates gene expression through genome-wide binding to methylated CpG dinucleotides. While neurons have highest level expression, astrocytes other cell types also express detectable levels MeCP2....
Microglia show a rich repertoire of activation patterns regulated by complex ensemble surface ion channels, receptors, and transporters. We others have investigated whether microglia vary their K+ channel expression as means to achieve functional diversity. However, most the prior studies were conducted using in vitro models such BV2 cells, primary microglia, or brain slices culture, which may not accurately reflect physiology adult individuals. Here we employed an vivo mouse model selective...
Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the gene encoding MeCP2, epigenetic modulator that binds methyl CpG dinucleotide target genes to regulate transcription. Previously, we and others reported a role of microglia pathophysiology RTT. To understand mechanism dysfunction RTT, identified MeCP2 gene, SLC38A1 , which encodes major glutamine transporter (SNAT1), characterized its microglia. We found acts as microglia-specific transcriptional...
Microglia play a pivotal role in the initiation and progression of Alzheimer's disease (AD). We here tested therapeutic hypothesis that Ca2+-activated potassium channel KCa3.1 constitutes potential target for treating AD by reducing neuroinflammation.To determine if is relevant to AD, we cultured microglia or hippocampal slices with Aβ oligomer (AβO) activated microglia, microglial was upregulated 5xFAD mice human brains. The expression/activity examined qPCR, Western blotting,...
Inheritance of APOE alleles is associated with varying clinical outcomes in several neurodegenerative diseases that are innate immune response brain. We tested the hypothesis inheritance different would significantly modulate neurotoxicity arising from glial response. first used dissociated cultures wild-type (wt) murine neurons and glia derived mice targeted replacement (TR) epsilon2, epsilon3, or, epsilon4 allele. Our results showed vast majority bystander damage to wt microglia was...
There exists an urgent need for new target discovery to treat Alzheimer's disease (AD); however, recent clinical trials based on anti-Aβ and anti-inflammatory strategies have yielded disappointing results. To expedite drug discovery, we propose reposition targets which been previously pursued by both industry academia indications other than AD. One such is the calcium-activated potassium channel KCa3.1 (KCNN4), in brain primarily expressed microglia significantly upregulated when are...
Microglia-mediated inflammation exerts adverse effects in ischemic stroke and neurodegenerative disorders such as Alzheimer's disease (AD). Expression of the voltage-gated potassium channel Kv1.3 is required for microglia activation. Both genetic deletion pharmacological inhibition are effective reducing activation associated inflammatory responses, well improving neurological outcomes animal models AD stroke. Here we sought to elucidate molecular mechanisms underlying therapeutic...
Abstract Background Chronic consumption of high sugar and fat diet associated with liver inflammation cognitive decline. This paper tests a hypothesis that the development resolution diet-induced nonalcoholic fatty disease (NAFLD) has an impact on neuroplasticity cognition. Methods C57BL/6 wild-type mice were fed either healthy control (CD) or fructose, palmitate, cholesterol (FPC)-enriched since weaning. When 3-months old, FPC diet-fed randomly assigned to receive FPC-enriched without 6%...
Fatty acids are metabolized by β-oxidation within the "mitochondrial ketogenic pathway" (MKP) to generate β-hydroxybutyrate (BHB), a ketone body. BHB can be generated most cells but largely hepatocytes following exercise, fasting, or diet consumption. has been shown modulate systemic and brain inflammation; however, its direct effects on microglia have little studied. We investigated impact of Aβ oligomer (AβO)-stimulated human iPS-derived (hiMG), model relevant pathogenesis Alzheimer's...
Abstract Fucosylation, especially core fucosylation of N‐glycans catalyzed by α1‐6 fucosyltransferase (fucosyltransferase 8 or FUT8), plays an important role in regulating the peripheral immune system and inflammation. However, its microglial activation is poorly understood. Here we used human induced pluripotent stem cells‐derived microglia (hiMG) as a model to study FUT8‐catalyzed amyloid‐β oligomer (AβO)‐induced activation, view significant relevance pathogenesis Alzheimer's disease (AD)....