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Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer's disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transg

The ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer's disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-β (Aβ) accumulation. Here, we generate neurons and astrocytes from isogenic human induced pluripotent stem cells (hiPSCs) carrying either APOE ε3 or APOE ε4 allele and investigate the effect of astrocytic ApoE4 on neuronal

Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. U

The oral multi-target kinase inhibitor regorafenib, which targets the oncogenic receptor tyrosine kinase (RTK), is an effective therapeutic for patients with advanced gastrointestinal stromal tumors or metastatic colorectal cancer. However, whether regorafenib treatment has beneficial effects on neuroinflammation and Alzheimer's disease (AD) pathology has not been carefully addressed. Here, we report the regulatory function of regorafenib in neuroinflammatory responses and AD-related pathology i

Diacylglycerol (DAG) is an important signaling molecule at neuronal synapses. Generation of synaptic DAG is triggered by the activation of diverse surface receptors including N-methyl-D-aspartate (NMDA) receptors and metabotropic glutamate receptors. The action of DAG is terminated by enzymatic conversion of DAG to phosphatidic acid (PA) by DAG kinases (DGKs). DGKζ, one of many mammalian DGKs, is localized to synapses through direct interaction with the postsynaptic scaffolding protein PSD-95, a

Introduction: Lomerizine is a calcium channel blocker that crosses the blood-brain barrier and is used clinically in the treatment of migraines. However, whether lomerizine is beneficial in modulating neuroinflammatory responses has not been tested yet. Methods: To assess the potential of lomerizine for repurposing as a treatment for neuroinflammation, we investigated the effects of lomerizine on LPS-induced proinflammatory responses in BV2 microglial cells, Alzheimer's disease (AD) excitatory n

Alzheimer's disease (AD) is a progressive neurodegenerative disease that represents a major cause of death in many countries. AD is characterized by profound memory loss, disruptions in thinking and reasoning, and changes in personality and behavior followed by malfunctions in various bodily systems. Although AD was first identified over 100 years ago, and tremendous efforts have been made to cure the disease, the precise mechanisms underlying the onset of AD remain unclear. The recent developme

The innate immune system can develop a form of memory called priming, where prior exposure to a stimulus enhances subsequent responses. While well-characterized in peripheral immunity, its function in brain-resident cells such as astrocytes under non-disease conditions remains unclear. Here we show that human astrocytes derived from the induced pluripotent stem cells of healthy female donors, but not microglia, acquire a primed state following transient immune stimulations. Upon subsequent expos

Sphingosine-1-phosphate (S1P) is a significant lipid messenger modulating many physiological responses. S1P plays a critical role in autoimmune disease and is suggested to be involved in Sjögren's syndrome pathology. However, the mechanism of S1P signaling in salivary glands is unclear. Here we studied the effects of S1P on normal human submandibular gland cells. S1P increased levels of the intracellular Ca(2+) concentration ([Ca(2+)](i)), which was inhibited by pre-treatment with U73122 or 2-am

Ribosome-associated quality control (RQC) is a pivotal biological process that governs the fidelity of messenger RNA (mRNA) homeostasis and protein synthesis. Defects in RQC are implicated in cellular dysfunction and proteotoxicity, but their impact on aging remains elusive. Here, we show that Pelota, the ribosome rescue factor, promotes longevity and protects against age-related pathological phenotypes in multiple metazoan species. By performing a targeted genetic screen, we find that Pelota is

A general method developed for the parallel solid-phase synthesis of sn-1,2- and sn-2,3-diacyglycerol derivatives. The technique relies on the use of carboxylic acid-promoted epoxide ring-opening reactions of the glycidyl-bound resin 3. The polymer-bound monoacylglycerol 5, formed in this manner, is transformed to the respective polymer-bound diacylglycerols 7 and 9 by reaction of the free alcohol moiety with a second carboxylic acid under conditions that lead to retention or inversion of C-2 st