Neuronal MHC-I complex is destabilized by amyloid-β and its implications in Alzheimer's disease.

Backgrounds: The expression of major histocompatibility complex I (MHC-I) in neurons has recently been shown to regulate neurite outgrowth and synaptic plasticity. However, its contribution to neurodegenerative diseases such as Alzheimer's disease (AD) remains largely unknown.

Methods: In this study, we investigated the relationship between impaired MHC-I-β2M complex and AD in vitro and human AD samples.

Monoclonal antibody Y01 prevents tauopathy progression induced by lysine 280-acetylated tau in cell and mouse models.

The spatiotemporal pattern of the spread of pathologically modified tau through brain regions in Alzheimer's disease (AD) can be explained by prion-like cell-to-cell seeding and propagation of misfolded tau aggregates. Hence, to develop targeted therapeutic antibodies, it is important to identify the seeding- and propagation-competent tau species. The hexapeptide 275VQIINK280 of tau is a critical region for tau aggregation, and K280 is acetylated in various tauopathies, including AD.

Tau acetylation at K280 regulates tau phosphorylation.

Purpose/aim Of The Study: Accumulation of hyperphosphorylated tau is a key pathological finding of Alzheimer's disease. Recently, acetylation of tau is emerging as another key pathogenic modification, especially regarding the acetylation of tau at K280 of the hexapeptide VQIINK, a critical sequence in driving tau aggregation. However, the relationship between these two key post-translational modifications is not well known.

TLQP-21 mediated activation of microglial BV2 cells promotes clearance of extracellular fibril amyloid-β.

β-Amyloid (Aβ) plaque in the brains of patients with Alzheimer's disease (AD) is mainly caused by impaired clearance of Aβ by glial cells, including microglia and astrocytes. Because microglia play an important protective role in the central nervous system, many efforts have been made to identify agents that effectively improve microglial Aβ phagocytosis. This study found that TLQP-21, which is cleaved from VGF (VGF nerve growth factor inducible) precursor protein, enhanced Aβ phagocytosis and degradation by microglial BV2 cells.

Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer's disease.

A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia.

Small-molecule drug screening identifies drug Ro 31-8220 that reduces toxic phosphorylated tau in Drosophila melanogaster.

The intraneuronal aggregates of hyperphosphorylated and misfolded tau (neurofibrillary tangles, NFTs) cause a stereotypical spatiotemporal Alzheimer's disease (AD) progression that correlates with the severity of the associated cognitive decline. Kinase activity contributes to the balance between neuron survival and cell death. Hyperactivation of kinases including the conventional protein kinase C (PKC) is a defective molecular event accompanying associative memory loss, tau phosphorylation, and progression of AD or related neurodegenerative diseases.

V232M substitution restricts a distinct O-glycosylation of PLD3 and its neuroprotective function.

The link between Val232Met variant of phospholipase D3 (PLD3) and late-onset Alzheimer's disease (AD) is still obscure. While it may not affect directly the amyloid precursor protein function, PLD3 could be regulating multiple cellular compartments. Here, we investigated the function of wild-type human PLD3 (PLD3) and the Val232Met variant (PLD3) in the presence of β-amyloid (Aβ) in a Drosophila melanogaster model of AD.

Ouabain activates transcription factor EB and exerts neuroprotection in models of Alzheimer's disease.

The number of neurofibrillary tangles containing abnormal hyperphosphorylated tau protein correlates with the degree of dementia in Alzheimer's disease (AD). In addition, autophagosome accumulation and disturbance of autophagy, the process by which toxic aggregate proteins are degraded in the cytosol, are also found in AD models. These indicate that regulation of the autophagy-lysosome system may be a potential therapeutic target for AD.

Autophagy deficiency in myeloid cells exacerbates eosinophilic inflammation in chronic rhinosinusitis.

Background: Eosinophilic inflammation is a major pathologic feature of chronic rhinosinusitis (CRS) and is frequently associated with severe refractory disease. Prostaglandin (PG) D levels are increased in patients with CRS, and PGD is an important contributing factor to eosinophilic inflammation. Autophagy has a pleiotropic effect on immune responses and disease pathogenesis.

Orexin Impairs the Phagocytosis and Degradation of Amyloid-β Fibrils by Microglial Cells.

Background: Intracranial accumulation of amyloid-β (Aβ) is a characteristic finding of Alzheimer's disease (AD). It is thought to be the result of Aβ overproduction by neurons and impaired clearance by several systems, including degradation by microglia. Sleep disturbance is now considered a risk factor for AD, but studies focusing on how sleep modulates microglial handling of Aβ have been scarce.

The Alzheimer's Disease-Associated R47H Variant of TREM2 Has an Altered Glycosylation Pattern and Protein Stability.

The R47H coding variant of the triggering receptor expressed on myeloid cells-2 (TREM2) increases the risk of Alzheimer's disease (AD) similar to apolipoprotein E4. TREM2 R47H has recently been shown to have impaired binding to damage-associated lipid or apolipoprotein ligands. However, it is not known how this R47H variant affects the biochemical characteristics of TREM2 and alters the pathogenesis of AD.

Sorting nexin-4 regulates β-amyloid production by modulating β-site-activating cleavage enzyme-1.

Background: Amyloid precursor protein (APP) is cleaved by β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) to produce β-amyloid (Aβ), a critical pathogenic peptide in Alzheimer's disease (AD). Aβ generation can be affected by the intracellular trafficking of APP or its related secretases, which is thus important to understanding its pathological alterations. Although sorting nexin (SNX) family proteins regulate this trafficking, the relevance and role of sorting nexin-4 (SNX4) regarding AD has not been studied yet.

Impaired macrophage autophagy induces systemic insulin resistance in obesity.

Obesity-induced insulin resistance and diabetes are significantly associated with infiltrates of inflammatory cells in adipose tissue. Previous studies recognized the involvement of autophagy in the regulation of metabolism in multiple tissues, including β-cells, hepatocytes, myocytes, and adipocytes. However, despite the importance of macrophages in obesity-induced insulin resistance, the role of macrophage autophagy in regulating insulin sensitivity is seldom addressed.

Alzheimer's disease genes and autophagy.

Autophagy is a process to degrade and recycle cellular constituents via the lysosome for regulating cellular homeostasis. Its dysfunction is now considered to be involved in many diseases, including neurodegenerative diseases. Many features reflecting autophagy impairment, such as autophagosome accumulation and lysosomal dysfunction, have been also revealed to be involved in Alzheimer's disease (AD).

c-Jun N-terminal Kinase (JNK) induces phosphorylation of amyloid precursor protein (APP) at Thr668, in okadaic acid-induced neurodegeneration.

Several lines of evidence have revealed that phosphorylation of amyloid precursor protein (APP) at Thr668 is involved in the pathogenesis of Alzheimer's disease (AD). Okadaic acid (OA), a protein phosphatase-2A inhibitor, has been used in AD research models to increase tau phosphorylation and induce neuronal death. We previously showed that OA increased levels of APP and induced accumulation of APP in axonal swellings.

Regulation of amyloid precursor protein processing by its KFERQ motif.

Understanding of trafficking, processing, and degradation mechanisms of amyloid precursor protein (APP) is important because APP can be processed to produce β-amyloid (Aβ), a key pathogenic molecule in Alzheimer's disease (AD). Here, we found that APP contains KFERQ motif at its C-terminus, a consensus sequence for chaperone-mediated autophagy (CMA) or microautophagy which are another types of autophagy for degradation of pathogenic molecules in neurodegenerative diseases. Deletion of KFERQ in APP increased C-terminal fragments (CTFs) and secreted N-terminal fragments of APP and kept it away from lysosomes.

Calpain-mediated cleavage of DARPP-32 in Alzheimer's disease.

Toxicity induced by aberrant protein aggregates in Alzheimer's disease (AD) causes synaptic disconnection and concomitant progressive neurodegeneration that eventually impair cognitive function. cAMP-response element-binding protein (CREB) is a transcription factor involved in the molecular switch that converts short-term to long-term memory. Although disturbances in CREB function have been suggested to cause memory deficits in both AD and AD animal models, the mechanism of CREB dysfunction is still unclear.

Disease-Associated Mutations of TREM2 Alter the Processing of N-Linked Oligosaccharides in the Golgi Apparatus.

The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune-modulatory receptor involved in phagocytosis and inflammation. Mutations of Q33X, Y38C and T66M cause Nasu-Hakola disease (NHD) which is characterized by early onset of dementia and bone cysts. A recent, genome-wide association study also revealed that single nucleotide polymorphism of TREM2, such as R47H, increased the risk of Alzheimer's disease (AD) similar to ApoE4.

Vancomycin blocks autophagy and induces interleukin-1β release in macrophages.

Systemic inflammatory response syndrome (SIRS) is a serious condition that can cause organ failure as an exaggerated immunoresponse to the infection or other causes. Recently, autophagy was reported as a key process that regulates inflammatory responses in macrophages. Vancomycin is one of the most commonly prescribed antibiotics for sepsis treatment or following surgery.

Autophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome.

Accumulation of β-amyloid (Aβ) and resultant inflammation are critical pathological features of Alzheimer disease (AD). Microglia, a primary immune cell in brain, ingests and degrades extracellular Aβ fibrils via the lysosomal system. Autophagy is a catabolic process that degrades native cellular components, however, the role of autophagy in Aβ degradation by microglia and its effects on AD are unknown.

Interleukin-1β promotes the LC3-mediated secretory function of osteoclast precursors by stimulating the Ca²⁺-dependent activation of ERK.

Bone resorption by osteoclasts requires the release of secretory lysosomes containing cathepsin K, which degrades the organic bone matrix. The activity of this secretory function is determined by the level of lipidation of microtubule-associated protein 1 light chain 3 (LC3). Although the inflammatory cytokine IL-1β increases osteoclast activity, the underlying mechanism(s) remains undefined.

Molecular cloning, regulation, and functional analysis of two GHS-R genes in zebrafish.

Mammalian ghrelin is derived from stomach and regulates growth hormone release and appetite by modulating GHS-R (Growth hormone secretagogue receptor) activity. Zebrafish has been developed as a forward genetic screening model system and previous screening identified a number of genes involved in multiple signaling pathways. In this system, ghrelin has been identified and its function and regulation have been shown to be highly conserved to that of mammals.