Discovery and characterization of stereodefined PMO-gapmers targeting tau.

Antisense oligonucleotides (ASOs) are an important class of therapeutics to treat genetic diseases, and expansion of this modality to neurodegenerative disorders has been an active area of research. To realize chronic administration of ASO therapeutics to treat neurodegenerative diseases, new chemical modifications that improve activity and safety profiles are still needed. Furthermore, it is highly desirable to develop a single stereopure ASO with a defined activity and safety profile to avoid any efficacy and safety concerns due to the batch-to-batch variation in the composition of diastereomers.

Histidine 131 in presenilin 1 is the pH-sensitive residue that causes the increase in Aβ42 level in acidic pH.

Alzheimer disease (AD) is the most common neurodegenerative disease worldwide. The pathological hallmark of AD is the presence of senile plaques in the brain, which are accumulations of amyloid-β peptide (Aβ) ending at the 42nd residue (i.e.

Retrograde transport of γ-secretase from endosomes to the trans-Golgi network regulates Aβ42 production.

Unlabelled: The aberrant metabolism of amyloid-β protein (Aβ) in the human brain has been implicated in the etiology of Alzheimer disease (AD). γ-Secretase is the enzyme that generates various forms of Aβ, such as Aβ40 and Aβ42, the latter being an aggregation-prone toxic peptide that is involved in the pathogenesis of AD. Recently, we found that clathrin-mediated endocytosis of γ-secretase affects the production and deposition of Aβ42 in vivo, suggesting that the membrane trafficking of γ-secretase affects its enzymatic activity.

Molecular mechanisms of the genetic risk factors in pathogenesis of Alzheimer disease.

Alzheimer disease (AD) is a neurodegenerative disease characterized by the extensive deposition of senile plaques and neurofibrillary tangles. Until recently, only the gene had been known as a genetic risk factor for late-onset AD (LOAD), which accounts for more than 95% of all AD cases. However, in addition to this well-established genetic risk factor, genome-wide association studies have identified several single nucleotide polymorphisms as genetic risk factors of LOAD, such as and .

Partial loss of CALM function reduces Aβ42 production and amyloid deposition in vivo.

Aberrant production, clearance and deposition of amyloid-β protein (Aβ) in the human brain have been implicated in the aetiology of Alzheimer disease (AD). γ-Secretase is the enzyme responsible for generating various Aβ species, such as Aβ40 and toxic Aβ42. Recently, genome-wide association studies in late-onset AD patients have identified the endocytosis-related phosphatidylinositol-binding clathrin assembly protein (PICALM) gene as a genetic risk factor for AD.

Membrane trafficking and proteolytic activity of γ-secretase in Alzheimer's disease.

γ-Secretase is an intramembrane-cleaving protease that generates various forms of amyloid-β peptides (Aβ) that accumulate in the brains of Alzheimer's disease (AD) patients. The intracellular trafficking and subcellular localization of γ-secretase are linked to both qualitative and quantitative changes in Aβ production. However, the precise intracellular localization of γ-secretase as well as its detailed regulatory mechanisms have remained elusive.

Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase.

A body of evidence suggests that aberrant metabolism of amyloid-β peptide (Aβ) underlies the aetiology of Alzheimer disease (AD). Recently, a single-nucleotide polymorphism in phosphatidylinositol binding clathrin assembly protein (PICALM/CALM) gene, which encodes a protein implicated in the clathrin-mediated endocytosis, was identified as a genetic protective factor for AD, although its mechanistic details have little been explored. Here we show that loss of CALM leads to the selective decrease in the production ratio of the pathogenic Aβ species, Aβ42.

IgM-immune complex glomerulonephritis associated with sarcoidosis.

We present a case of proliferative glomerulonephritis with peculiar IgM deposition associated with sarcoidosis. A 62-year-old woman, who had been diagnosed with sarcoidosis 3 years previously because of abnormalities on chest X-ray radiophotographs and lymph node pathology, was admitted to our hospital for the evaluation of proteinuria and microscopic hematuria. Laboratory findings showed renal dysfunction (creatinine clearance, 52 ml/min), a moderate range of urinary protein (1.

Mucosal irritative and healing impairment action of risedronate in rat stomachs: comparison with alendronate.

Background And Aim: We used alendronate and risedronate as bisphosphonates and examined whether or not these agents have a mucosal irritative action in the stomach and impair the healing of pre-existing gastric ulcers in rats.

Methods: Male Sprague Dawley (SD) rats were used in the following two studies: (i) the effects of risedronate and alendronate on gastric potential difference (PD), gastric mucosal blood flow (GMBF) and acid back-diffusion in the stomach mounted on ex vivo chamber under urethane anesthesia and; (ii) the influence of daily treatment with these drugs on the healing of acetic acid-induced gastric ulcers was examined.

Results: Mucosal application of risedronate produced PD reduction in the saline-perfused stomachs in a dose-dependent manner.

Ulcerogenic influence of selective cyclooxygenase-2 inhibitors in the rat stomach with adjuvant-induced arthritis.

Cyclooxygenase (COX)-2 inhibitors have been developed as new gastric sparing anti-inflammatory drugs. We previously reported that the ulcerogenic response to conventional nonselective COX inhibitors, such as indomethacin and aspirin, was markedly increased in arthritic rats. The ulcerogenic effect of selective COX-2 inhibitors in arthritic animals, however, remains unknown.

Protection against dextran sulfate sodium-induced colitis by microspheres of ellagic acid in rats.

Ellagic acid (EA), a naturally occurring plant phenol, has the antioxidant and anti-inflammatory activities. In the present study, we examined the effect of EA contained in microspheres on the ulcerative colitis induced experimentally in rats by dextran sulfate sodium (DSS). Experimental colitis was induced in male Fisher 344 rats by daily treatment with 3% DSS solution in drinking water for 7 days.

Effect of taurine on ulcerogenic response and impaired ulcer healing induced by monochloramine in rat stomachs.

Background: It is well known that neutrophil-derived hypochlorous acid interacts with ammonia (NH4OH) to generate monochloramine (NH2Cl) and that NH2Cl irritates the gastric mucosa and impairs ulcer healing.

Aim: To examine the effect of taurine, a hypochlorous acid scavenger, on the mucosal ulcerogenic and the impaired healing response induced by NH2Cl in rat stomachs, in comparison with those of methionine and glycine.

Methods And Results: Under anaesthesia, oral administration of NH2Cl (120 mmol/L) produced severe lesions in male Sprague-Dawley rat stomachs.

Protective effect of thiaton, an antispasmodic drug, against indomethacin-induced intestinal damage in rats.

The effect of thiaton [3-(di-2-thienylmethylene)-5-methyl-trans-quinolizidinium bromide], an antispasmodic drug, on indomethacin-induced intestinal damage was examined in rats. The animals were given indomethacin, s.c.

Protective effect of rebamipide on indomethacin-induced intestinal damage in rats.

Background And Aim: We evaluated the effect of rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid), a novel anti-ulcer drug, on indomethacin-induced small intestinal lesions in rats.

Methods: The animals were administered indomethacin (10 mg/kg, s.c.

Role of endogenous prostacyclin in gastric ulcerogenic and healing responses--a study using IP-receptor knockout mice.

Endogenous prostaglandins (PGs) play an important role in the cytoprotective and healing responses in the stomach, by altering various functions, i.e., an increase of the mucosal blood flow, yet the role of prostacyclin (PGI(2)) and its receptor (IP-receptor) in these responses remains unclarified.

Effect of polaprezinc on impaired healing of chronic gastric ulcers in adjuvant-induced arthritic rats--role of insulin-like growth factors (IGF)-1.

Polaprezinc, N-(3-aminopropionyl)-L-histidinatozinc, has been shown to stimulate the production of insulin-like growth factor-1 (IGF-1) in mesenchymal cells, the polypeptide playing a role in the gastric epithelial wound repair. The present study was performed to examine the effect of polaprezinc on the impaired healing of chronic gastric ulcers in adjuvant-induced arthritic rats, in relation to IGF-1. Arthritis was induced in male Dark Agouti (DA) rats by a single injection of Freund's complete adjuvant (FCA), and the gastric ulcers were induced by thermal cauterization (70 degrees C for 30 sec) 7 days after FCA injection.

Renal expression of insulin-like growth factor-l in acute renal failure: a preliminary report.

Renal expression of insulin-like growth factor-I (IGF-I) was examined in the specimens obtained at renal biopsy from five patients with acute renal failure (ARF) at the recovering phase. IGF-I peptide and mRNA were demonstrated in the cytoplasm of the epithelial cells of focal proximal tubules in four patients in whom renal function had been ameliorating. The stainings of IGF-I peptide and mRNA were intense in patients with favorable prognosis.

An adult-onset case of argininosuccinate synthetase deficiency presenting with atypical citrullinemia.

A 52-year-old heavy drinker presented with repeated episodes of disturbance of consciousness and an increase in serum ammonia level, triggered by excessive alcohol intake. He was diagnosed as having adult-onset citrullinemia with deficiency of hepatic argininosuccinate synthetase (ASS) activity. Cranial magnetic resonance imaging (MRI) showed high-intensity lesions in the central pons and the bilateral middle cerebellar peduncles on T2-weighted images.

A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy.

Background: Lipoprotein glomerulopathy (LPG) is characterized by intraglomerular lipoprotein thrombosis and high plasma concentrations of apolipoprotein (apo) E. An apo E variant, apo E2 (Arg145Pro) Sendai, was recently identified in three patients with LPG. We detected a novel point mutation in the apo E gene in a patient with LPG, and we characterized the mutant apo E.

Mesangiolytic glomerulopathy in severe congestive heart failure.

To study the glomerular morphological abnormalities in congestive heart failure (CHF), we analyzed 27 autopsy cases without other causes of renal disease. Their mean age was 59 years, and they showed mild prerenal azotemia. They had generally been treated with digitalis and diuretics, and a few of them with captopril or nifedipine.

Demonstration of DNA replication factor C in human glomerular lesions.

Glomerulosclerosis is a common pathological finding in many human glomerular diseases that ultimately leads to end-stage kidney disease. The regulatory mechanism that controls mesangial proliferation as well as accumulation of mesangial matrix, however, is not known. Recently, a protein factor (MSW) which binds to the specific sequence of the promoter of the alpha 1 and alpha 2 type IV collagen genes was cloned.

[A case of nephrotic syndrome associated with minimal renal amyloidosis--a four-year follow-up].

A 61-year-old male had nephrotic syndrome in association with minimal renal amyloidosis. The amyloid deposits were inconspicuous and had been initially overlooked, and the biopsy specimen was thought to show minimal glomerular changes. Accordingly he was diagnosed as having minimal change nephrotic syndrome (MCNS).

Intraglomerular deposition of intact cross-linked fibrin in IgA nephropathy and Henoch-Schönlein purpura nephritis.

To investigate the significance of intraglomerular coagulation and fibrinolysis in IgA nephropathy (IgA-N) and Henoch-Schönlein purpura nephritis (HSPN), the distribution of intact cross-linked fibrin (XFb) modulated by plasmin activity was examined in 25 patients with IgA-N and in 12 with HSPN. In addition to the conventional method detecting fibrin-related antigen (FRA) with an antibody against fibrinogen, the enhanced intensity of immunoreactivity of cross-linked FRA (KL-FRA) using the monoclonal antibody DD3B6/22 after plasmin exposure was evaluated to assess intraglomerular deposition of intact XFb. Also, intraglomerular invasion of macrophages was detected using the monoclonal antibody KP1 against CD68.