nnc-26-9100 and Alzheimer-Disease

Microglia are the resident immune cell of the brain involved in the development and progression of Alzheimer's disease (AD). Modulation of microglia activity represents a potential mechanism for treating AD. Herein, the compound NNC 26-9100 (NNC) was evaluated in toxicity, nitric oxide release, Aβ1-42 uptake and cytosolic calcium assays during lipopolysaccharide (LPS)-activated conditions using mouse BV2 microglia cells. After 24 hours, LPS increased cell toxicity in the alamar blue and lactate dehydrogenase assays, increased nitrite release, and increase cytoplasmic calcium. Addition of NNC decreased the LPS-induce lactate dehydrogenase release, had no effect in the alamar blue assay, decreased nitrite release and decreased cytosolic calcium. In the absence of LPS, NNC increased uptake of FITC-tagged Aβ1-42. These data demonstrate that NNC treatment decreases nitrosative stress and microglia cell damage during LPS-induced activation and enhances phagocytosis of Aβ1-42 during non-inflammatory conditions. Thus, NNC 26-9100 may have beneficial effects in AD and in inflammatory diseases of the brain through enhancement of microglial Aβ clearance, and cell protective effects through prevention of elevated cytosolic calcium and inhibition of nitric oxide release.

Topics: Alzheimer Disease; Aminopyridines; Amyloid beta-Peptides; Animals; Calcium; Cell Line; Inflammation; Lipopolysaccharides; Mice; Microglia; Nitric Oxide; Peptide Fragments; Phagocytosis; Thiourea

Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in memory and cognitive impairment. The use of somatostatin receptor subtype-4 (SSTR

Topics: Alzheimer Disease; Aminopyridines; Animals; Brain; Catalase; Down-Regulation; Insulysin; Mice, Transgenic; Microglia; Neprilysin; Phagocytosis; Receptors, Somatostatin; RNA, Messenger; Scavenger Receptors, Class A; Sialic Acid Binding Ig-like Lectin 3; Thiourea; Up-Regulation

Soluble amyloid-β peptide (Aβ) oligomers have been hypothesized to be primary mediators of Alzheimer's disease progression. In this regard, reduction of soluble Aβ-oligomers levels within the brain may provide a viable means in which to treat the disease. Somatostatin receptor subtype-4 (SSTR4) agonists have been proposed to reduce Aβ levels in the brain via enhancement of enzymatic degradation. Herein we evaluated the effect of selective SSTR4 agonist NNC 26-9100 on the changes in learning and soluble Aβ42 oligomer brain content with and without co-administration of the M13-metalloproteinase family enzyme-inhibitor phosphoramidon, using the senescence-accelerated mouse prone-8 (SAMP8) model. NNC 26-9100 treatment (0.2 µg i.c.v. in 2 µL) improved learning, which was blocked by phosphoramidon (1 and 10mM, respectively). NNC 26-9100 decreased total soluble Aβ42, an effect which was blocked by phosphoramidon (10mM). Extracellular, intracellular, and membrane fractions were then isolated from cortical tissue and assessed for soluble oligomer alterations. NNC 26-9100 decreased the Aβ42 trimeric (12 kDa) form within the extracellular and intracellular fractions, and produced a band-split effect of the Aβ42 hexameric (25 kDa) form within the extracellular fraction. These effects were also blocked by phosphoramdon (1 and 10mM, respectively). Subsequent evaluation of NNC 26-9100 in APPswe Tg2576 transgenic mice showed a similar learning improvement and corresponding reduction in soluble Aβ42 oligomers within extracellular, intracellular, and membrane fractions. These data support the hypothesis that NNC 26-9100 reduces soluble Aβ42 oligomers and enhances learning through a phosphoramidon-sensitive metalloproteinase-dependent mechanism.

Topics: Alzheimer Disease; Aminopyridines; Amyloid beta-Peptides; Animals; Blotting, Western; Cerebral Cortex; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Male; Maze Learning; Metalloproteases; Mice; Mice, Transgenic; Receptors, Somatostatin; Thiourea