Somatostatin Receptor Subtype‐4 Agonist Increases Microglia Amyloid‐beta 1‐42 Uptake

Abstract

This research evaluated the somatostatin receptor subtype‐4 (SSTR4) agonist, NNC 26‐9100, on microglial amyloid‐beta 1‐42 (Aβ42) uptake with inflammatory stimulation. Microglia mediated events have been identified as critical to Alzheimer's disease (AD) progression. Considering microglia have been shown to express SSTR4 and have the capacity to take up and degrade hallmark Aβ isoforms, we hypothesized that a SSTR4 agonist may increase beta amyloid uptake dependent upon the level of inflammation.The effect of NNC 26‐9100 was evaluated in immortalized BV2 microglia cells against inflammatory activation using lipopolysaccharide (LPS). BV2 cells were plated at a density of 62,500 cells/cm2 in 12 well plates for 24hrs. FITC‐Aβ42 (100nM) uptake was then assessed following 24hr NNC 26‐9100 treatment (0, 1μM) against increasing concentrations of LPS (0, 0.83, 8.3 ng/mL) by flow cytometry. A two‐way ANOVA with Tukey post‐hoc tests were utilized to assess the impact of NNC 26‐9100, LPS and their interaction on FITC‐Aβ42 uptake. Both LPS (p<0.0001) and NNC 26‐9100 (p=0.0004) significantly affected mean FITCA‐β42 uptake by BV2 cells. While no significant interaction was found between LPS and NNC 26‐9100 on mean FITC‐Aβ42 uptake (p=0.2963), FITC‐Aβ42 uptake significantly increased with each additional increase in LPS (p<0.0001, Tukey). Moreover, FITC‐Aβ42 uptake significantly increased with 1 μM NNC 26‐9100 treatment when compared to vehicle control (p=0.0004, Tukey).In conclusion, the SSTR4 agonist NNC 26‐9100 and LPS significantly increased microglial uptake of Aβ42. These results identify a novel mechanism for enhancing microglial uptake of Aβ42 by an SSTR4 agonist under inflammatory conditions.Support or Funding InformationThis work is supported by the National Institutes of Health, National Institute of Aging (R01AG047858)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.