Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction in a Mouse Model That Exhibits Age-Dependent Progression of Alzheimer's Disease-Related Pathology

Chronic MW-151 administration attenuates microglial activation. A, Representative images of IBA1-stained microglia in cortex of 11-month old APP/PS1 mouse, demonstrating the positive pixel and nuclear algorithms used for quantification of the staining. A computer-generated markup of the algorithm is created by the ScanScope software, which validates the specificity of the method. In the positive pixel algorithm, the microglia shown in shades of gray (indicating intensity of positive staining) is segregated from the background shown as black. The markup in the nuclear algorithm shows the reliable detection and quantification of individual cells (shown by the black markup). B, C, The APP/PS1 mice treated with vehicle (veh; gray bars) show increased microglial staining compared to WT mice treated with vehicle (white bars). MW-151 treatment of the APP/PS1 mice (black bars) reduced the microglial activation as assessed by either the stained area (B) or the number of stained microglia (C). *p < 0.05 compared to vehicle-treated APP/PS1 mice. **p < 0.01 compared to vehicle-treated APP/PS1 mice.

Chronic MW-151 administration attenuates astrocyte activation. A, Representative images of GFAP-stained sections. B, The APP/PS1 mice treated with vehicle (veh; gray bars) show increased astrocyte staining in cortex compared to WT mice treated with vehicle (white bars). MW-151 treatment of the APP/PS1 mice (black bars) reduced the astrocyte activation. C, MW-151 treatment had no effect on GFAP mRNA levels but did reduce mRNA levels of two other astrocyte markers, S100B and vimentin. **p < 0.01 compared to vehicle-treated APP/PS1 mice.

Chronic MW-151 administration prevents synaptic loss. Neocortex tissue was analyzed for the levels of synaptic proteins by Western blots. Compared to WT mice treated with vehicle (veh; white bars), the APP/PS1 mice treated with vehicle (gray bars) show reduced levels of the synaptic proteins PSD95 (A), synaptophysin (B), syntaxin (C), and SNAP25 (D). MW-151 treatment of the APP/PS1 mice protected against this loss of synaptic protein levels, restoring the levels back toward WT values. *p < 0.05 compared to vehicle-treated APP/PS1 mice.

Effects of short-term MW-151 treatment in acute intervention paradigm. Eleven-month-old mice were treated with either saline vehicle (veh; white bars, WT; gray bars, APP/PS1) or with 2.5 mg/kg/d MW-151 i.p. (black bars, APP/PS) once daily for 1 week. Neocortex tissue was harvested and endpoints were measured. A, Short-term MW-151 treatment reduced the levels of IL-1β, but not IL-10, and had no effect on microglial (IBA1) or astrocyte (GFAP) activation. B, MW-151 treatment prevented the loss of PSD95 and synaptophysin, but the protection against syntaxin and SNAP25 loss did not reach significance. *p < 0.05 compared to vehicle-treated APP/PS1 mice.

No effect of MW-151 treatment on Aβ pathology. A, Representative images of Aβ-stained hemi-brain sections. B, C, In either the chronic intervention paradigm (B) or the acute intervention paradigm (C), MW-151 treatment of APP/PS1 mice did not reduce the amyloid plaque load when measured as a percentage of the area stained or as the number of plaques per unit area. There were also no differences in the number of small (20–300), medium (301–1000), or large (1001-∞) amyloid plaques detected. MW-151 treatment of APP/PS1 mice also had no significant effect on the levels of soluble or aggregated forms of Aβ, as measured by levels of Aβ40 or Aβ42 in PBS-soluble and FA-soluble fractions. veh, Vehicle.