Compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one Downregulation of Galectin‐3 Alleviates Amyloid beta-induced Neuroinflammation and Cognitive Impairment in a mouse Alzheimer's disease model

Abstract

Abstract Background: Amyloid β (Aβ) and neuroinflammation are recognized as crucial to the pathogenesis of Alzheimer's disease (AD). Compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one (D30), a pyromeconic acid derivative, inhibits Aβ aggregation and reverses scopolamine-induced cognitive impairment. However, the in vivo therapeutic potential of D30was not known for Aβ-induced neuropathology. Thus, we investigated the effects and mechanisms of D30 in a fibril Aβ(fAβ)-induced AD mouse model. Methods: We established an AD model by intracerebroventricular injection of fAβ to determine whether D30 could alleviate fAβ-induced neuropathology. Behavior tests (Open Field, New Object Recognition, Morris Water Maze) were conducted to evaluate cognitive function. Aβ were assessed by immunohistochemistry, immunofluorescence staining, and immunoblotting of cortex and hippocampus. Glial cell morphology, neuroinflammation, and neuronal properties were assessed by immunofluorescence staining of hippocampal brain slices. Cortex and hippocampus were also subjected to ELISA and immunoblotting assays. The effects of D30 on primary microglia were measured by immunoblotting, immunofluorescence, and real-time quantitative PCR. Results: Compound D30 alleviated fAβ-induced cognitive impairment. D30 promoted the removal of injected fAβ from the hippocampus and cortex and suppressed oxidative stress and activation of microglia and astrocytes. D30 reversed the fAβ-induced loss of dendritic spines and synaptic proteins. We demonstrated for the first time that exogenous intracerebroventricular injection of fAβ greatly increased Galectin-3 (Gal-3) level in the mouse brain, and the increase in Gal-3 was blocked by D30. In addition, D30 activated the p62/Nrf2/HO-1 signaling pathway in primary microglia and promoted the disposal of Aβ and relief of fAβ-induced neuroinflammation. Thus, by its comprehensive activities in Aβ disposal, antioxidation, and anti-neuroinflammation, D30 protected synapses and cognitive function, with a strong involvement in Gal-3 regulation, thereby exhibiting novel AD therapeutic potential.