ANGPTL4 promoted the cognitive impairment in vascular dementia via increasing integrin/p-Syk signalings induced mitochondrial autophagy and apoptosis in the hippocampus

The aim of this study was to investigate the effects and mechanisms of ANGPTL4 on cognitive impairment in vascular dementia rats. 36 SD rats were randomly divided into Sham(n= 9), VaD(n= 9), VaD + ANGPTL4 OE(n= 9), and VaD + ANGPTL4 KD(n= 9). A bilateral carotid artery ligation (2-VO) rat VaD was established to study the effects of ANGPTL4. Spatial memory was tested in rats using the Morris water maze. Morphological changes of neurons were detected in the CA1 region of the hippocampus by hematoxylin-eosin staining. The expression of ANGPTL4, p-Syk in the cells of hippocampal CA1 area was also detected by immunohistochemistry. Afterwards, protein expression of ANGPTL4, p-Syk, p-JNK, BNIP3 was detected by Western blot (WB). Afterwards, the mechanism of ANGPTL4 effect on cognitive impairment in vascular dementia rats was further explored by ANGPTL4 OE hippocampal cells 1%O₂ low-serum low-glucose stimulation with Syk inhibitor, JNK inhibitor. ANGPTL4 OE aggravated cognitive dysfunction in 2VO rats. ANGPTL4 KD treatment improved the memory performance of 2VO rats.Hippocampal tissue damage was obvious in the VaD group.Hippocampal tissue damage was aggravated in the ANGPTL4 OE group (P < 0.001).ANGPTL4 KD group Pathological features were significantly improved(P < 0.001). WB assay showed that the expression of ANGPTL4, p-Syk, p-JNK, and BNIP3 proteins was increased in 2VO rats(P < 0.05), which was further up-regulated by ANGPTL4 OE treatment, and significantly inhibited by ANGPTL4 KD treatment in 2VO rats(P < 0.05). In vitro cellular experiments revealed that ANGPTL4 OE treatment again up-regulated ANGPTL4, integrin, p-Syk, and p-JNK protein expression consistent with the in vivo results(P < 0.05), where the Syk inhibitor suppressed both p-Syk, and p-JNK protein expression(P < 0.05). It is also worth noting that the mitochondrial autophagy-related proteins BNIP3, PINK1, Parkin and JC-1 mitochondrial membrane potential assayed by wb revealed that ANGPTL4 OE treatment exacerbated mitochondrial stress(P < 0.05) and apoptosis(P < 0.05) in hippocampal cells, and that Syk inhibitor, and JNK inhibitor significantly inhibited the modulation of ANGPTL4 OE(P < 0.05). ANGPTL4 promotes mitochondrial autophagy and apoptosis in the hippocampal CA1 region by activating the integrin/p-Syk signalling pathway, thus aggravating cognitive impairment in vascular dementia rats.