ApoE4 dysregulation incites depressive symptoms and mitochondrial impairments in mice

Abstract

AbstractApolipoprotein E4 (ApoE4) is involved in the stress‐response processes and is hypothesized to be a risk factor for depression by means of mitochondrial dysfunction. However, their exact roles and underlying mechanisms are largely unknown. ApoE4 transgenic mice (B6. Cg‐ApoEtm1UncCdh18Tg(GFAP−APOE i4)1Hol/J) were subjected to stress (lipopolysaccharides, LPS) to elucidate the aetiology of ApoE4‐induced depression. LPS treatment significantly aggravated depression‐like behaviours, concurrent with neuroinflammation and impaired mitochondrial changes, and melatonin/Urolithin A (UA) + 5‐aminoimidazole‐4‐carboxamide 1‐β‐D‐ribofuranoside (AICAR) reversed these effects in ApoE4 mice. Concurrently, ApoE4 mice exhibited mitophagy deficits, which could be further exacerbated by LPS stimulation, as demonstrated by reduced Atg5, Beclin‐1 and Parkin levels, while PINK1 levels were increased. However, these changes were reversed by melatonin treatment. Additionally, proteomic profiling suggested mitochondria‐related signalling and network changes in ApoE4 mice, which may underlie the exaggerated response to LPS. Furthermore, HEK 293T cells transfected with ApoE4 showed mitochondria‐associated protein and mitophagy defects, including PGC‐1α, TFAM, p‐AMPKα, PINK1 and LC3B impairments. Additionally, it aggravates mitochondrial impairment (particularly mitophagy), which can be attenuated by triggering autophagy. Collectively, ApoE4 dysregulation enhanced depressive behaviour upon LPS stimulation.