APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline

Abstract

Population-based studies reveal that apolipoprotein E (APOE) ε4 gene allele is closely associated with late-life depression (LLD). However, its exact role and underlying mechanism remain obscure. The current study found that aged apoE4-targeted replacement (TR) mice displayed obvious depression-like behavior when compared with age-matched apoE3-TR mice. Furthermore, apoE4 increased stress-induced depression-like behaviors, accompanied by declines in the hippocampal 5-HT (1A) radioligand [18F] MPPF uptake evidenced by positron emission tomography (PET). In [18F]-fluorodeoxyglucose PET ([18F]-FDG PET) analyses, the FDG uptake in the prefrontal cortex, temporal cortex and hippocampus of apoE4-TR mice significantly declined when compared with that of apoE3-TR mice after acute stress. Further biochemical analysis revealed that ATP levels in the prefrontal cortex of apoE4-TR mice decreased during aging or stress process and ATP supplementation effectively rescued the depression-like behaviors of elderly apoE4-TR mice. In primary cultured astrocytes from the cortex of apoE-TR mice, apoE4, when compared with apoE3, obviously decreased the mitochondrial membrane potential, mitochondrial respiration, and glycolysis in a culture time-dependent manner. Our findings highlight that apoE4 is a potential risk factor of depression in elderly population by impairing the glucose metabolism, reducing ATP level, and damaging mitochondrial functions in astrocytes, which indicates that in clinical settings ATP supplementation may be effective for elderly depression patients with apoE4 carrier.

Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype

“…Human studies have consistently documented lower CMRglc in subjects possessing one or more APOE ε4 gene, even at early ages (Reiman et al, 1996;Reiman et al, 1998;Small et al, 1995). An age-dependent reduction in glucose transport into the CNS has been reported in the ApoE-TR lines used here (Alata et al, 2015;Fang et al, 2021), though this was reported to occur at ages (8-12 months) far beyond most of the mice we examined. Surprisingly, another ApoE4-expressing model exhibits elevated CMRglc as it progresses into advanced ages (Kotredes et al, 2021).…”

ATP5O Hypo-crotonylation Caused by HDAC2 Hyper-Phosphorylation Is a Primary Detrimental Factor for Downregulated Phospholipid Metabolism under Chronic Stress

“…In our study, the ATP5O level significantly reduced and, accordingly, ATP levels also significantly decreased under CS. The correlation of reduced ATP level with abnormal metabolism has been reported [36,37,46]; however, details regarding how the metabolism is altered are still lacking. Our quantitative crotonyl-omics demonstrated that the crotonylation level of ATP5O decreased the most and much more than another ATP synthase subunit, Atp5f1a, indicating that the decrotonylation activity of HDAC2 has good preference for ATP5O.…”

“…Presumably, ATP5O decrement will significantly decrease the function of ATP synthetase and reduce the cytoplasmic energy level, as verified within CS oocytes (Figure 2(p)) and liver (Figure 3(a)). Because it has been reported that decreased cytoplasmic energy level could cause abnormal metabolism [36,37], we sent plasma samples for fullspectrum metabolomics (Figure 3(b)). At a threshold of CS/control ≥ 1.5 or ≤0.67, there were 435 downregulated and 189 upregulated metabolites, and the downregulated metabolites covered 69.71% of all metabolites (Figures 3(c) and 3(d)).…”

A multi‐hit hypothesis for an APOE4‐dependent pathophysiological state

“…Preclinical evidence suggests that APOE isoform modulates cerebral glucose uptake but with unclear directionality. Reports of increased brain glucose uptake (Venzi et al, 2017) are contradicted by decreased CNS‐wide glucose uptake following dietary/cognitive challenge (Johnson et al, 2019) or environmental stress in aged E4‐TR mice (Fang et al, 2021). Further, young E4‐TR mice demonstrated impaired brain glucose metabolic rate which was rescuable with rapamycin treatment, which also reduced CypA expression (Lin et al, 2017), hinting at a potential conserved target between the APOE4 ‐mediated vascular impairment (Hit 2), neuroinflammation (Hit 3) and metabolic disruption (Hit 6).…”

“…ApoE4 fragments accumulate in the mitochondria and ER, impairing mitochondrial complex function and inducing cellular toxicity. Abbreviations: ApoE4, apolipoprotein E4; GLUT4, glucose transporter 4; IDE, insulin degrading enzyme; PPARy, peroxisome proliferator-activated receptor y.Created with BioRender.com (Johnson et al, 2019) or environmental stress in aged E4-TR mice (Fang et al, 2021). Further, young E4-TR mice demonstrated impaired brain glucose metabolic rate which was rescuable with rapamycin treatment, which also reduced CypA expression (Lin et al, 2017), hinting at a potential conserved target between the APOE4-mediated vascular impairment (Hit 2), neuroinflammation (Hit 3) and metabolic disruption (Hit 6).…”