Identification of<em> APOE4-</em>driven lipid accumulation in the aging brain with compromised myelin integrity — The Association Specialists
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  3. Identification of APOE4-driven lipid accumulation in the aging brain with compromised myelin integrity

Identification of APOE4-driven lipid accumulation in the aging brain with compromised myelin integrity (#3)

Gerald W.Y. Cheng 1 , Jianpan Huang 2 , Shirley Zhang 3 , Martin H.Y. Yeung 1 , Pei Cai 2 , Zilin Chen 4 , Sunny H.S. Yeung 1 , Henry K.F. Mak 2 , Kannie W.Y. Chan 4 , Karl Herrup 5 , Kai-Hei Tse 1 6 7
  1. Department of Health Technology and Informatics, , The Hong Kong Polytechnic University , Kowloon, Hong Kong
  2. Department of Diagnostic Radiology, The University of Hong Kong , Hong Kong
  3. Department of Rehabilitation Sciences, The Hong Kong Polytechnic University , Kowloong, Hong Kong
  4. Department of Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong
  5. Department of Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
  6. Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia
  7. Royal Prince Alfred Hospital, Sydney, NSW, Australia

Apolipoprotein E allele ε4 (APOE4) is the most significant genetic risk factor for sporadic Alzheimer’s disease (sAD). We reported earlier that myelinating oligodendrocytes (OL) are lost in APOE4 carrier brain and APOE4 protein impairs astrocyte-to-OL lipid transport and OL differentiation, independent of amyloid plaque formation. Here, we hypothesize that APOE4 compromises intrinsic myelin integrity by causing lipid buildup in the aging brain. First, we examined the magnetic resonance spectroscopy (MRS) of a retrospective cohort of 80 healthy individuals (mean age=51 [20-84] years; 62.5% female).In human, MRS detected a significant increase of lipid (0.9-ppm, +4.41-folds, P=0.0174; 1.3-ppm, +4.81-folds, P=0.0002) in the anterior cingulate of APOE4 carriers above 40 years of age, but not in young cases. These human findings were then verified in a cohort of humanized APOE knock-in mice (hAPOE3 and hAPOE4) at 6, 10 and 16 months old (n=46). While body composition was unchanged, hAPOE4 mice showed a significantly reduced basal metabolic rate, activity and energy expenditure than hAPOE3. At 10-month-old, but not earlier. Importantly, MRS revealed substantial lipid buildup in hAPOE4 mouse brains (0.9-ppm, +17.7%, P=0.0066; 1.3-ppm, +22.9%, P=0.043), concurrent with compromised myelin integrity detected by diffusion kurtosis imaging(mean, axial and radial diffusivity, P<0.05). Liquid chromatography-mass spectrometry identified the accumulated lipids as being enriched in the ceramide pathway, a key metabolite for myelination. Further MALDI-TOF imaging and transcriptomic analyses are underway to confirm these results. In conclusion, APOE4 may lead to abnormal lipid accumulation and myelin degradation in the aging brain, potentially increasing the risk for sAD.