The Effects of APOE4 on Mitochondrial Dynamics and Proteins in vivo

Article type: Research Article

Authors: Simonovitch, Shira^a | Schmukler, Eran^a | Masliah, Eliezer^{b; c; d} | Pinkas-Kramarski, Ronit^a | Michaelson, Daniel M.^{a; *}

Affiliations: [a] Department of Neurobiology, Sagol School of Neuroscience, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel | [b] Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA | [c] Department Neurosciences, School of Medicine, University of California, La Jolla, San Diego, CA, USA | [d] Department of Pathology, School of Medicine, University of California, La Jolla, San Diego, CA, USA

Correspondence: [*] Correspondence to: Daniel M. Michaelson, Department of Neurobiology, Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel. Tel.: +972 3 640 9624; E-mail: [email protected].

Abstract: This study examined the effects of apolipoprotein E4 (APOE4), the most prevalent genetic risk factor for Alzheimer’s disease (AD), on proteins involved in mitochondrial dynamics and autophagy, in the hippocampus of targeted replacement mice. Immunohistochemical measurements revealed that the levels of the mitochondrial fusion-mediating protein, MFN1, were higher, whereas those of corresponding fission-regulating protein, DRP-1, were lower in the hippocampus of ApoE4 mice than in the corresponding ApoE3 mice, indicating that APOE4 is associated with increased mitochondrial fusion and decreased fission. A similar ApoE4-driven decrease in DRP-1 was also observed in AD brains. The levels of the mitochondrial proteins COX1 and Tom40, were higher in the ApoE4 mice, which is consistent with the increased fusion. Measurements of the levels of cleaved PINK1 and parkin, which mark and target mitochondria for mitophagic degradation, revealed lower levels of cleaved PINK1, suggesting reduced mitochondrial membrane potential, and higher levels of parkin in the hippocampus of ApoE4 compared with the ApoE3 mice, indicating altered mitophagy. The levels of the ubiquitin-binding scaffold protein, p62/SQSTM1, which directs selected cargo to the autophagosomes, were also higher in the ApoE4 mice. These findings suggest that APOE4 is associated with enhanced mitochondrial fusion and decreased fission. Additionally, the results indicate that mitophagy/autophagy is reduced in ApoE4 mice, resulting in higher levels of proteins such as parkin and p62, which are normally degraded during this process. Taken together, these results suggest a novel mechanism that may underlie the pathological effects of APOE4 and indicate that use of APOE4 genotyping could pave the way for identification of novel APOE4-related therapeutic targets.

Keywords: Alzheimer’s disease, apolipoprotein E4, autophagy, mitochondrial dynamics, mitophagy

DOI: 10.3233/JAD-190074

Journal: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 861-875, 2019