The Contributions of the Endolysosomal Compartment and Autophagy to APOEɛ4 Allele-Mediated Increase in Alzheimer’s Disease Risk

Article type: Review Article

Authors: Asiamah, Ernest Amponsah^{a; b} | Feng, Baofeng^{a; c; d} | Guo, Ruiyun^{a; c} | Yaxing, Xu^{a; c} | Du, Xiaofeng^{a; c} | Liu, Xin^{a; c} | Zhang, Jinyu^{a; c} | Cui, Huixian^{a; c; d; *} | Ma, Jun^{a; c; d; *}

Affiliations: [a] Hebei Medical University-Galway University of Ireland Stem Cell Research Center, Hebei Medical University, Hebei, China | [b] Department of Biomedical Sciences, College of Health and Allied Sciences, University of Cape Coast, PMB UCC, Cape Coast, Ghana | [c] Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei, China | [d] Hebei Technology Innovation Center for Stem Cell and Regenerative Medicine, Hebei, China | [e] Department of Human Anatomy, Hebei Medical University, Hebei, China

Correspondence: [*] Correspondence to: Huixian Cui and Jun Ma, Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Technology Innovation Center for Stem Cell and Regenerative Medicine, Hebei Medical University, Hebei Province 050017, China. E-mail: [email protected], [email protected].

Abstract: Apolipoprotein E4 (APOE4), although yet-to-be fully understood, increases the risk and lowers the age of onset of Alzheimer’s disease (AD), which is the major cause of dementia among elderly individuals. The endosome-lysosome and autophagy pathways, which are necessary for homeostasis in both neurons and glia, are dysregulated even in early AD. Nonetheless, the contributory roles of these pathways to developing AD-related pathologies in APOE4 individuals and models are unclear. Therefore, this review summarizes the dysregulations in the endosome-lysosome and autophagy pathways in APOE4 individuals and non-human models, and how these anomalies contribute to developing AD-relevant pathologies. The available literature suggests that APOE4 causes endosomal enlargement, increases endosomal acidification, impairs endosomal recycling, and downregulates exosome production. APOE4 impairs autophagy initiation and inhibits basal autophagy and autophagy flux. APOE4 promotes lysosome formation and trafficking and causes ApoE to accumulate in lysosomes. APOE4-mediated changes in the endosome, autophagosome and lysosome could promote AD-related features including Aβ accumulation, tau hyperphosphorylation, glial dysfunction, lipid dyshomeostasis, and synaptic defects. ApoE4 protein could mediate APOE4-mediated endosome-lysosome-autophagy changes. ApoE4 impairs vesicle recycling and endosome trafficking, impairs the synthesis of autophagy genes, resists being dissociated from its receptors and degradation, and forms a stable folding intermediate that could disrupt lysosome structure. Drugs such as molecular correctors that target ApoE4 molecular structure and enhance autophagy may ameliorate the endosome-lysosome-autophagy-mediated increase in AD risk in APOE4 individuals.

Keywords: Alzheimer’s disease, Apolipoprotein E, endosomes, lysosomes

DOI: 10.3233/JAD-230658

Journal: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1007-1031, 2024