Full-length amyloid precursor protein regulates lipoprotein metabolism and amyloid- clearance in human astrocytes

Autor(es)

Fong, Lauren K. ^{[1, 2]} ; Yang, Max M. ^{[1, 2]} ; Chaves, Rodrigo dos Santos ^{[1, 2]} ; Reyna, Sol M. ^{[1, 2]} ; Langness, Vanessa F. ^{[1, 2]} ; Woodruff, Grace ^{[1, 2]} ; Roberts, Elizabeth A. ^{[1, 2]} ; Young, Jessica E. ^{[1, 3, 4]} ; Goldstein, Lawrence S. B. ^{[1, 2, 5]}

Afiliação do(s) autor(es)

^[1] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 - USA

^[2] Sanford Consortium Regenerat Med, La Jolla, CA 92093 - USA

^[3] Univ Washington, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 - USA

^[4] Univ Washington, Dept Pathol, Seattle, WA 98195 - USA

^[5] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 - USA

• Tipo de documento: Artigo Científico
• Fonte: Journal of Biological Chemistry; v. 293, n. 29, p. 11341-11357, JUL 20 2018.
• Citações Web of Science: 7

Resumo

Mounting evidence suggests that alterations in cholesterol homeostasis are involved in Alzheimer's disease (AD) pathogenesis. Amyloid precursor protein (APP) or multiple fragments generated by proteolytic processing of APP have previously been implicated in the regulation of cholesterol metabolism. However, the physiological function of APP in regulating lipoprotein homeostasis in astrocytes, which are responsible for de novo cholesterol biosynthesis and regulation in the brain, remains unclear. To address this, here we used CRISPR/Cas9 genome editing to generate isogenic APP-knockout (KO) human induced pluripotent stem cells (hiPSCs) and differentiated them into human astrocytes. We found that APP-KO astrocytes have reduced cholesterol and elevated levels of sterol regulatory element-binding protein (SREBP) target gene transcripts and proteins, which were both downstream consequences of reduced lipoprotein endocytosis. To elucidate which APP fragments regulate cholesterol homeostasis and to examine whether familial AD mutations in APP affect lipoprotein metabolism, we analyzed an isogenic allelic series harboring the APP Swedish and APP V717F variants. Only astrocytes homozygous for the APP Swedish (APP(Swe/Swe)) mutation, which had reduced full-length APP (FL APP) due to increased -secretase cleavage, recapitulated the APP-KO phenotypes. Astrocytic internalization of -amyloid (A), another ligand for low-density lipoprotein (LDL) receptors, was also impaired in APP-KO and APP(Swe/Swe) astrocytes. Finally, impairing cleavage of FL APP through -secretase inhibition in APP(Swe/Swe) astrocytes reversed the LDL and A endocytosis defects. In conclusion, FL APP is involved in the endocytosis of LDL receptor ligands and is required for proper cholesterol homeostasis and A clearance in human astrocytes. (AU)

• Processo FAPESP: 13/18028-9 - Influência do cálcio e das proteínas MIRO sobre o transporte mitocondrial em neurônios humanos derivados de células troncos de pluripotência induzida de pacientes de Alzheimer
• Beneficiário: Rodrigo dos Santos Chaves
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto