APOE4 impairs myelination via altered cholesterol biosynthesis and transport in oligodendroglia

US12285440B2 · kind B2 · utility

Assignee

• Massachusetts Institute of Technology · US

Inventors

• Joel Blanchard · Arlington, US
• Manolis Kellis · Boston, US
• Li-Huei Tsai · Cambridge, US
• Jose Davila Velderrain · Saltillo, MX
• Leyla Akay · Cambridge, US
• Djuna Von Maydell · Somerville, US
• Audrey Effenberger · Cambridge, US
• Matheus Victor · Cambridge, US

Key dates

• Filing date: Mar 14, 2022
• Grant date: Apr 29, 2025
• Expiry date: Mar 14, 2042

Classification

• Technology area (CPC A): Human Necessities
• CPC primary: A61P25/28
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

The present disclosure provides methods of inhibiting amyloid synthesis in a subject using cyclodextrin and analogs thereof. Small molecules (cyclodextrin) reverse APOE4-associated cholesterol phenotypes and lead to significantly improved myelination both human in vitro cultures and APOE4 targeted replacement mice. This demonstrates that APOE4 alters cholesterol synthesis and transport in oligodendrocytes which impairs myelination. Collectively, this work uncovers a pathogenic role of APOE4 in oligodendrocytes and myelination and enables therapeutic opportunities for Alzheimer's Disease.