Achucarro Seminars

25 Oct [2018]

at 16.00 CET

Mobilizing Cholesterol in the Brain to Treat Niemann-Pick Type C Disease and Alzheimer's Disease

Dr. T.Y. Chang and Dr. Catherine Chang

Dartmouth College (Hanover, USA)


Abstract

All cells require cholesterol; a portion of cellular cholesterol is stored sa cholesterol esters; this process is catalyzed by the storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1). Once formed, cholesterol esters cannot substitute the functions of cholesterol. In certain neurodegenerative diseases, needs for additional cholesterol in the brain arise. Inhibiting ACAT1 may benefit these diseases, by preventing cholesterol from being stored, thus providing the additional cholesterol that the diseased cells need. We tested this idea in 2 neurodegenerative diseases: Niemann-Pick Type C disease (NPCD), and Alzheimer's disease (AD). NPCD is a rare and genetic neurodegenerative disease. The NPCD patients almost invariably die before reaching teenage year. In mutant NPC cells, malfunction in endosomal cholesterol egress occurs, causing chronic functional cholesterol deficiency in the plasma membrane and Golgi membrane. We show that Acat1 KO or ACAT1 inhibitors provides more cholesterol to Golgi membranes of mutant NPC1 cells. In vivo, Acat1 KO increases the life span and improves several other distinguishing features of the mutant NPC1 mouse. We next show that in a mouse model for AD, inhibiting ACAT1 provides more cholesterol to cell membranes of neuronal cells, and produces multiple benefits that include: reducing Abeta production, increasing oligomeric Abeta degradation, and increasing unhyperphosphorylated mutant human Tau degradation. ACAT1 blockage also ameliorates the cognitive defcits of the AD mouse. In summary, we show that inhibiting ACAT1 mobilizes a specific cholesterol pool in the brain to benefits 2 different neurodegenerative diseases, NPCD and AD

 
This seminar will be held at the "Salon de Grados" on the Faculty of Medicine and Nursery of the UPV/EHU (Campus of Leioa, Bizkaia)


Host: Mazahir T. Hasan

 

https://geiselmed.dartmouth.edu/chang/

 

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