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Volume 8
Journal of Alzheimers Disease & Parkinsonism
ISSN: 2161-0460
Dementia 2018
October 29-31, 2018
Page 40
Notes:
conference
series
.com
October 29-31, 2018 | Valencia, Spain
12
th
International Conference on
Alzheimer’s Disease & Dementia
T Y Chang et al., J Alzheimers Dis Parkinsonism 2018, Volume 8
DOI: 10.4172/2161-0460-C7-054
Mobilizing cholesterol in the brain to treat Niemann-Pick type C disease and Alzheimer’s disease
A
ll cells require cholesterol and a portion of cellular cholesterol is stored as 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 dieases, 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 two neurodegenerative dieases i.e., 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. 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 provide 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 includes reducing Abeta production, increasing oligomeric Abeta degradation
and increasing unhyperphosphorylated mutant human tau degradation. ACAT1 blockage also ameliorates the cognitive deficits
of the AD in mouse. In summary, we show that inhibiting ACAT1 mobilizes a specific cholesterol pool in the brain to benefit two
different neurodegenerative diseases i.e., NPCD and AD.
Biography
TY Chang and Catherine Chang are a husband/wife team, and share the same laboratory, with TY as the PI and Cathy as the co-PI, at Geisel School of Medicine at
Dartmouth. They have been working on cholesterol metabolism research for more than four decades. The Changs and their colleagues did ground breaking work by
identifying the gene that encodes the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1). Subsequently, they performed extensive
functional analysis of the enzyme. More recently, they demonstrated ACAT1 as a potential target for treating several human diseases, including Alzheimer’s disease and
Niemann-Pick type C disease.
Ta.Yuan.Chang@Dartmouth.EduT Y Chang & Catherine Chang
Geisel School of Medicine, USA