of the administrative supplement proposal for the parent grant ?Alleviating lysosomal lipid defects in ADRD by blocking cholesterol storage? The long-term goal of this laboratory is to produce cholesterol metabolism-based therapeutics to treat AD and ADRDs. Vascular dementia (VaD), an ADRD, is the second most common form of dementia after AD in the US. The etiology of VaD is complex, but is closely associated with dyslipidemia, atherosclerosis, stroke, and diabetes. Atherosclerosis is characterized by accumulation of cholesterol, cholesteryl esters and other lipids in macrophages and smooth muscle cells within the arterial walls. Acyl coenzyme A: cholesterol acyltransferase 1 (ACAT1) is an enzyme that converts cholesterol to cholesterol esters for storage in all cells, including macrophages, smooth muscle cells, as well as microglia and neurons in the brain. Our laboratory has been working on ACAT1 for several decades. We and others demonstrated that in mouse models, inhibiting ACAT1 benefit several diseases, including atherosclerosis, diet induced obesity, and AD. ApoE is a lipoprotein that transports cholesterol and other lipids in the body and in the brain. Apoe3 is the major allele. Apoe4, a minor allele, is a major genetic risk factor for AD; it is also a genetic risk factor for stroke associated VaD. It is desirable to produce animal models that partially recapitulate the essential features of VaD, such that candidate drug(s) can be tested at the preclinical level. However, at present, no mouse model for atherosclerosis associated VaD in ApoE isoform specific manner is available. To begin to fill this void, in the supplement request, we propose to produce such a model, and we refer it as the Athero/E3 and Athero/E4 mice. Compound F is a clinically approved small molecule ACAT1 inhibitor, originally intended to treat atherosclerosis, but was abandoned because compound F was not as efficient as statin in reducing serum cholesterol levels in men. Whether F was permeable to blood brain barrier was unknown. We have developed a nanoparticle platform and showed that F present in this nanoparticle is permeable to blood brain barrier. We have also shown that after IP injections to mice, nanoparticle F efficiently inhibited ACAT1 in body cells and in brain cells. In the supplement request, we propose to use nanoparticle F to treat the Athero/E3 and Athero/E4 mice under Western diet.
Supplement Narrative The outcomes of the supplement proposal will determine at the proof-of-principle level whether a clinically tested drug originally intended to treat atherosclerosis can be repurposed to treat 2 neurodegenerative diseases, VaD, and NPCD.
