The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease

CE enhance the production of Aβ in vivo and in vitro, indicating that CE can contribute to AD pathogenesis.

“CE enhance the production of Aβ in vivo and in vitro indicating that CE can contribute to AD pathogenesis (Di Paolo and Kim, 2011, Hutter-Paier et al., 2004, Huttunen et al., 2009, Puglielli et al., 2001, Puglielli et al., 2003).”

Previous studies using commercial ACAT inhibitors including AVAS, and ACAT-knockout mice, show reduced AD-like pathology and APP processing in familial AD-transgenic mice.

“Previous studies using commercial ACAT inhibitors, including avasimibe (AVAS), as well as ACAT-knock out (KO) mice, exhibit reduced AD-like pathology and amyloid precursor protein (APP) processing in familial AD (FAD)-transgenic (Tg) mice.”

Using non-isoform-specific ACAT inhibitors like AVAS, APP processing is reduced in brains of FAD-Tg mice.

“Using non-isoform specific ACAT inhibitors like AVAS, APP processing is reduced in brains of FAD-Tg mice ([75, 76]; reviewed in [77]).”

In this study, AVAS treatment reduced both amyloidogenic and non-amyloidogenic processing of APP, with no change in total APP.

“we did see a reduction in both amyloidogenic and non-amyloidogenic processing of APP, with no change in total APP (Fig. 8)”

ACAT inhibition significantly reduces palmitoylated APP in lipid rafts, thus reducing APP processing.

“ACAT inhibition significantly reduces palmitoylated APP in lipid rafts, thus reducing APP processing [75–77, 105, 131].”

In this study, AVAS did not produce an overall improvement during Morris water maze acquisition trials; latency to platform on day 1 was lower in AVAS- versus vehicle control-treated mice, suggesting enhanced learning on that day only, and latency was not significantly different between groups for days 2-5.

“While we did not see an overall improvement during MWM acquisition trials with AVAS treatment, the latency to platform on day 1 was lower in AVAS- vs. VC-treated mice, suggesting that the AVAS treatment enhanced learning on that day only; the latency to platform was not significantly different between VC- and AVAS-treated mice for days 2–5 (Fig. 3b), an effect observed with other AVAS-treated FAD-”

Interventions that promote cholesterol-regulating processes reduce Aβ pathology, including increasing ER-free cholesterol via inhibiting cholesteryl ester formation by ACAT1 inhibition.

“Interestingly, interventions that promote these processes reduce Aβ pathology, including increasing ER-FC via inhibiting CE formation by ACAT1 inhibition [74, 75, 103, 111].”

AVAS reduces soluble oligomeric Aβ, soluble and insoluble Aβ42, Aβ deposition, amyloid deposition, and neuroinflammation in a FAD-Tg mouse expressing human apoE4, not mouse apoE, and without modifying the lipidation state of apoE particles.

“Specifically, we show a reduction in soluble oAβ, soluble and insoluble Aβ42 levels, Aβ deposition, amyloid deposition, and neuroinflammation (Figs. 5 and 6) [75, 76]. Remarkably, this occurs in a FAD-Tg-mouse expressing h-apoE4, not m-apoE, and without modifying the lipidation state of apoE-particles (Fig. 7).”

CE reduction has previously been reported to reduce Aβ levels.

“In addition to our findings on pTau, CE reduction has previously been reported to reduce Aβ levels (Hutter-Paier et al., 2004, Huttunen et al., 2009, Puglielli et al., 2001), and Aβ secretion from our iPSC-derived neurons was also decreased by statins (Figure 3D).”

Lipid droplets are composed of neutral lipids, primarily cholesteryl esters and triacylglycerol, so the data are consistent with previous findings that inhibition of ACAT reduces brain cholesteryl ester levels.

“LD are composed of neutral lipids, primarily CE and TAG, thus our data are consistent with previous findings that inhibition of ACAT reduces brain CE levels [75, 76].”

Previous studies demonstrate that ACAT inhibition improves Morris water maze learning.

“With MWM, previous studies demonstrate that ACAT inhibition improves MWM learning [75].”