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The Acyl-Coenzyme A: Cholesterol Acyltransferase Inhibitor CI-1011 Reverses Diffuse Brain Amyloid Pathology in Aged Amyloid Precursor Protein Transgenic Mice
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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]).”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [76]
The Introduction identifies CI-1011 as avasimibe, and the Results report reduced APP processing in the brains of hAPP transgenic mice treated with it. Our copy does not establish the claim’s additional description of avasimibe as non-isoform-specific. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAVAS treatment reduces APP processing, reducing the production of Aβ, consistent with previous studies using FAD-Tg mouse models expressing mouse apoE.
“Thus, AVAS treatment reduces APP processing, reducing the production of Aβ, consistent with previous studies using FAD-Tg mouse models expressing m-apoE [76, 105].”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [76]
The Introduction identifies CI-1011 as avasimibe, and the Results report reduced APP cleavage fragments and Aβ levels in treated hAPP transgenic mice (page unavailable). The Discussion suggests that treatment may limit generation of new Aβ, but presents this mechanism as a possibility rather than an established reduction in Aβ production. The passages do not specify whether the mice expressed mouse ApoE. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAVAS 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).”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [76]
The Results report that CI-1011 (avasimibe) reduced diffuse amyloid deposits and SDS-extractable Aβ42 in aged hAPP mice. They do not report a reduction in soluble oligomeric Aβ, and the change in formic-acid-extracted Aβ42 was not significant. The paper reports reduced cortical astrogliosis but increased hippocampal microglial activation, rather than an unqualified reduction in neuroinflammation. The h-apoE4 and unchanged apoE-particle-lipidation statements appear in the citing paper’s next sentence, to which this citation is not attached; this source does not establish them. (LLM, conf=0.88)
Experimental — accuracy not yet measuredACAT 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].”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [76]
The Results section ('ACAT Inhibition by CI-1011 Reduces APP Processing and Aβ Generation in Cells'; page unavailable) reports reduced APP C-terminal fragments and secreted Aβ after CI-1011 treatment, supporting reduced APP processing. The paper does not report a significant reduction in palmitoylated APP in lipid rafts or establish that as the mechanism; its Discussion instead proposes an effect on APP trafficking and maturation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn 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)”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [76]
The Results sections report that CI-1011 (avasimibe) reduced both APP-C99 and APP-C83, supporting reduced amyloidogenic and non-amyloidogenic processing. The copy does not establish that total APP was unchanged; the Discussion instead says treatment appears to affect mature APP. Page numbers are unavailable in the indexed copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
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.”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [76]
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].”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [76]
AVAS has previously been administered to FAD-Tg mice by subcutaneous pellet.
“AVAS has previously been administered to FAD-Tg mice by subcutaneous pellet [76].”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [76]
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van der Kant, R., Langness, V. F., Herrera, C. M., Williams, D. A., Fong, L. K., Leestemaker, Y., Steenvoorden, E., Rynearson, K. D., Brouwers, J. F., Helms, J. B., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2018.12.013 · Cited by 350
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“Previous work from this and other laboratories showed that blocking ACAT1 decreases amyloidopathy in cell culture and in mouse models for AD (Puglielli et al., 2001; Hutter-Paier et al., 2004; Bryleva et al., 2010; Huttunen et al., 2010; Bhattacharyya et al., 2013; Murphy et al., 2013).”
BackgroundResultValencia-Olvera, A. C., Balu, D., Faulk, N., Amiridis, A., Wang, Y., Pham, C., Avila-Munoz, E., York, J. M., Thatcher, G. R. J., & LaDu, M. J. (2023) · Neurotherapeutics · doi:10.1007/s13311-023-01375-3 · Cited by 22
Metadata
- Authors
- Huttunen, H. J., Havas, D., Peach, C., Barren, C., Duller, S., Xia, W., Frosch, M. P., Hutter-Paier, B., Windisch, M., & Kovacs, D. M.
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-08
- Volume
- 69
- Issue
- 8
- Pages
- 777-788
- ISSN
- 0022-3069
- 1554-6578
- PMC
- PMC2918281
- Cited by
- 54
- References
- 11
- Language
- en
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