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Cited by 48

The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.

Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway

Huttunen, Henri J., Peach, Camilla, Bhattacharyya, Raja, Barren, Cory, Pettingell, Warren, Hutter-Paier, Birgit, Windisch, Manfred, Berezovska, Oksana, Kovacs, Dora M.·2009·The FASEB Journal
DOI 10.1096/fj.09-134999
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Abstract

Amyloid β‐peptide (Aβ) has a central role in the pathogenesis of Alzheimer's disease (AD). Cellular cholesterol homeostasis regulates endoproteo‐ lytic generation of Aβ from the amyloid precursor protein (APP). Previous studies have identified acyl‐ coenzyme A: cholesterol acyltransferase (ACAT)’ an enzyme that regulates subcellular cholesterol distribu‐tion, as a potential therapeutic target for AD. Inhibition of ACAT activity decreases Aβ generation in cell‐ and animal‐based models of AD through an unknown mechanism. Here we show that ACAT inhibition retains a fraction of APP molecules in the early secretory pathway, limiting the availability of APP for secretase‐ mediated proteolytic processing. ACAT inhibitors delayed the trafficking of immature APP molecules from the endoplasmic reticulum (ER) as shown by metabolic labeling and live‐cell imaging. This resulted in partial ER retention of APP and enhanced ER‐associated deg‐radation of APP by the proteasome, without activation of the unfolded protein response pathway. The ratio of mature APP to immature APP was reduced in brains of mice treated with ACAT inhibitors’ and strongly correlated with reduced brain APP‐C99 and cerebrospinal fluid Aβ levels in individual animals. Our results identify a novel ACAT‐dependent mechanism that regulates secretory trafficking of APP, likely contributing to decreased Aβ generation in vivo. —Huttunen, H. J., Peach, C., Bhattacharyya, R., Barren, C., Pettingell, W., Hutter‐Paier, B., Windisch, M., Berezovska, O., Kovacs, D. M. Inhibition of acyl‐coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway. FASEB J. 23, 3819‐3828 (2009). www.fasebj.org

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Crossref · 10.1096/fj.09-134999

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  • CE-dependent regulation of Aβ generation is mediated by altered trafficking of APP through the early secretory pathway.

    “CE-dependent regulation of Aβ generation is mediated by altered trafficking of APP through the early secretory pathway (Huttunen et al., 2009).”

    From Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer’s Disease Neurons (2019) · cites this paper as Huttunen et al., 2009

    The Discussion (page not specified) says ACAT inhibition alters APP trafficking in the early secretory pathway, reducing APP maturation and its availability for Aβ generation. But the paper describes this as a suggested contributing mechanism, not definitive mediation; it also does not isolate reduced cholesteryl ester production from other effects of ACAT inhibition. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • 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).”

    From Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer’s Disease Neurons (2019) · cites this paper as Huttunen et al., 2009

    The Abstract reports that ACAT inhibition decreases Aβ generation in cell- and animal-based models, and the Discussion says reduced ACAT activity reduces cholesteryl ester production. This supports a link between cholesterol esterification and Aβ, but the paper does not show that cholesteryl esters themselves enhance Aβ production in vivo or in vitro. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • AVAS 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 [105]

    The Results report that ACAT inhibitors reduced mature APP and APP processing products, and describe reduced Aβ in treated transgenic mice. However, the treatments named are CP-113,818 and CI-1011, not AVAS; the Materials and Methods describe the hAPP transgenic mice but do not establish that they expressed mouse apoE. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • 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].”

    From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [105]

    The Results report reduced mature APP and APP processing fragments after ACAT inhibition, and the Discussion links reduced APP maturation to reduced Aβ generation (page numbers unavailable). The paper does not report a reduction in palmitoylated APP in lipid rafts or establish that as the mechanism. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • 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).”

    From Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer’s Disease Neurons (2019) · cites this paper as Huttunen et al., 2009

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Metadata

Authors
Huttunen, H. J., Peach, C., Bhattacharyya, R., Barren, C., Pettingell, W., Hutter-Paier, B., Windisch, M., Berezovska, O., & Kovacs, D. M.
Affiliations
  • Neurobiology of Disease Laboratory Genetics and Aging Research Unit Harvard Medical School Charlestown MA USA
  • Department of Neurology Massachusetts General Hospital Harvard Medical School Charlestown MA USA
  • MassGeneral Institute for Neurodegenerative Disease Harvard Medical School Charlestown MA USA
Venue
The FASEB Journal
Publisher
Wiley
Published
2009-07-22
Volume
23
Issue
11
Pages
3819-3828
ISSN
  • 0892-6638
  • 1530-6860
DOI
10.1096/fj.09-134999
Cited by
48
References
5
Language
en
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Funders
  • National Institutes of Health (R01 NS45860)
  • Maud Kuistilan Muistosäätiö (CI-1011, CP-113, CP-818)

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