Neurobiology of Lipids (ISSN 1683-5506) Vol.6 article 1 -- R Koldamova


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Neurobiol Lipids 6, 1 (17 October 2007)
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AMYLOID PRECURSOR PROTEIN REGULATES BRAIN CHOLESTEROL METABOLISM

Radosveta Koldamova

Dr. Radosveta Koldamova, MD, PhD, Department of Environmental & Occupational Health, University of Pittsburgh, Bridgeside Point Bldg, 100 Technology Drive, Room 306, Pittsburgh, PA 15219-3130 USA
email: radak[at]pitt.edu

Published online: 17 October, 2007 | Article readership
Copyright © 2007 R Koldamova, Licensee Neurobiology of Lipids

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ABSTRACT

There is a scientific evidence, suggesting that amyloid precursor protein (APP) processing and Alzheimer's (AD) amyloid beta generation are regulated by cholesterol. Latest study by Liu et al. published in Neuron (56:66-78, 2007) shines a new light on the connection between cholesterol metabolism and APP processing. At this time the story is reversed - now it appears that APP proteolytic fragments are regulating cholesterol levels in brain and inside the cells.

ARTICLE TEXT

The study by Liu et al. [1] shines a new light on the emerged a decade ago connection between cholesterol metabolism and APP processing [2,3]. However, at this time the story is reversed - now it appears that APP proteolytic fragments are regulating cholesterol levels in brain and inside the cells. In a series of elegant experiments, the authors describe a mechanism by which the C-terminal fragment of APP, named AICD, modulates brain ApoE and cholesterol metabolism by directly regulating the expression and function of the lipoprotein receptor LRP1. Knocking out APP/APLP2 or components of the g-secretase complex significantly affected the expression of LRP1, as well as ApoE and intracellular cholesterol levels. These alterations were partially restored by forced expression of AICD. Finally, Liu et al. provide evidence that deletion of LRP1 in forebrain neurons of adult mice significantly increased ApoE levels, while cholesterol levels were conversely decreased.

What makes this study powerful is that, to confirm their in vitro findings, the authors have used numerous mutated cell lines, including APP/APPL2-DKO and PS1/PS2-DKO primary cells, as well as several lines of knockout mice. As the authors suggest, a possible overall explanation is that the altered expression of LRP significantly affects the catabolism of ApoE, eventually affecting intracellular cholesterol concentration. It is well known that the neuronal uptake of ApoE particles, and possibly ApoE uptake by other cells in brain, is mediated by lipoprotein receptors of the LDLR family [4]. Interestingly, in other studies, brain cholesterol levels were not affected in mice with targeted disruption of genes directly related to cholesterol transport and metabolism such as Abca1, LDRL, and, most importantly, ApoE [5, 6, 7, 8]. In this connection, it would be worth knowing what effect AICD has on the level and lipidation of ApoE-containing lipoproteins in CSF and lipoproteins secreted in the conditioned media of astrocytes isolated from APP/APPL2-DKO or LRP1 KO mice.

PROSPECT

Some questions require further investigation. Because LRP1 and ApoE affect amyloid beta (Ab) clearance [9, 10, 11], it is important to reveal how the lack of LRP1 in LRP1 knockout mice or the suppression of LRP1 expression by g-secretase inhibitors would affect this process. Most importantly, and relevant to AD, it is interesting to see how the familial mutations of presenilin that increase AICD would affect LRP1 expression and ApoE/cholesterol metabolism.

WEB ENHANCED REFERENCES
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1. Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, Herz J, Muglia L, Bu G.
Amyloid Precursor Protein Regulates Brain Apolipoprotein E and Cholesterol Metabolism through Lipoprotein Receptor LRP1. Neuron. 56(1), 66-78 (4 October 2007) [ PubMed ][ NoL Noteworthy record ][ ARF News and Commentary ][ Back2Text ].

2. Sparks DL, Scheff SW, Hunsaker JC, Liu H, Landers T, Gross DR. Induction of Alzheimer-like b-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol.126, 88-94 (1994) [ PubMed ][ Back2Text ].

3. Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci (USA). 95, 6460-4 (1998) [ PubMed ][ Back2Text ].

4. Herz J, Bock HH. Lipoprotein receptors in the nervous system. Annu Rev Biochem. 71, 405-34 (2002) [ PubMed ][ Back2Text ].

5. Han X, Cheng H, Fryer JD, Fagan AM, Holtzman DM. Novel role for apolipoprotein E in the central nervous system. Modulation of sulfatide content. J Biol Chem. 278(10), 8043-51 (2003) [ PubMed ][ ARF Commentary ][ Back2Text ].

6. Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem. 279(39), 40987-93 (2004) [ PubMed ][ ARF Commentary ][ Back2Text ].

7. Elder GA, Cho JY, English DF, Franciosi S, Schmeidler J, Sosa MA, Gasperi RD, Fisher EA, Mathews PM, Haroutunian V, Buxbaum JD. Elevated plasma cholesterol does not affect brain Abeta in mice lacking the low-density lipoprotein receptor. J Neurochem. 102(4), 1220-31 (2007) [ PubMed ][ Back2Text ].

8. Fryer JD, Demattos RB, McCormick LM, O'Dell MA, Spinner ML, Bales KR, Paul SM, Sullivan PM, Parsadanian M, Bu G, Holtzman DM. The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice. J Biol Chem. 280(27), 25754-9 (2005) [ PubMed ][ ARF Commentary ][ Back2Text ].

9. Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J, Higgs R, Liu F, Malkani S, Bales KR, Paul SM. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med. 10(7), 719-26 (2004) [ PubMed ][ Back2Text ].

10. Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, Marky A, Lenting PJ, Wu Z, Zarcone T, Goate A, Mayo K, Perlmutter D, Coma M, Zhong Z, Zlokovic BV. Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med. 13(9), 1029-31 (2007) [ PubMed ][ ARF commentary ][ Back2Text ].

11. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest. 106(12), 1489-99 (2000) [ PubMed ][ Back2Text ].


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This article should be cited in the following way:

Koldamova R. Amyloid precursor protein regulates brain cholesterol metabolism. Neurobiol. Lipids Vol. 6, 1 (2007), Published online October 17, 2007, Available at: http://neurobiologyoflipids.org/content/6/1/

Please note: Because Neurobiology of Lipids is published online only, the articles are identified with an article number rather than with traditional (printed) page numbers. Adobe Acrobat (.PDF) reprint, however, allows citation with page numbers, and serves the algorithmic needs of tenure committees to count published print pages.

^#Footnote: This commentary discusses the following NoL Noteworthy 2007 article [1]: Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, Herz J, Muglia L, Bu G. Amyloid Precursor Protein Regulates Brain Apolipoprotein E and Cholesterol Metabolism through Lipoprotein Receptor LRP1. Neuron. 2007 Oct 4;56(1):66-78. [PubMed Record and Abstract].


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