+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Reduction of brain beta-amyloid (Abeta) by fluvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, through increase in degradation of amyloid precursor protein C-terminal fragments (APP-CTFs) and Abeta clearance



Reduction of brain beta-amyloid (Abeta) by fluvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, through increase in degradation of amyloid precursor protein C-terminal fragments (APP-CTFs) and Abeta clearance



Journal of Biological Chemistry 285(29): 22091-22102



Epidemiological studies suggest that statins (hydroxymethylglutaryl-CoA reductase inhibitors) could reduce the risk of Alzheimer disease. Although one possible explanation is through an effect on beta-amyloid (Abeta) metabolism, its effect remains to be elucidated. Here, we explored the molecular mechanisms of how statins influence Abeta metabolism. Fluvastatin at clinical doses significantly reduced Abeta and amyloid precursor protein C-terminal fragment (APP-CTF) levels among APP metabolites in the brain of C57BL/6 mice. Chronic intracerebroventricular infusion of lysosomal inhibitors blocked these effects, indicating that up-regulation of the lysosomal degradation of endogenous APP-CTFs is involved in reduced Abeta production. Biochemical analysis suggested that this was mediated by enhanced trafficking of APP-CTFs from endosomes to lysosomes, associated with marked changes of Rab proteins, which regulate endosomal function. In primary neurons, fluvastatin enhanced the degradation of APP-CTFs through an isoprenoid-dependent mechanism. Because our previous study suggests additive effects of fluvastatin on Abeta metabolism, we examined Abeta clearance rates by using the brain efflux index method and found its increased rates at high Abeta levels from brain. As LRP1 in brain microvessels was increased, up-regulation of LRP1-mediated Abeta clearance at the blood-brain barrier might be involved. In cultured brain microvessel endothelial cells, fluvastatin increased LRP1 and the uptake of Abeta, which was blocked by LRP1 antagonists, through an isoprenoid-dependent mechanism. Overall, the present study demonstrated that fluvastatin reduced Abeta level by an isoprenoid-dependent mechanism. These results have important implications for the development of disease-modifying therapy for Alzheimer disease as well as understanding of Abeta metabolism.

(PDF emailed within 0-6 h: $19.90)

Accession: 055432592

Download citation: RISBibTeXText

PMID: 20472556

DOI: 10.1074/jbc.M110.102277


Related references

An alternative approach to amyloid fibrils morphology: CdSe/ZnS quantum dots labelled beta-amyloid peptide fragments Abeta (31-35), Abeta (1-40) and Abeta (1-42). Colloids and Surfaces. B, Biointerfaces 50(2): 104-111, 2006

Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (Abeta) in mammalian lenses, and Abeta has toxic effects on lens epithelial cells. Journal of Biological Chemistry 271(17): 10169-10174, 1996

Alzheimers disease Physiological and pathogenetic role of the amyloid precursor protein , its Abeta-amyloid domain and free Abeta-amyloid peptide. Beyreuther, Konrad , Reprint Author, Christen, Yves, Masters, Colin L Neurodegenerative disorders: Loss of function through gain of function: 97-117, 2001

Angiotensin-converting enzyme converts amyloid beta-protein 1-42 (Abeta(1-42)) to Abeta(1-40), and its inhibition enhances brain Abeta deposition. Journal of Neuroscience 27(32): 8628-8635, 2007

Poly-N-methylated amyloid beta-peptide (Abeta) C-terminal fragments reduce Abeta toxicity in vitro and in Drosophila melanogaster. Journal of Medicinal Chemistry 52(24): 8002-8009, 2010

Single chain variable fragments against beta-amyloid (Abeta) can inhibit Abeta aggregation and prevent abeta-induced neurotoxicity. Biochemistry 43(22): 6959-6967, 2004

Self-oligomerization of NACP, the precursor protein of the non-amyloid beta/A4 protein component of Alzheimers disease amyloid, observed in the presence of a C-terminal Abeta fragment. FEBS Letters 421(1): 73-76, Jan 2, 1998

Substitution of methionine 35 inhibits apoptotic effects of Abeta(31-35) and Abeta(25-35) fragments of amyloid-beta protein in PC12 cells. Medical Science Monitor 11(11): Br381-5, 2005

Abeta(31-35) and Abeta(25-35) fragments of amyloid beta-protein induce cellular death through apoptotic signals: Role of the redox state of methionine-35. Febs Letters 579(13): 2913-2918, 2005

Agrin binds to beta-amyloid (Abeta), accelerates abeta fibril formation, and is localized to Abeta deposits in Alzheimer's disease brain. Molecular and Cellular Neurosciences 15(2): 183-198, 2000

Amyloid beta-protein (Abeta)-containing astrocytes are located preferentially near N-terminal-truncated Abeta deposits in the human entorhinal cortex. Acta Neuropathologica 100(6): 608-617, 2000

Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proceedings of the National Academy of Sciences of the United States of America 100(1): 330-335, 2002

Etiological roles of Abeta and carboxyl terminal peptide fragments of amyloid precursor protein in Alzheimer disease. Tanaka, Chikako [Author], McGeer, Patrick L [Author], Ihara, Yasuo [Author] Neuroscientific basis of dementia 217-224, 2001

Apolipoprotein E co-localizes with newly formed amyloid beta-protein (Abeta) deposits lacking immunoreactivity against N-terminal epitopes of Abeta in a genotype-dependent manner. Acta Neuropathologica 110(5): 459-471, 2005

Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice. Journal of Biological Chemistry 281(7): 4292-4299, 2005