Retrospective clinical studies indicate that individuals chronically treated with cholesterol synthesis inhibitors, statins, are at lower risk of developing AD (Alzheimer's disease). Moreover, treatment of guinea pigs with high doses of simvastatin or drastic reduction of cholesterol in cultured cells decrease Aβ (β-amyloid peptide) production. These data sustain the concept that high brain cholesterol is responsible for Aβ accumulation in AD, providing the scientific support for the proposed use of statins to prevent this disease. However, a number of unresolved issues raise doubts that high brain cholesterol is to blame. First, it has not been shown that higher neuronal cholesterol increases Abeta production. Secondly, it has not been demonstrated that neurons in AD have more cholesterol than control neurons. On the contrary, the brains of AD patients show a specific down-regulation of seladin-1, a protein involved in cholesterol synthesis, and low membrane cholesterol was observed in hippocampal membranes of ApoE4 (apolipoprotein E4) AD cases. This effect was also evidenced by altered cholesterol-rich membrane domains (rafts) and raft-mediated functions, such as diminished generation of the Aβ-degrading enzyme plasmin. Thirdly, numerous genetic defects that cause neurodegeneration are due to defective cholesterol metabolism. Fourthly, in female mice, the most brain-permeant statin induces neurodegeneration and high amyloid production. Altogether, this evidence makes it difficult to accept that statins are beneficial through acting as brain cholesterol-synthesis inhibitors. It appears more likely that their advantageous role arises from improved brain oxygenation.
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January 2005
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Review Article|
January 01 2005
The conflicting role of brain cholesterol in Alzheimer's disease: lessons from the brain plasminogen system.
Maria Dolores Ledesma;
Maria Dolores Ledesma
1
1Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, A.O. San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano (Torino), Italy.
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Carlos G. Dotti
Carlos G. Dotti
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1Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, A.O. San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano (Torino), Italy.
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Publisher: Portland Press Ltd
Online ISSN: 1744-1439
Print ISSN: 0067-8694
© 2005 The Biochemical Society
2005
Biochem Soc Symp (2005) 72: 129–138.
Citation
Jeff McIlhinney, Nigel Hooper, Maria Dolores Ledesma, Carlos G. Dotti; The conflicting role of brain cholesterol in Alzheimer's disease: lessons from the brain plasminogen system.. Biochem Soc Symp 1 January 2005; 72 129–138. doi: https://doi.org/10.1042/bss0720129
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