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P1‐261: Lipidomic characterization of postmortem amyloid plaques isolated by laser capture microdissection
Author(s) -
Panchal Maï,
Gaudin Mathieu,
Cossec Jack-Christophe,
Auzeil Nicolas,
Loeper Jacqueline,
Pompon Denis,
Laprévote Olivier,
Duyckaerts Charles
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.813
Subject(s) - laser capture microdissection , neuropil , senile plaques , chemistry , cholesterol , amyloid (mycology) , apolipoprotein e , alzheimer's disease , biochemistry , pathology , biology , medicine , central nervous system , endocrinology , disease , gene , inorganic chemistry , gene expression
Background: Recent evidence suggests a role for APP processing in the regulation of apoE and cholesterol endocytosis. We have previously demonstrated that the entire cholesterol biosynthesis pathway is upregulated in Tg2576 mouse brain. Tg2576 mice over-express the APPswe mutation and accumulate the BACE1 cleavage products, C99 and Ab. Methods: It is well known that impairment of cholesterol endocytosis increases cholesterol biosynthesis gene expression. We therefore determined whether apoE endocytosis was dysregulated in Tg2576. Results: We found that extracellular cholesterol levels and apoE protein levels were significantly increased in young Tg2576 brain, implying that apoE lipoprotein particles are not being endocytosed and degraded in vivo. By directly examining the effect of APPswe overexpression on lipoprotein endocytosis in vitro we found that primary neurons from Tg2576 showed a dramatic deficit in lipoprotein endocytosis relative to wild type (WT) neurons. Given that Tg2576 cultures massively accumulate both C99 and Ab we wished to determine which cleavage product mediated the inhibitory effects on endocytosis. To directly test this, we treated WT neurons with a g-secretase inhibitor to increase intracellular C99, but reduce Ab levels. Inhibition of g-secretase led to a dose dependant inhibition of lipoprotein endocytosis. This inhibition could be blocked when co-dosed with a b-secretase inhibitor. Importantly, Ab was inhibited > 95 % by the g-secretase inhibitor alone, implying that it was the accumulation of C99 that inhibits lipoprotein endocytosis. Conclusions: These experimental results suggest a role for the amyloidogenic processing of APP in regulating apoE lipoprotein endocytosis and provide further evidence in support of the growing association between Alzheimer’s disease and cholesterol metabolism. Moreover they further establish a biological link between APP, g-secretase and apoE, the major genetic determinants of Alzheimer’s disease.