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P1–387: Comparative analysis of heparan sulfate co–localization with Aβ40 and Aβ42 in different Aβ deposits of APP transgenic mice and Alzheimer's disease patients
Author(s) -
O' Callaghan Paul,
Yu Hong,
Nilsson Lars N.G.,
Ingelsson Martin,
Hyman Bradley T.,
Li Jin-Ping,
Lindahl Ulf,
Lannfelt Lars,
Zhang Xiao
Publication year - 2006
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.2006.05.765
Subject(s) - senile plaques , genetically modified mouse , heparan sulfate , pathology , amyloid (mycology) , antibody , hippocampal formation , transgene , in vivo , chemistry , congo red , alzheimer's disease , immunohistochemistry , microbiology and biotechnology , biology , glycosaminoglycan , biochemistry , medicine , immunology , endocrinology , disease , gene , genetics , organic chemistry , adsorption
interaction of genetic, physiologic and pathologic factors. Deficiencies of folate, vitamin B12 and vitamin B6 are important because of the alteration of S-adenosylmethionine (SAM)/Hcy metabolism. This could lead to the increase of Hcy and S-adenosylhomocysteine (SAH) levels, and the decrease of SAM /SAH ratio, known as “methylation potential”, SAM being the main methyl donor in living organisms. Furthermore, low SAM levels and low B vitamin status are often observed in AD and in aging subjects. It has already been shown that gene methylation is involved in amyloid -protein precursor (APP) processing and amyloid production through the regulation of PS1 and BACE expression. Thus, it was intriguing to study the relationships between homocysteine, SAM/SAH ratio in plasma and tissues, the DNA methylation status and amyloid production. Objective(s): In order to achieve a molecular model for AD, we used transgenic mice that have an accelerated amyloid accumulation; these mice are a good model to study the metabolic alterations caused by folate, vitamin B12 and vitamin B6 deprivations and the effects on DNA methylation and amyloid production. Methods: CRND8 mice, with a double mutated APP, together with wild type mice were fed with a deprived diet (without folate, vitamin B12, and vitamin B6) or with a control diet, for 45 or 60 days. Then they were sacrificied to analyze plasma Hcy, SAM and SAH, brain and liver SAM and SAH by HPLC technique, brain DNA methylation, amyloid accumulation. Results: The diet deprived of folate, vitamin B12 and vitamin B6 led to a marked hyperhomocysteinemia, to an accumulation of SAH (strong inhibitor of SAM-dependent methyl transferases), and to a decrease in SAM/SAH ratio in plasma, brain and liver. This is associated with brain DNA hypomethylation, with liver hypertrophy and with amyloid plaque deposition. Conclusions: These results are important because they correlate SAM/SAH ratio (methylation potential) with amyloid accumulation.