P3‐126: Increased Phosphorylation of Collapsin Response Mediator Protein‐2 at THR514 Is Associated with Abeta Burden and Axonal Deficits in Dementia with Lewy Bodies

Abstract

Background:The contribution of apolipoprotein E (APOE) E4 to the cerebrovascular dysfunction in Alzheimer's disease (AD) is characterized by the presence of severe cerebral amyloid angiopathy, increased blood-brain-barrier (BBB) breakdown, reduced cerebral vascularization, and basement membrane thinning in E4 carriers compared to non-carriers. It has also been proposed that the diminished capacity of the apoE4 protein to transport essential polyunsaturated fatty acids (PUFAs) that are required for the structural and functional maintenance and vascular integrity of the brain also contribute to AD pathogenesis. However, it remains to be determined if there are changes in the profiles of phospholipids (PL) and in the expression of lipid transporters within the brain vasculature in relation to the E4 allele and AD diagnosis. Methods:We performed liquid chromatography/mass spectrometry based lipidomic analysis of the cerebrovascular and parenchymal fractions from autopsied human brain tissue of pathologically confirmed AD cases and controls stratified by APOE genotype. In order to determine if there were changes in the expression of lipid transporters in relation to the APOE E4 allele, we performed antibody based examination of the major facilitator superfamily domain containing 2A (mfsd2a) protein in the cerebrovasculature from these subjects. Results: Total phosphatidylcholine (PC) was significantly lower in the cerebrovascular fractions of AD patients compared to controls. While docosahexaenoic acid (DHA) containing PL species were lower in heterozygous E4 AD patients compared to E4 controls in both the cerebrovascular and parenchymal fractions, an ether PC species containing arachidonic acid (AA) was elevated within the cerebrovasculature of E4 carriers relative to non-carriers and was highest among E4 AD specimens compared to E4 controls. We also observed an APOE E4 dependent difference in mfsd2a expression. Among AD patients, E4 homozygotes had lower expression of mfsd2a than E4 heterozygotes and non-carriers. Conclusions: These findings demonstrate that deficiencies in DHA within the brains of APOE E4 carriers may, in part, be due to lower expression of mfsd2a. Thus, targeting this transport mechanism may improve the bioavailability of DHA to the brain of APOE E4 individuals providing a novel approach to the treatment of AD. Background: Alzheimer's disease (AD) is a neurological disorder which culminates after the accumulation and aggregation of protein Amyloid beta (Ab-42). All the newly translated proteins reaches to endoplasmic reticulum (ER) for further process but when they are present in misfolded form, they can cause stress to ER. This stress could be also on external addition of the protein Ab-42 which we speculated as a result of endocytic transport of the protein. Previously it was found that 7-ketocholesterol (7-KC) [1] could not facilitate the transport of Ab-42. Endocytosis is a movement which influences by cytoskeleton, raft domain and composition of the cell membrane so we have used two types ...