Premium
P3‐124: APOE4 Genotype‐Dependent Deficits in DHA Containing Phospholipids and DHA Transporters in the Cerebrovasculature of Alzheimer's Disease Patients
Author(s) -
Abdullah Laila,
Evans James,
Shackleton Ben,
Ojo Joseph,
Nguyen Thinh,
Reed Jon,
Mullan Michael,
Crawford Fiona,
Bachmeier Corbin
Publication year - 2016
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.2016.06.1782
Subject(s) - cerebral amyloid angiopathy , apolipoprotein e , docosahexaenoic acid , pathogenesis , arachidonic acid , parenchyma , biology , polyunsaturated fatty acid , pathology , chemistry , biochemistry , fatty acid , immunology , dementia , medicine , disease , enzyme
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.