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[P4–120]: APOE‐E4 DEPENDENT DEFICITS IN DHA PHOSPHOLIPIDS AND TRANSPORTERS IN ALZHEIMER's DISEASE PATIENTS WITH SEVERE CEREBRAL AMYLOID ANGIOPATHY
Author(s) -
Abdullah Laila,
Evans Jim E.,
Shackleton Ben,
Ojo Joseph,
Mullan Michael,
Crawford Fiona,
Bachmeier Corbin
Publication year - 2017
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.2017.06.1986
Subject(s) - cerebral amyloid angiopathy , apolipoprotein e , parenchyma , pathogenesis , pathology , docosahexaenoic acid , transporter , neurodegeneration , blood–brain barrier , chemistry , medicine , fatty acid , disease , biochemistry , dementia , central nervous system , polyunsaturated fatty acid , gene
Background: The contribution of apolipoprotein E (APOE) e4 to Alzheimer’s disease (AD) pathology is characterized by the presence of severe cerebral amyloid angiopathy (CAA), increased blood-brain-barrier (BBB) breakdown and reduced cerebral vascularization in e4 carriers. It has been proposed that the diminished capacity of the apoE4 protein to transport docosahexaenoic acid (DHA), an essential fatty acid that is required for the structural and functional maintenance and vascular integrity of the brain also contributes to AD pathogenesis. However, it remains to be determined if there are changes in brain DHA content of phospholipids (PL) and in DHA transporters in relation to the e4 allele and AD diagnosis and brain cerebrovascular amyloid pathology. Methods:We performed liquid chromatography/mass spectrometry based PL analysis of the cerebrovascular and parenchymal fractions from autopsied human brain tissue of pathologically confirmed AD cases and controls. We performed antibody-based examination of the major facilitator superfamily domain containing 2A (mfsd2a) protein in the cerebrovasculature from these subjects. Results: In the cerebrovascular and parenchymal fractions, DHA containing PL species were lower in e4 carriers with AD cases compared to control ε4 carriers. We observed an APOE e4 dependent decreases in mfsd2a expression in the brain cerebrovasculature. The mfsd2a expression was lower in e4 carriers compared to non-carriers. Stratification of DHA containing PL by CAA showed that these PL levels were reduced in e4 positive AD patients with severe CAA. Conclusions: These findings demonstrate that brain DHA deficiencies in e4 carriers may be due to reduced mfsd2a expression and partly associated with CAA. Thus, targeting this transport mechanism may improve the bioavailability of DHA to the brain of e4 carriers who are at risk of developing AD.