title: LDL density and oxidation are modulated by PON1 promoter genotype in patients with Alzheimer's disease.
abstract: Cholesterol metabolism alteration is a hot topic in the field of Alzheimer's disease (AD). However, data on plasma lipoproteins cholesterol distribution and oxidation in AD and their possible genetic determinants are lacking. The paraoxonase-1 (PON1) gene -107C/T promoter polymorphisms have been found associated with AD. One of the fundamental functions of PON1 enzyme is the inhibition of low-density lipoproteins (LDL) oxidation. We therefore evaluated plasma lipoprotein profile and LDL density and oxidation in late-onset AD patients and healthy elderly subjects, without neuroimaging evidence of cerebrovascular lesions and not on lipid-lowering treatment, and their interaction with PON1 -107C/T and apolipoprotein E (APOE) genotypes. Mean plasma total cholesterol and LDL levels were higher in AD than controls (p < 0.05). Lipoproteins cholesterol distribution shifted toward a greater prevalence of smaller, denser LDL (sd-LDL, p < 0.05) only in AD patients with PON1 -107TT genotype, who also showed increased plasma levels of oxidized LDL (ox-LDL, p = 0.02). A significant association was observed between sd-LDL and ox-LDL levels (p < 005) in AD patients. APOE genotype did not modulate lipoprotein distribution. Increased levels of sd-LDL and ox-LDL particles in the AD PON1 TT patients could be explained by the combined effect of an AD-related pro-oxidant milieu and an ineffective PON1 gene polymorphism-related antioxidant capacity. The functional correlate of the association between PON1 -107C/T polymorphism and AD may be the abnormal modulation of LDL oxidation. Ox-LDL may amplify the processes of endothelial injury promoted by vascular amyloid deposition, which represents one of the potential pathways explaining the cross-road between vascular and neurodegenerative pathomechanisms in AD.
authors.affiliation: On leave at IRCCS, San Camillo Hospital Foundation, Venezia, Italy Department of Neurosciences: SNPSRR, University of Padova, Padova, Italy. annachiara.cagnin@unipd.it
authors.forename: Annachiara
authors.initials: A
authors.lastname: Cagnin
authors.forename: Alberta
authors.initials: A
authors.lastname: Leon
authors.forename: Daniela
authors.initials: D
authors.lastname: Vianello
authors.forename: Davide
authors.initials: D
authors.lastname: Colavito
authors.forename: Silvia
authors.initials: S
authors.lastname: Favaretto
authors.forename: Giulia
authors.initials: G
authors.lastname: Zarantonello
authors.forename: Anna
authors.initials: A
authors.lastname: Stecca
authors.forename: Mario
authors.initials: M
authors.lastname: Ermani
authors.forename: Alberto
authors.initials: A
authors.lastname: Zambon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000235:genetics*; D002499:Centrifugation, Density Gradient / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D009434:Neural Pathways / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology*
chemical_list: D008077:Lipoproteins, LDL; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human