Increased Apolipoprotein D Dimer Formation in Alzheimer's Disease Hippocampus is Associated with Lipid Conjugated Diene Levels

Abstract

Previous studies indicate that apolipoprotein D (apoD) may have a lipid antioxidant function in the brain. We have shown that apoD can reduce free radical-generating lipid hydroperoxides to inert lipid hydroxides in a reaction that involves conversion of surface exposed apoD methione-93 (Met93) residue to Met93-sulfoxide (Met93-SO). One consequence of this reaction is the formation of a stable dimerized form of apoD. As cerebral lipid peroxidation is associated with Alzheimer's disease (AD), in the present study we aimed to assess the possible presence of apoD dimers in postmortem hippocampal and cerebellar tissues derived from a cohort of pathologically defined cases ranging from control to late stage AD. Both soluble and insoluble (requiring guanidine HCl extraction) fractions of tissue homogenates were analyzed for apoD and its dimerized form. We also assessed amyloid-β levels by ELISA and levels of lipid peroxidation by lipid conjugated diene and F2-isoprostane analysis. Our studies reveal a significant association between soluble apoD levels and AD Braak stage whereas apoD dimer formation appears to increase predominantly in the advanced stages of disease. The formation of apoD dimers is closely correlated to lipid conjugated diene levels and occurs in the hippocampus but not in the cerebellum. These results are consistent with the hypothesis that apoD acts as a lipid antioxidant in the brain.

Apolipoprotein D modulates amyloid pathology in APP/PS1 Alzheimer's disease mice

“…Several previous studies have shown that apoD levels are up-regulated in the AD brain (Bhatia et al, 2013;Terrisse et al, 1998;Thomas et al, 2003;Thomas et al, 2001), that there is a marked increase of neuronal apoD expression in AD (Desai et al, 2005;Kalman et al, 2000), and that apoD is found in amyloid plaques (Desai et al, 2005). Three studies have also reported associations between variations in the APOD gene and AD risk (Chen et al, 2008;Desai et al, 2003;Helisalmi et al, 2004).…”

“…It is also established that apoD levels are increased in affected brain regions in Alzheimer's disease (AD) and in AD mouse models (Bhatia et al, 2013;Terrisse et al, 1998;Thomas et al, 2003;Thomas et al, 2001). Additional studies show that brain lipid peroxidation is increased during aging (Cristiano et al, 1995;Droge and Schipper, 2007), as well as in AD and AD mouse models (Abdul et al, 2008;Markesbery and Carney, 1999;Montine et al, 2007;Sayre et al, 1997;Schuessel et al, 2005).…”

“…One consequence of this reaction is the formation of a Met-sulfoxide residue that destabilizes the protein and promotes its noncovalent dimerization . Interestingly, apoD dimers have been identified in the hippocampus, but not in the pathologically spared cerebellum, of human AD subjects (Bhatia et al, 2013). There is now a growing consensus that apoD may play a protective role in AD, and other neurological diseases (Bhatia et al, 2013;Dassati et al, 2014).…”

“…Additional studies show that brain lipid peroxidation is increased during aging (Cristiano et al, 1995;Droge and Schipper, 2007), as well as in AD and AD mouse models (Abdul et al, 2008;Markesbery and Carney, 1999;Montine et al, 2007;Sayre et al, 1997;Schuessel et al, 2005). Furthermore, recent studies show that the increase in apoD associated with aging and AD in human brain tissues is correlated with markers of lipid oxidative stress (Bhatia et al, 2013;Kim et al, 2009). …”

Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex

“…At the cellular and organismal levels, this lipocalin has been proven to have various functions: protection from oxidative stress through lipid peroxide reduction (Bajo-Graneras et al, 2011a,b;Bhatia et al, 2011Bhatia et al, , 2013Ganfornina et al, 2008), neuronal differentiation (Kosacka et al, 2010;Ruiz et al, 2013) and regeneration of damaged nerves (Ganfornina et al, 2010;Garcia-Mateo et al, 2014). However, in spite of the established link between ApoD and aging, mostly with the aging nervous system, an experimental test causally associating ApoD to mammalian longevity or brain aging is still missing.…”