MK886 Reduces Cerebral Amyloid Angiopathy Severity in TgCRND8 Mice

Abstract

Background: Deposition of amyloid-β (Aβ) in blood vessel walls as cerebral amyloid angiopathy (CAA) is observed in the majority of Alzheimer's disease (AD) brains. Inhibition of the 5-lipoxygenase (5-LOX) pathway has recently been suggested to play a role in reducing parenchymal Aβ deposition. However, products of the 5-LOX pathway also activate the peroxisome proliferator-activated receptor (PPAR) family, which promotes clearance of Aβ from the brain. Methods: In the present study, we investigated the effect of MK886, a 5-LOX-activating protein (FLAP) inhibitor and PPARα antagonist, on CAA severity in TgCRND8 mice overexpressing the human Swedish and Indiana amyloid precursor protein mutations. Results: We found that MK886 significantly reduced brain levels of nicastrin and PPARα, but did not affect levels of β-secretase, apolipoprotein E or low-density lipoprotein receptor-related protein-1. CAA severity and parenchymal plaque load was significantly decreased in both the cortex and hippocampus of mice treated with MK886 compared to control mice. Conclusion: These data suggest that 5-LOX and FLAP inhibitors may be useful in the treatment of CAA and AD.

Novel lipid signaling pathways in Alzheimer's disease pathogenesis

“…Aberration in Y-maze exploratory behavior represents impairment in short-term working memory while fear-conditioned memory impairment assesses hippocampal-dependent and hippocampal-independent memory building processes. In line with our data on synaptic integrity and LTP, 5LO inhibition and knockout restored learning and memory impairments in the transgenic mice as assessed by these paradigms to a level indistinguishable from their wild-type controls [15, 17, 32]. Therefore, given this collective data, we have established that 5LO plays a role in improving the behavioral phenotype of AD animal models as well as its biochemical and electrophysiological dysfunctions.…”

“…Thus, we fed Tg2576 animals rodent chow supplemented with the 5LO inhibitor zileuton, from early adulthood, and found as with our knockout studies, that this pharmacologic approach also reduced brain Aβ peptide levels and amyloid plaques burden [16]. Interestingly, a recent paper showed that pharmacologic blockade of 5LO activating protein reduces amyloid angiopathy in TgCRND8 mice and this reduction was associated with a significant decrease in the steady state levels of nicastrin, one of the components of the γ-secretase complex [17]. …”

High Levels of Homocysteine Results in Cerebral Amyloid Angiopathy in Mice

“…The Thioflavin S staining was performed as previously described by Hawkes et al [13]. Briefly, brain sections were deparaffinized and hydrated with the clearing agent xylene and a series of grade ethanol.…”

Alzheimer’s disease: relevant molecular and physiopathological events affecting amyloid-β brain balance and the putative role of PPARs

“…Several authors have suggested that the perivascular accumulation of Aβ damages the BBB, leading to microbleedings, inflammatory reactions, and subsequent damage to the neuronal network (Zlokovic, 2010; Popa-Wagner et al, 2013; Zolezzi and Inestrosa, 2013). On this regard, several authors have demonstrated the role of PPARs as an endothelial protective agents (Zhou et al, 2008; Bae et al, 2010; Kröller-Schön et al, 2013; Zarzuelo et al, 2013; d’Uscio et al, 2014; Hawkes et al, 2014). Recently, it has been demonstrated that PPARs are able to protect endothelial cells from oxidative damage, thus preventing vascular dysfunction, which could favor brain parenchyma alterations (d’Uscio et al, 2012; Papadopoulos et al, 2013).…”

“…Recently, it has been demonstrated that PPARs are able to protect endothelial cells from oxidative damage, thus preventing vascular dysfunction, which could favor brain parenchyma alterations (d’Uscio et al, 2012; Papadopoulos et al, 2013). Based on current knowledge and on our own work, we have proposed that PPAR activation, through natural or synthetic ligands, could protect and recover BBB integrity and functionality by increasing cell antioxidant capacity and improving energy metabolism, leading to the increased expression of specific transporters that could influence the Aβ-clearance rate (Nicolakakis et al, 2008; Zolezzi and Inestrosa, 2013; Zolezzi et al, 2013b; Hawkes et al, 2014). Energy metabolism is vital for both, neurons and the BBB, primarily because the preservation of the ion gradients (in the case of neurons) and the traffic across the BBB requires large amounts of energy (Abbott et al, 2010; Liebner and Plate, 2010; Popa-Wagner et al, 2013).…”