Potential Roles of Peroxisomes in Alzheimer's Disease and in Dementia of the Alzheimer's Type

Abstract

In Alzheimer's disease (AD) and dementia of the Alzheimer's type (DAT), the role played by peroxisomes is not well known. Peroxisomes are present in all eukaryotic cells, with the exception of erythrocytes. They are involved in the β-oxidation process of long-chain fatty acids, very-long-chain fatty acids, and branched-chain fatty acids. They participate in the α-oxidation of phytanic acid, the biosynthesis of bile acids, and the breakdown of eicosanoids. Peroxisomes are also involved in the synthesis of specific fatty acids such as docosahexaenoic acid (DHA), which is essential for the brain and retina, and plasmalogens (PLGN), which play crucial roles in neural cells and are essential components of myelin. Several studies conducted in animal models and in humans provided evidence for a role of DHA in preventing brain degeneration. Significantly lower levels of PLGN were observed in patients with severe dementia. Moreover, a decreased activity of carnitine acetyltransferase, an enzyme present in peroxisome (but also detected in mitochondria, endoplasmic reticulum, and nucleus), was reported in AD patients. We give an overview of the potential role of peroxisomes, especially in the part played by DHA, PLGN, carnitine, and carnitine-dependent peroxisomal enzymes, on the development of AD and DAT. The potential of developing novel therapies targeted on peroxisomal metabolism to prevent cognitive decline and other age-related neurological disorders is discussed.

Impact of C24:0 on actin-microtubule interaction in human neuronal SK-N-BE cells: evaluation by FRET confocal spectral imaging microscopy after dual staining with rhodamine-phalloidin and tubulin tracker green

“…Peroxisomal function declines with age (Titorenko and Terlecky, 2011), and this can affect lipid and oxidative stress homoeostasis (Schrader and Fahimi, 2008;Del Rio, 2011); it is suggested that peroxisomes may play a critical part in regulating cellular aging and in the development of neurodegenerative diseases, including AD (Antonenkov et al, 2010). In agreement with this hypothesis, some lipid modifications resulting from peroxisomal dysfunctions are observed in the brains of AD patients (Kou et al, 2011): reduced levels of docosahexaenoic acid (DHA; C22:6 n-3) and plasmalogens, and increased levels of C22:0 and very long chain fatty acids (VLCFAs: C24:0 and C26:0) (Lizard et al, 2012). Increased levels of VLCFAs have also been found in the plasma and red blood cells of patients with AD (Zarrouk, 2013).…”

The peroxisome: an update on mysteries

“…Thus, the elevated levels of VLCFA found in Alzheimers' disease might point to disturbances in peroxisomal metabolism leading to ROS generation, which then triggers the reported peroxisomal and ROS-scavenging compensatory responses. Additionally, the altered levels of docosahexaenoic acid and plasmalogens may also contribute to Alzheimer pathogenesis (Lizard et al 2012). Thus, peroxisomes may represent an interesting target to mitigate or even stop the progress of Alzheimer-related diseases.…”

“…Age-related neurodegenerative diseases like Alzheimer exhibit altered levels of plasmalogens, VLCFA and docosahexaenoic acid suggesting a peroxisomal contribution to the pathology (see Lizard et al 2012 for review). Indeed, changes in peroxisome abundance and specific protein content have been described in Alzheimer mouse models in early, still asymptomatic disease stages (Cimini et al 2009b).…”

A UHPLC–TOF/MS method based metabonomic study of total ginsenosides effects on Alzheimer disease mouse model

“…This result could be attributed to a downstream modulation mechanism. After PC hydrolysis, enhanced oxidative stress induces DHA transformation product neuroprotectin D1 generation in order to protect neurons, which may result in DHA decrease [48]. Besides, ROS accumulation in AD brain could trigger lipid peroxidation, consume large amounts of PUFA, and finally affect PUFA concentration [49].…”