Ether lipid-mediated antioxidant defense in Alzheimer’s disease.

Jové M, Mota-Martorell N, Obis E, Sol J, Martín-Garí M, Ferrer I, Portero-Otin M, and Pamplona R. (2023) Ether lipid-mediated antioxidant defense in Alzheimer’s disease. Antioxidants

The human brain is composed of the highest concentration of lipids within the body with lipids making up 50% of the dry matter in the brain. Because they make up such a large portion of the brain, the classes of lipids present are necessary for the structural and functional needs for membrane composition and organization of neurons and glial cells, as well as cellular signaling and homeostasis of oxidative stress. Brain regions have very specific control over body function and cognitive abilities, and because of this are each vulnerable to aging and neurodegenerative diseases, such as Alzheimer’s disease (AD), to different extents. However, what causes some people to develop these disorders and others to not seems to be influenced by many factors but is not well understood. Plasmalogens, a unique class of lipids containing a vinyl-ether bond, have structural roles in cell membranes, are involved in membrane trafficking, cell signaling, and have antioxidant properties. In their review, Jové et al hypothesized that there are lipid-derived adaptive mechanisms that are used by the body to maintain homeostasis of oxidative stress within the brain and to help maintain the health of neural cells. We previously posted a blog covering the excellent summary on plasmalogens that was also detailed in this review article and here we cover their discussion on the role of plasmalogens in brain physiology, antioxidant properties in neurons, and the changes to the lipidome associated with AD.

An important characteristic of plasmalogens is their role as antioxidants in cells. Interestingly, the use of plasmalogens in eukaryotic cells generates reactive oxygen species (ROS), therefore there was a need within the cell for plasmalogens to also have antioxidant mechanisms. The vinyl-ether bond on plasmalogens gives these lipids their ROS sensitivity, however, to add this double bond to plasmalogens, oxidative metabolism is required, and this produces ROS. This means that the oxidative metabolism required to produce plasmalogens also results in a molecule that is sensitive to oxidative damage, but since the vinyl-ether bond is a target for ROS, this means plasmalogens can scavenge the free radicals and help prevent oxidative stress. The plasmalogen-rich environment of the brain may be an adaptive response to high oxidative conditions within the brain and protecting other lipids, like unsaturated membrane lipids from oxidation.

A complete deficiency in plasmalogens causes severe systemic disorders, but reductions in their levels have also been associated with different disorders including multiple sclerosis, Parkinson’s disease and Alzheimer’s disease. AD is the most prevalent neurodegenerative disease and because of the important roles of plasmalogens in brain function, it reasons that distinct changes to the lipidome could initiate or influence the progression of AD. To further support this, the regions of the brain most affected by AD are associated with lower levels of plasmalogens when postmortem brain samples have been analyzed. A reduction in plasmalogens has also been associated with aging but not in the same magnitude as its association with AD. In people with AD, the decrease has been shown in white matter very early in the disease and in the grey matter where it has been shown to correlate to neuropathological staging and cognitive decline. As well, some studies have shown a plasmalogen decrease in plasma and serum of people with AD.

The mechanism causing this plasmalogen level decline in AD is unknown but is theorized to be the result of these lipids being targets for oxidative stress, which is known to be increased in AD. Peroxisomal dysfunction has also been associated with AD and aging and this is the organelle where plasmalogen biosynthesis begins. Although it is not consistently found, the accumulation of toxic proteins like beta-amyloid and hyperphosphorylated tau have been thought to drive the neurodegeneration seen in AD.  Plasmalogen reductions can result in changes to signaling pathways such as the ERK and AKT pathways which may cause further damage through increasing hyperphosphorylation of tau. Plasmalogens also influence the generation of beta-amyloid since its generation occurs in lipid rafts, which also have an abundance of plasmalogens.

Jové et al were interested in the role of plasmalogens in the brain and specifically on their antioxidant properties and how this impacts the pathology of AD. With the increase in complexity and cognitive function of brains comes the increase in evolution and magnitude of difference between brain tissue composition and peripheral tissue composition. It is unclear whether plasmalogen reductions are caused by the pathology of AD or if they play a role in its development, but it is likely a combination of both with their decrease also amplifying the oxidative stress within the brain, exacerbating the effects. However, knowledge about this reduction in plasmalogens could be used as a biomarker for cognitive decline. As well, further validation of this testing could allow for plasmalogen level to be an early indicator of disease onset or progression. More work is needed to fully elucidate the role of plasmalogens as antioxidants and their role in AD.