Shotgun lipidomics of liver and brain tissues of Alzheimer’s disease model mice treated with acitretin.

Lauer AA, Janitschke D, Santos Guilherme M, Nguyen VTT, Bachmann CM, Qiao S, Schrul B, Boehm U, Grimm HS, Hartmann T, Endres K, and Grimm MOW. (2021) Shotgun lipidomics of liver and brain tissues of Alzheimer’s disease model mice treated with acitretin. Scientific Reports

Retinoids are a class of chemical compounds that are related to vitamin A and can regulate developmental processes. Vitamin A is a nutritional supplement that is often used for inflammatory skin diseases such as psoriasis or ichthyosis. A common synthetic retinoid used to treat severe psoriasis, especially in older populations, is acitretin. Interestingly, acitretin was also identified as a potential drug for Alzheimer’s disease (AD) during a screening attempt. This was determined due to its ability to enhance α-secretase expression and activity in neuronal cells, which is protective against neurotoxic pathways that process amyloid precursor protein (APP) into beta-amyloid (β-amyloid) products, and improve behavioural defects seen in AD mouse models. Although promising, the most common side effect of acitretin is elevated serum triglycerides and the target population could suffer comorbidities and poly-medication. AD is associated with an alteration in the lipidome, therefore another concern is whether this treatment would exacerbate these effects. One of the classes of lipids affected in AD are plasmalogens which contain a vinyl-ether bond at the sn-1 position and are involved in membrane structure and fluidity, vesicular fusion, and have anti-oxidative properties, and they are known to be reduced in AD. As brain and liver lipid homeostasis and metabolism have not been assessed after treatment with acitretin, Lauer et al investigated this effect in a mid-age mouse model of AD using semi-quantitative shotgun mass spectrometry.

To study the effects of acitretin on the lipidome, 30 week old 5xFAD mice, a model developed to express five AD-linked mutations, were treated with 10 mg/kg acitretin through intraperitoneal injection for 7 days and were compared against 30 week old 5xFAD mice that did not receive the treatment. A lipid analysis using volcano plots was performed on the liver and the brain to determine if there were any changes to the lipidome from acitretin administration. Of the 750 parameters analyzed, 114 lipids tended to increase and 176 decreased with an effect greater than the standard error of the mean (SEM) and of these six were significantly increased while four were significantly decreased. In the liver, 178 parameters tended to be increased after treatment and 93 were decreased with 14 showing a significant increase and 13 a significant decrease. When looking at triacylglycerides (TAG), 28 species were decreased and 11 were increased in the brain, with 13 of the decreased species having a greater effect than the average SEM and all the increased TAG were within the SEM. The opposite effect was seen in the liver with 36 TAG species being increased, of which 15 had an effect greater than the SEM, and 3 were decreased and all within the SEM. These results are in line with the previous reported prevalence of nonalcoholic fatty liver disease in patients treated with acitretin and that it is thought to cause hyperlipidemia.

When they looked at the effect of acitretin on plasmalogens, an increase was observed in the brain. Of the 39 plasmalogen species measured, 38 were increased with 29 showing an effect greater than the SEM. In the liver, 30 were increased, 11 of which were greater than the SEM, while 9 were decreased and all within the SEM. The upregulation of plasmalogens was significant in both tissues with an increase to ~110% levels in the brain and ~105% levels in the liver.

Lauer et al were interested in investigating acitretin treatment in an AD model because of its known protective pathways and potential side effect of hyperlipidemia. It can be dangerous for some lipid classes, like triglycerides, to be altered in the liver especially if an individual already has heightened levels, as it can cause nonalcoholic fatty liver disease, but another lipid class, plasmalogens, are known to be reduced in AD. Through studying the different lipid classes, authors found that some lipids were altered similarly in the brain and liver while others had tissue-specific changes. For example, TAGs showed an inverse relationship with more species trending toward increases in the liver and decreases in the brain but plasmalogens showed general increases in both tissues. This increase in plasmalogens could be very beneficial for AD, however more work would be needed to figure out how to not alter all lipids with a retinoid treatment, or by developing another treatment that would be plasmalogen specific.