PLA2G4E, a candidate gene for resilience in Alzheimer´s disease and a new target for dementia treatment

Abstract

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Acyl-CoA synthetase 6 is required for brain docosahexaenoic acid retention and neuroprotection during aging

“…Surprisingly, we did not observe a genotype effect, but rather we observed age-induced increases in lipid mediator metabolism genes, including several phospholipases that generate substrate, several enzymes that generate lipid mediators, and those that degrade mediators (Figure 6F). While a majority of the genes increased with age, 2 phospholipase A2 genes, paraoxonase 2 and glutathione peroxidase 4, which are associated with aging and oxidative stress (43)(44)(45), decreased with age (Figure 6F). Together these data indicate that membrane acyl-chain composition does not greatly impact overall lipid mediator homeostasis or expression of related metabolizing enzymes.…”

Prodromal Alzheimer’s Disease: Constitutive Upregulation of Neuroglobin Prevents the Initiation of Alzheimer’s Pathology

“…Also, in sporadic forms of AD, increased Aβ levels are detected in plasma-derived neuronal exosomes up to 10 years before the manifestation of the first symptoms (Fiandaca et al, 2015). All these data imply the existence of robust resilience mechanisms, such as the recently identified PLA2 G4E (Perez-Gonzalez et al, 2020), counteracting the detrimental effect of different toxicity factors, including excessive production of the more damaging forms of Aβ peptide. The identification of these mechanisms is a fundamental process if we want to prevent or cure this disease.…”

Updating Phospholipase A2 Biology

“…Since genetic deletion or pharmacological inhibition of NAPE-PLD disturbs lipid metabolism in the liver, intestine, and adipose tissue [ 107 ], as well as emotional behavior [ 108 ], it is tempting to speculate that cPLA 2 ε, which lies upstream of NAPE-PLD for NAE biosynthesis, may also participate in these events to improve metabolism and neuronal functions. The potential neuroprotective role of cPLA 2 ε is supported by the association between reduced expression of cPLA 2 ε and dementia, where adenoviral overexpression of cPLA 2 ε in hippocampal neurons completely restores cognitive deficits in the elderly APP/PS1 mouse, a model of Alzheimer’s disease [ 109 ].…”