“Lipid raft aging” in the human frontal cortex during nonpathological aging: gender influences and potential implications in Alzheimer's disease

Abstract

Lipid rafts are highly dynamic membrane domains featured by distinctive biochemical composition and physicochemical properties compared with the surrounding plasma membrane. These microstructures are associated not only with cellular signaling and communication in normal nerve cells but also with pathological processing of amyloid precursor protein in Alzheimer's disease. Using lipid rafts isolated from human frontal cortex in nondemented subjects aging 24 to 85 years, we demonstrate here that lipid structure of lipid rafts undergo significant alterations of specific lipid classes and phospholipid-bound fatty acids as brain cortex correlating with aging. Main changes affect levels of plasmalogens, polyunsaturated fatty acids (especially docosahexaenoic acid and arachidonic acid), total polar lipids (mainly phosphatidylinositol, sphingomyelin, sulfatides, and cerebrosides), and total neutral lipids (particularly cholesterol and sterol esters). Besides, relevant relationships between main fatty acids and/or lipid classes were altered in an age-related manner. This "lipid raft aging" exhibits clear gender differences and appear to be more pronounced in women than in men, especially in older (postmenopausal) women. The outcomes led us to conclude that human cortical lipid rafts are modified by aging in a gender-dependent fashion. Given the central role of bilayer lipid matrix in lipid rafts functionality and neuronal signaling, we hypothesize that these findings might underlie the higher prevalence of cognitive decline evolving toward Alzheimer's disease in postmenopausal women.

Differential Aggregation and Phosphorylation of Alpha Synuclein in Membrane Compartments Associated With Parkinson Disease

“…In particular, aged LRs exhibit altered raft lipidomic profiles and physicochemical properties that affect protein associations and may contribute to the cell-cell propagation of toxic α-syn aggregates (Marin et al, 2017; Rodriguez et al, 2018). In this order of ideas, we have demonstrated in the human frontal cortex of both incidental and advanced PD subjects, the presence of lipid changes in LRs that correlate with the progression of the disease (Fabelo et al, 2011; Diaz et al, 2018). Noticeably, even in asymptomatic incidental PD (iPD) brains, there was a detectable reduction of AA and DHA, in parallel with an increase of saturated fatty acids (SFA, 16:0 and 18:0).…”

“…Our previous work has shown that LRs exhibit pathological modifications with the progression of aging that are exacerbated in age-related neuropathologies (Marin et al, 2016, 2017; Canerina-Amaro et al, 2017; Diaz et al, 2018; Marin and Diaz, 2018). In particular, aged LRs exhibit altered raft lipidomic profiles and physicochemical properties that affect protein associations and may contribute to the cell-cell propagation of toxic α-syn aggregates (Marin et al, 2017; Rodriguez et al, 2018).…”

“…Here, using the MPTP mouse model of PD, we have analyzed the consequences of PD-like pathology and aging on either α-syn distribution or configuration in membrane biochemical fractionation of the midbrain, cortex and cerebellum. We selected cortical regions based upon our previous observations in human brains where profound changes in lipid profiles were detected (Marin et al, 2017; Diaz et al, 2018). Both the cortex and the midbrain have been characterized as the main brain regions affected by PD pathology.…”

Lipid rafts in glial cells: role in neuroinflammation and pain processing

“…The other example is work with nerve injury and persistent inflammation, where TLR4 signaling has been reported to play a pivotal role in males in mediating the persistent pain state after nerve injury (7) and inflammation (8). With regard to aging, recent work has revealed that cortical lipid rafts are modified by aging in a sex-dependent fashion being more pronounced in women than in men (134). The effect of such sex-dependent changes in nociceptive processing remain to be assessed.…”

Characterisation of the dynamic nature of lipids throughout the lifespan of genetically identical female and male Daphnia magna

“…This is partly, due to different reproduction, hormonal and growth needs of both sexes. Furthermore, several studies have demonstrated that there are clear sex associated differences in lipid profile with age [31][32][33][34][35] . However, further detailed studies are required to enhance our understanding of the role of lipids in regulation of lifespan between sexes.…”