Using neurolipidomics to identify phospholipid mediators of synaptic (dys)function in Alzheimer's Disease

Abstract

Not all of the mysteries of life lie in our genetic code. Some can be found buried in our membranes. These shells of fat, sculpted in the central nervous system into the cellular (and subcellular) boundaries of neurons and glia, are themselves complex systems of information. The diversity of neural phospholipids, coupled with their chameleon-like capacity to transmute into bioactive molecules, provides a vast repertoire of immediate response second messengers. The effects of compositional changes on synaptic function have only begun to be appreciated. Here, we mined 29 neurolipidomic datasets for changes in neuronal membrane phospholipid metabolism in Alzheimer's Disease (AD). Three overarching metabolic disturbances were detected. We found that an increase in the hydrolysis of platelet activating factor precursors and ethanolamine-containing plasmalogens, coupled with a failure to regenerate relatively rare alkyl-acyl and alkenyl-acyl structural phospholipids, correlated with disease severity. Accumulation of specific bioactive metabolites [i.e., PC(O-16:0/2:0) and PE(P-16:0/0:0)] was associated with aggravating tau pathology, enhancing vesicular release, and signaling neuronal loss. Finally, depletion of PI(16:0/20:4), PI(16:0/22:6), and PI(18:0/22:6) was implicated in accelerating Aβ42 biogenesis. Our analysis further suggested that converging disruptions in platelet activating factor, plasmalogen, phosphoinositol, phosphoethanolamine (PE), and docosahexaenoic acid metabolism may contribute mechanistically to catastrophic vesicular depletion, impaired receptor trafficking, and morphological dendritic deformation. Together, this analysis supports an emerging hypothesis that aberrant phospholipid metabolism may be one of multiple critical determinants required for Alzheimer disease conversion.

A Blood-Based, 7-Metabolite Signature for the Early Diagnosis of Alzheimer's Disease

“…Similar decreases in plasma PC levels [22,49] and increased CSF levels of PC metabolites [50] have also been previously described in AD patients. In agreement with previous reports [51,52], we also observed alterations in the levels of PI and PE species in patient groups as compared with healthy controls: levels of diacyl PE species were increased, while those of ether-linked PE species were decreased in aMCI and AD patients. DHA, which featured in the final seven-metabolite panel, accounts for 30-40% of the long chain polyunsaturated fatty acid (LCPUFA) content of the cerebral cortex, and has been implicated in multiple brain functions (e.g., cell membrane fluidity, receptor affinity, modulation of signal transduction molecules).…”

Peroxisomal Dysfunction in Age-Related Diseases

“…The synaptic vesicle is enriched in ether lipids [58], and neurotransmitter release from these vesicles into the presynaptic cleft is impaired in synaptosomes isolated from the brains of mice with knockout of the ether lipid synthetic enzyme dihydroxacetone phosphate acyl transferase (DHAPAT) [59]. Examination of 29 independent neurolipidomic datasets consistently revealed increased hydrolysis of ethanolamine-containing membrane plasmalogens and decreased levels of other ether-linked structural phospholipids in AD, potentially contributing to the vesicular depletion [60]. Taken together, these data indicate a role for peroxisomal dysfunction in both the pathogenesis and progressive worsening of AD.…”

Relation between plasma and brain lipids

“…The brain is the most lipid-rich organ in the body [3], and almost all major classes of lipids have some correlation with Alzheimer's disease pathogenesis [4]. These lipid classes affect not only the structural properties of CNS membranes, but also numerous signaling and trafficking pathways that are heavily involved in the normal functioning of cells throughout the CNS [4,5]. Here, we review experimental and human evidence regarding the involvement of lipids, lipoproteins, and apolipoproteins in neurodegenerative diseases, and appraise current literature on effects of cholesterol-lowering treatment on cognition.…”