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.
Highlights
Not all of the mysteries of life lie in our genetic code
The potential impact of these changes is presented in this schematic likely manifesting as a thinner dendritic spine and with bulkier lipid rafts more susceptible to drift from pre-synaptic densities into peri-synaptic domains given the (1) loss of PI and PI metabolites from the inner leaflet, (2) progressive reduction in PE(16:0/22:6), PE(18:0/22:6), PlsEtn(16:0/22:6), PlsEtn(18:0/22:6), and PS(18:0/22:6) throughout the bilayer, and (3) aberrant remodeling and accumulation of PS(22:6/22:6) at the outer leaflet demonstrated by neurolipidomic approaches
We argue that the major advance in rational therapeutic design will come from tying the dynamics of the susceptible cellular metabolome into these genomic and proteomic maps of disease
Summary
Not all of the mysteries of life lie in our genetic code. Some can be found buried in our membranes. We postulated that variations between datasets in the composition of smaller glycerophospholipid intermediates (i.e., the lysophospholipids, free fatty acids, and their downstream metabolites) (Figure 1C) are not “noise” but likely (1) snapshots of the structural species being actively mobilized to maintain critical structural membrane compositions at time of extraction and (2) identify the neuroactive phospholipid www.frontiersin.org signaling molecules that transiently accumulate in different disease states.
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