The Lipids Issue in the Brain

(Sept. 2021)

Mitochondrial dysfunction is a common feature of many neurodegenerative diseases, including proteinopathies such as Alzheimer’s or Parkinson’s disease, which are characterized by the deposition of aggregated proteins in the form of insoluble fibrils or plaques. The distinct molecular processes resulting in mitochondrial dysfunction during neurodegeneration are well studied but still not fully understood. However, defects in mitochondrial fission and fusion, mitophagy, oxidative phosphorylation and mitochondrial bioenergetics have been linked to cellular demise. These processes are influenced by the lipid environment within mitochondrial membranes as, besides membrane structure and curvature, recruitment and activity of different proteins also largely depend on the respective lipid composition. Hence, the interaction of neurotoxic proteins with certain lipids and the modification of lipid composition in different cell compartments, in particular mitochondria, decisively impact cell death associated with neurodegeneration. Here, we discuss the relevance of mitochondrial lipids in the pathological alterations that result in neuronal demise, focussing on proteinopathies.
The association of blood lipids with Alzheimer’s disease has been demonstrated by lipidomics analysis.
Untargeted lipidomic analysis on 148 AD and 152 elderly control plasma samples and used univariate and multivariate analysis methods in order to (1) replicate previous associations between six blood lipids and Alzheimer’s disease (AD) and (2) identify novel associations between lipids, clinical AD diagnosis, disease progression and brain atrophy (left/right hippocampus/entorhinal cortex).
A combination of 24 molecules classified AD patients with >70% accuracy in a test and a validation data set, and we identified lipid signatures that predicted disease progression (R2 = 0.10, test data set) and brain atrophy (R2 ≥ 0.14, all test data sets except left entorhinal cortex). We putatively identified a number of metabolic features including cholesteryl esters/triglycerides and phosphatidylcholines.
In the case of Multiple sclerosis (MS), a chronic autoimmune disease that affects the central nervous system (CNS) characterized by demyelination and neurodegeneration, driven by a Th17/Th1-immune response, which afflicts mainly young women. Although MS causes are not completely known, it is notorious that the disease is characterized by an extended focal degradation of the myelin sheath, with ulterior axon and neuronal damage. Lipid molecules play a main dual role in MS, both as target molecules of myelin destruction and as mediators of inflammation. Indeed, recent cumulative evidence suggests that abnormalities in the lipid-binding proteins of myelin and sphingolipid content that confer increased immunogenicity may underlie the autoimmune response against the myelin sheath. CNS is after all, the second organ richer on lipid content after adipose tissue. On the other hand, soluble factors called adipokines, secreted by adipose tissue, modulate inflammatory responses and contribute to metabolic dysfunction, which may be important in MS pathophysiology. Disability accumulation in MS patients is slow but persistent, often leading to a decreased mobility and physical activity, resulting in more weakness, fatigue and associated increased risk of the metabolic syndrome (MetS). In turn, MetS may trigger MS in susceptible individuals and is a worse prognostic factor. Here we review what are the facts linking lipids, MetS and MS, what we do not know yet, and what we should do to move this field forward.

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