Lipidomics in brain diseases

Following the previous article "Brain Lipidomics: From Function to Disease (Part 1)" this article focuses on exploring the causal relationship between brain lipid dysregulation and neuro-psychiatric diseases.

In brain research, lipidomics can be used to discover biomarkers for the early diagnosis and prognosis of brain diseases and to understand the biological functions of the brain and its specific regions. In recent years, several studies have reported on various types of lipids and their dysregulation being associated with neurodegenerative and psychiatric diseases (Table 1).

Table 1. Lipidomics associated with brain diseases

Alzheimer's Disease (AD)

Brain lipid metabolism is involved in the processing of amyloid precursor protein (APP), the production of β-amyloid (Aβ), and Aβ aggregation in Alzheimer's disease. Research has shown that there is a dysfunction in the transfer of cholesterol from astrocytes to neurons in Alzheimer's disease, which may be closely related to apolipoprotein E (APOE). APOE is a major cholesterol carrier that can bind to and clear Aβ. A genetic variation in APOE is one of the risk factors for AD and is associated with changes in cholesterol and sphingolipids. Lipid rafts in the cell membrane are rich in cholesterol and sphingolipids, which anchor transmembrane proteins associated with AD, such as β-secretase 1 (BACE1) and γ-secretase. Moreover, the protein activities of BACE1 and γ-secretase are affected by cholesterol levels.

Sphingolipid metabolism is highly correlated with the formation of Aβ oligomers, with the accumulation of sphingomyelin leading to reduced γ-secretase activity and thus decreased Aβ secretion. In Alzheimer's disease patients, the levels of acidic sphingomyelinase and acidic ceramidase are significantly elevated, leading to a reduction in the level of SM and production of ceramides. Ceramide stabilizes BACE1 and increases its half-life, thereby enhancing the rate of Aβ formation. Glycosphingolipids also contribute to the formation of amyloid fibrils. In summary, sphingolipids influence the processing of APP, the production of Aβ, and the subsequent aggregation of amyloid proteins.

Phospholipids are associated with the activity of γ-secretase and proteins involved in the processing of APP. Previous studies on the brains of AD patients have reported alterations in various types of phospholipids, including PC, PE, and PI, as well as phospholipid-metabolizing enzymes such as phospholipase C (PLC) and phospholipase D (PLD). Regarding AD-related cognitive impairment, the deficiency of phospholipid transfer protein leads to a reduction in PE and PI, accelerating the accumulation of intracellular Aβ and causing memory dysfunction, indicating significant correlation between phospholipid metabolism and APP processing.

Parkinson's Disease (PD)

Parkinson's disease is the second most common neurodegenerative disease, mainly occurring in individuals aged 60 and above. PD patients exhibit symptoms of motor dysfunction, such as tremors, bradykinesia, rigidity, and impaired balance. In addition to motor symptoms, cognitive changes are also common in PD patients and often lead to dementia. Over the past few decades, cellular pathways related to PD have been implicated, including oxidative stress, lysosomal dysfunction, endoplasmic reticulum stress, and immune response.

The hallmark feature of PD is the aggregation of α-synuclein (α-syn), a neuronal protein that affects the regulation of synaptic vesicles and neurotransmitter release, the production of Lewy bodies, and the loss of dopaminergic neurons. In a normal physiological state, α-syn maintains synaptic function stability and regulates dopamine formation. However, in Parkinson's patients, there is abnormal aggregation of α-syn, leading to the formation of Lewy bodies (i.e., fibrillar α-syn) and the loss of dopaminergic neurons.

In Parkinson's disease (PD) patients, the levels of triglycerides in the primary visual cortex are decreased, while the levels of diacylglycerols are increased. Phospholipase D1 can inhibit a-synuclein accumulation through autophagic flux, reducing its cellular toxicity, but PD patients show reduced phospholipase D1 activity. Lipid alterations in lipid rafts have been confirmed in the human frontal cortex of PD donors.

Huntington's disease (HD)

Huntington's disease (HD), also known as Huntington's chorea, is an autosomal dominant inherited neurodegenerative disease. It is characterized by abnormal motor function (chorea and muscle rigidity), psychiatric complications (anxiety and depression), and cognitive dysfunction (dementia). The mutation of the Huntington protein (HTT) gene is well known as the cause of HD. HTT gene and other related proteins participate in intracellular functions, such as postsynaptic signaling, protein transport, and protein aggregation.

In HD patients, the levels of sphingomyelin phosphodiesterase 1 (a key enzyme in sphingolipid metabolism) are increased in the striatum and cortex, suggesting disrupted sphingolipid metabolism. Human studies of HD have also investigated the disruption of neural cholesterol and cholesterol ester (CE) levels. Specifically, HD patients' caudate nucleus and putamen have been shown to have elevated CE levels, which, in turn, reduce cholesterol accumulation.

Schizophrenia

Schizophrenia (SCZ) is a mental disorder characterized by symptoms of disordered thinking and behavior, hallucinations, and delusions. It cannot be adequately treated with antipsychotic drugs. The neurobiology of SCZ can be explained by changes in the dopaminergic, glutamatergic, and serotonergic signaling pathways.

The membrane phospholipid composition is abnormal in the cortical tissue of schizophrenia (SCZ) patients, and the alterations in neuronal cell membrane lipid composition may affect neurotransmitter storage and release. Compared to healthy individuals, there is a significant alteration in 10.4% of prefrontal cortex (PFC) lipids in SCZ patients, which could increase membrane fluidity. Assessment of biomarkers in SCZ serum samples has shown lower levels of phosphatidylethanolamine (PE), phosphatidylcholine (PC), and lysophosphatidylcholine (LPC), while the levels of sphingomyelins (SMs) and most lysophosphatidylethanolamines (LPEs) are higher than in the control group.

At Metware lab in Boston we offer you the following services related to this research area:

•  Quantitative Lipidomics (over 4000 lipids on the panel)
•  Free Data Analysis Cloud platform with additional tools to support your research