## 6 Farber disease
#### 3.5.3 GSLs in Neurodegenerative Diseases  
The roles of GSLs in neurodegenerative diseases are complex and multifaceted. GSLs are prevalent within the nervous system and play integral roles in numerous processes including neuronal development, synaptic function, and myelination [159]. The supposition was that GSLs may contribute to the formation of protein aggregates, which represent the hallmark of neurodegenerative disease. In pathologies such as Alzheimer's disease (AD), GSLs have been shown to interact with beta amyloid (a protein that forms the characteristic plaques in brain tissue of patients with AD) [157]. GSLs may also be complicit in neuroinflammation, a commonly present feature of neurodegenerative diseases. They are also involved in the loss of neuronal function and cell apoptosis that occurs in neurodegenerative diseases [226]. Additional research is necessary to comprehensively grasp the involvement of GSLs in these conditions. Focusing on AD, with a technique mentioned previously (TLC- Blot- MALDI-TOF MS on a AXIMA-QIT-TOF MS, with nitrogen laser pulsed at 337 nm and 2.5 DHB as a matrix, in negative ion mode), Taki T. [158] analyzed samples from human brain tissues with a control, Parkinson's disease (PD), and AD as points of interest, using gray matter from the hippocampus areas. The author found that GM1 was the main peak in each sample (at \(m/z\) 1572 and \(m/z\) 1544), but while \(m/z\) 1572 (d20:1) was predominant in the control and PD samples, the situation was reversed in the AD sample, with \(m/z\) 1544 (d18:1) being the most predominant peak. The trend of elevated levels of molecular species containing sphingosine d18:1 in the samples from AD was also noted in the mass spectra of GD1a (\(m/z\) 1885 (d20:1), \(m/z\) 1857 (d18:1)), GD1b (\(m/z\) 1855 (d20:1), \(m/z\) 1857(d18:1)), and GT1b (\(m/z\) 2198 (d20:1), \(m/z\) 2170 (d18:1)), compared to the control samples and the PD samples, where d20:1 was of higher intensity. The authors note that AD should be viewed as a metabolic disease of ganglioside molecules [158]. The increase in molecular species containing sphingosine, d18:1, was found in other studies also [227; 228; 229]. The total levels of gangliosides were specifically low in the frontal cortex of the AD samples, with GM1 having significantly low levels in the brain tissue samples. While the MS successfully identified GM3, GA1, GM2, GM1, GD1a/GD1b-lactone, GD1a, and GT1a/GT1b-lactone, only with the ganglioside GM1 did the authors find significant differences, while GD1a/GD1-lactone also appeared to be present in smaller amounts. It should be mentioned that GD1b-lactone is not an artifact, but an authentic product of brain metabolism. The levels of b-series gangliosides, GD1b and GT1b in the gray matter of the hippocampus of patients with AD were found to be depressed. However, the total serum levels of gangliosides appeared to be normal compared to the control group, with elevated levels observed in AD patients for GM3 and GM2. Accumulating evidence, both in vivo and in vitro, indicates that the binding of A\(\beta\) to gangliosides in membranes, especially monosiaganglioside GM1, plays an important role in the aggregation of A\(\beta\)[230; 231; 232; 233; 234; 235; 236]. It has been reported that A\(\beta\) (1-40) and A\(\beta\) (1-42) bind to the sugar moiety of GM1 (the sialic acid group is essential for this interaction) and forms a string-like GM1 cluster induced by endosomal dysfunction or alterations in lipid metabolism (e.g., increase in cholesterol related to apoE4 allele). This results in the formation of an \(\alpha\)-helix-rich structure which will be further converted to preamyloid \(\beta\)-sheet-rich nontoxic oligomers (containing 15 A\(\beta\) molecules). An additional increase in the A\(\beta\) density leads to the formation of toxic \"amyloid tape\" fibrils containing parallel and antiparallel \(\beta\)-sheet structures, which will activate apoptosis via intricate signaling cascades [237; 238].