Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and chronic neuroinflammation. Emerging evidence suggests a crucial role of lipid signaling pathways in AD pathogenesis, particularly those mediated by autotaxin (ATX) and lysophosphatidic acid (LPA). ATX, an enzyme responsible for LPA production, has been implicated in neuroinflammatory processes, blood–brain barrier dysfunction, and neuronal degeneration. LPA signaling, through its interaction with specific G-protein-coupled receptors, influences neuroinflammation, synaptic plasticity, and tau pathology, all of which contribute to AD progression. This review synthesizes recent findings on the ATX/LPA axis in AD, exploring its potential as a biomarker and therapeutic target. Understanding the mechanistic links between ATX, LPA, and AD pathology may open new avenues for disease-modifying strategies.

Non-traumatic intracerebral hemorrhage (ICH) is one of the most devastating and disabling forms of stroke; however, there are no effective pharmacological therapies available following the insult. Angiogenesis appears as a key step to overcoming the damage and promoting functional recovery. In this context, endothelial progenitor cells (EPCs) mobilization improves oxidative stress and promotes neovascularization, which has been linked to beneficial outcomes following both ischemic and hemorrhagic stroke. The TNF-like weak inducer of apoptosis (TWEAK), binding to its receptor Fn14, has been suggested as an inducer of EPCs differentiation, viability and migration to the injury site in a model of myocardial infarction. Here, we have performed a proof-of-concept preclinical study in a rat model of ICH where we report that a 50 μg/kg dose of rat recombinant TWEAK (rTWEAK) promotes blood progenitor cells mobilization, mainly EPCs. As soon as 72 h post-injury, brain neovascularization, and, importantly, long-term hematoma reduction and improved functional recovery is reported. In contrast, a higher dose of 150 μg/kg blocked those beneficial outcomes. Therefore, a low dose of rTWEAK treatment promotes neovascularization and reduces brain damage in a rat model of ICH. Further clinical studies will be needed to demonstrate if rTWEAK could represent a new strategy to promote recovery following ICH.

Migraine is one of the most common neurological disorders and the second most disabling human condition. The molecular mechanisms of migraine have been linked to neuropeptide release, endothelial dysfunction, oxidative stress and inflammatory processes. Acid sphingomyelinase (aSMase) is a secreted enzyme that leads to sphingomyelin degradation to produce ceramide. Its activity has been associated with several molecular processes involved in migraine. Therefore, this cross-sectional study aims to study the potential role of aSMase in patients with episodic and chronic migraine. In this cross-sectional pilot study, serum samples from female healthy controls (n = 23), episodic migraine (EM) patients (n = 31), and chronic migraine (CM) patients (n = 28) were studied. The total serum levels of aSMase were determined by ELISA. In addition, the serum levels of sphingomyelin (SM), dihydro-sphingomyelin (dhSM), ceramide (Cer), and dihydro-ceramide (dhCer) were determined by mass spectrometry as biomarkers involved in the main molecular pathways associated with aSMase. aSMase serum levels were found significantly elevated in both EM (3.62 ± 1.25 ng/mL) and CM (3.07 ± 0.95 ng/mL) compared with controls (1.58 ± 0.72 ng/mL) (p < 0.0001). ROC analysis showed an area under the curve (AUC) of 0.94 (95% CI: 0.89–0.99, p < 0.0001) and 0.90 (95% CI: 0.81–0.99, p < 0.0001) for EM and CM compared to controls, respectively. Regarding other biomarkers associated with aSMase’s pathways, total SM serum levels were significantly decreased in both EM (173,534 ± 39,096 pmol/mL, p < 0.01) and CM (158,459 ± 40,010 pmol/mL, p < 0.0001) compared to the control subjects (219,721 ± 36,950 pmol/mL). Elevated serum levels of aSMase were found in EM and CM patients compared to the control subjects. The decreased SM levels found in both EM and CM indicate that aSMase activity plays a role in migraine. Therefore, aSMase may constitute a new therapeutic target in migraine that should be further investigated.