Unraveling molecular signaling in neurodegenerative diseases: focus on a protective mechanism mediated by linalool

Neurodegenerative conditions such as Alzheimer`s disease (AD) and stroke are characterized by progressive nervous system dysfunction. The main aim of this work was to propose new therapeutic targets in neurodegeneration and to identify possible phospholipid biomarkers that reflect the progression of the disease. We demonstrated that administration of the terpene, linalool was able to reduce the main pathological markers of AD (extracellular β-amyloidosis, tauopathy) and of ischemic stroke. Linalool treatment in animals improved motor coordination and cognition, along with a reduction of astrogliosis and microgliosis in the hippocampus. Besides, we investigated whether and how linalool exert a neuroprotective effect against glutamate-induced oxidative stress and might affect mitochondrial function. Administration of linalool reduced cell death mediated by glutamate, mitochondrial ROS formation, mitochondrial calcium uptake, lipid peroxidation and mediated a recovery of mitochondrial membrane potential, together with an increase in mitochondrial respiration. In addition, we detected remarkable changes in phospholipids in ischemic stroke, AD and CADASIL in brain samples, CSF and serum. These data could help to unravel novel molecular mechanisms and propose different therapeutic targets to treat transversal pathogenesis. Finally, we showed in a review the role of microglia in neurodegenerative diseases and we present the results of a differentiation protocol of human microglia from iPSC demonstrating the maturity and functionality of these cells. In conclusion, we present various strategies to model and study neurodegeneration and provide answers in the field of inflammation, lipidomics and at the same time we propose a new molecule as a potential therapy against AD and cerebral ischemia.