Cognitive enhancement, TAU phosphorylation reduction, and neuronal protection by the treatment of an LRRK2 inhibitor in a tauopathy mouse model.

Leucine-rich repeat kinase 2 (LRRK2) is a protein kinase whose activity plays an important role in neurodegenerative diseases. Although mutations in LRRK2 gene are the most common cause of monogenic Parkinson's disease, it has been reported that LRRK2 may promote Tau phosphorylation, increasing its aggregation. Thus, the modulation of LRRK2 activity by small molecules able to inhibit this kinase activity could be an innovative therapeutic strategy for different tauopathies.

CX3CR1-deficient microglia shows impaired signalling of the transcription factor NRF2: Implications in tauopathies.

TAU protein aggregation is the main characteristic of neurodegenerative diseases known as tauopathies. Low-grade chronic inflammation is also another hallmark that indicates crosstalk between damaged neurons and glial cells. Previously, we have demonstrated that neurons overexpressing TAU release CX3CL1, which activates the transcription factor NRF2 signalling to limit over-activation in microglial cells in vitro and in vivo.

Cx3cr1-deficiency exacerbates alpha-synuclein-A53T induced neuroinflammation and neurodegeneration in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the degeneration of dopaminergic neurons of the substantia nigra and the accumulation of protein aggregates, called Lewy bodies, where the most abundant is alpha-synuclein (α-SYN). Mutations of the gene that codes for α-SYN (SNCA), such as the A53T mutation, and duplications of the gene generate cases of PD with autosomal dominant inheritance. As a result of the association of inflammation with the neurodegeneration of PD, we analyzed whether overexpression of wild-type α-SYN (α-SYN ) or mutated α-SYN (α-SYN ) are involved in the neuronal dopaminergic loss and inflammation process, along with the role of the chemokine fractalkine (CX3CL1) and its receptor (CX3CR1).