2 research outputs found
Implication of type 4 NADPH oxidase (NOX4) in tauopathy.
Aggregates of the microtubule-associated protein tau are a common marker of neurodegenerative diseases
collectively termed as tauopathies, such as Alzheimer’s disease (AD) and frontotemporal dementia. Therapeutic
strategies based on tau have failed in late stage clinical trials, suggesting that tauopathy may be the consequence
of upstream causal mechanisms. As increasing levels of reactive oxygen species (ROS) may trigger protein aggregation
or modulate protein degradation and, we had previously shown that the ROS producing enzyme
NADPH oxidase 4 (NOX4) is a major contributor to cellular autotoxicity, this study was designed to evaluate if
NOX4 is implicated in tauopathy. Our results show that NOX4 is upregulated in patients with frontotemporal
lobar degeneration and AD patients and, in a humanized mouse model of tauopathy induced by AVV-TauP301L
brain delivery. Both, global knockout and neuronal knockdown of the Nox4 gene in mice, diminished the
accumulation of pathological tau and positively modified established tauopathy by a mechanism that implicates
modulation of the autophagy-lysosomal pathway (ALP) and, consequently, improving the macroautophagy flux.
Moreover, neuronal-targeted NOX4 knockdown was sufficient to reduce neurotoxicity and prevent cognitive
decline, even after induction of tauopathy, suggesting a direct and causal role for neuronal NOX4 in tauopathy.
Thus, NOX4 is a previously unrecognized causative, mechanism-based target in tauopathies and blood-brain
barrier permeable specific NOX4 inhibitors could have therapeutic potential even in established disease.post-print5895 K
New reactions under homogeneous conditions
BDTBPMB has been proven to be an essential ligand in carbonylation chemistry.
Its two tert-butyl groups and wide bite angle give it the ideal characteristics for this kind
of chemistry, and leads to high activity and selectivity with use of its complexes. During
this work the group of reactions where this ligand has been proven to be active has been
extended with two new protocols for hydroxycarbonylation and aminocarbonylation. In
the hydroxycarbonylation process, a large variety of unsaturated compounds were studied.
Dioxane was found to be the ideal solvent, due to its properties in terms of coordinability,
and miscibility with water. Using this solvent as the medium, a BDTBPMB complex of
palladium was found to be highly active and selective under mild conditions.
Initial attempts to address the aminocarbonylation of alkenes catalysed by the
Pd/BDTBPMB system did not give high activity. This problem was overcome by the
addition of an arylalcohol. Under those conditions, high selectivity and conversion was
obtained in a wide variety of amides. However, attempts to address the
aminocarbonylation of alkenes with ammonia gas to generate primary amides did not
result in any conversion. The generation of these primary amides was obtained with
transamidation of N-phenylnonamides which can be prepared by aminocarbonylation.
Amides have been successfully hydrogenated to amines catalysed by a
Ru/Triphos system. This system has been proven to be highly active in this reaction.
High selectivities have been obtained in the generation of secondary amine. However,
initial results of the hydrogenation of primary amides resulted in no formation of primary
amines. A careful analysis of the mechanism of the formation of various products from
the hydrogenation of primary amides allows the selective formation of primary amines by
the ruthenium/Triphos system in the presence of ammonia. The possibility of the
generation of primary amides in situ from acids under hydrogenation conditions, giving
primary amines was explored with high conversion and moderate selectivities.To complete this work, a system based on a palladium complex for the
decarboxylation of benzoic acids was developed. Usually, the decarboxylation reactions
catalysed by copper require high temperatures. However, palladium complexes of highly
electron donating ligands such as BDTBPMB or P(ᵗBu)₃ were found to be highly active
under milder conditions. This catalytic system was proven to be active in desulfonation
reactions giving high conversion