Alzheimer’s disease (AD) is one of the main human dementias around the world which is constantly increasing every year due to several factors (age, genetics, environment, etc.) and there are no prevention or treatment options to cure it. AD is characterized by memory loss associated with oxidative stress (OS) in brain cells (neurons, astrocytes, microglia, etc.). OS can be produced by amyloid beta (Aβ) protein aggregation and its interaction with metals, mitochondrial damage and alterations between antioxidants and oxidant enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADPH oxidase produces reactive oxygen species (ROS) and it is overexpressed in AD, producing large amounts of superoxide anions and hydrogen peroxide which damage brain cells and the vasculature. In addition, it has been reported that NADPH oxidase causes an imbalance of pH which could also influence in the amyloid beta (Aβ) production. Therefore, NADPH oxidase had been proposed as a therapeutic target in AD. However, there are no drugs for AD treatment such as an NADPH oxidase inhibitor despite great efforts made to stabilize the ROS production using antioxidant molecules. So, in this work, we will focus our attention on NADPH oxidase (NOX2 and NOX4) in AD as well as in AD models and later discuss the use of NADPH oxidase inhibitor compounds in AD.

The amyloid-β 1-42 (Aβ1-42) peptide is produced by proteolytic cleavage of the amyloid precursor protein (APP) by sequential reactions that are catalyzed by γ and β secretases. Aβ1-42, together with the Tau protein are two principal hallmarks of Alzheimer’s disease (AD) that are related to disease genesis and progression. Aβ1-42 possesses a higher aggregation propensity, and it is able to form fibrils via nucleated fibril formation. To date, there are compounds available that prevent Aβ1-42 aggregation, but none have been successful in clinical trials, possibly because the Aβ1-42 structure and aggregation mechanisms are not thoroughly understood. New molecules have been designed, employing knowledge of the Aβ1-42 structure and are based on preventing or breaking the ionic interactions that have been proposed for formation of the Aβ1-42 fibril U-shaped structure. Recently, a new Aβ1-42 fibril S-shaped structure was reported that, together with its aggregation and catalytic properties, could be helpful in the design of new inhibitor molecules. Therefore, in silico and in vitro methods have been employed to analyze the Aβ1-42 fibril S-shaped structure and its aggregation to obtain more accurate Aβ1-42 oligomerization data for the design and evaluation of new molecules that can prevent the fibrillation process.

N-(2′-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) is a VPA derivative designed to be a histone deacetylase (HDAC) inhibitor. HO-AAVPA has better antiproliferative effect than VPA in cancer cell lines. Therefore, in this work, the inhibitory effect of HO-AAVPA on HDAC1, HDAC6, and HDAC8 was determined by in silico and in vitro enzymatic assay. Furthermore, its antiproliferative effect on the cervical cancer cell line (SiHa) and the translocation of HMGB1 and ROS production were evaluated. The results showed that HO-AAVPA inhibits HDAC1, which could be related with HMGB1 translocation from the nucleus to the cytoplasm due to HDAC1 being involved in the deacetylation of HMGB1. Furthermore, an increase in ROS production was observed after the treatment with HO-AAVPA, which also could contribute to HMGB1 translocation. Therefore, the results suggest that one of the possible antiproliferative mechanisms of HO-AAVPA is by HDAC1 inhibition which entails HMGB1 translocation and ROS increased levels that could trigger the cell apoptosis.

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