Implication of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Its Inhibitors in Alzheimer’s Disease Murine Models

Abstract

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.

Gram-negative bacteria and their lipopolysaccharides in Alzheimer’s disease: pathologic roles and therapeutic implications

“…In addition, LPS is one of the potent factors capable of activating NOX2 in the CNS [ 164 , 175 ]. The NOX2 activation in glia and neurons can induce neuronal cell death through massive oxidative stress, which has been suggested as a contributor to several neurodegenerative diseases, including AD [ 176 , 177 ]. The LPS-induced neuroinflammation such as NOX2 activation can be a possible additional contributor to neurodegeneration in AD pathology.…”

Identification of the NADPH Oxidase (Nox) Subtype and the Source of Superoxide Production in the Micturition Centre

“…This may have important pathological implications, as oxidative damage to these structures as a result of increased Nox 2 activity could disrupt normal central control of the micturition reflex and cause voiding disorders. Indeed, in several other chronic brain disorders, Nox 2 has been suggested to contribute to inflammation and oxidative damage [ 14 , 15 , 17 ]. This warrants further investigation into the role of Nox 2 in these brain regions in neurogenic bladder dysfunctions.…”

“…Whilst Nox 4 is the first recognized Nox subtype in the CNS, and mainly participates in cell signalling but may also be involved in stroke, Nox 2 has been shown to mainly contribute to pathological damage [ 15 , 16 ]. The importance of Nox and associated ROS overproduction is evidenced by increased expression of Nox subtypes in experimental CNS damage and in certain pathological samples [ 14 , 15 , 17 ] and by the protective effect of interventions with small-molecule Nox inhibitors and Nox knockout [ 13 , 16 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. However, further progress in understanding the pathological basis of Nox-derived ROS in brain damage requires knowledge of the specific distribution of Nox subtypes and associated ROS production in specialized brain regions.…”

The tryptophan catabolite or kynurenine pathway in Alzheimer’s disease: a systematic review and meta-analysis

“…Previous studies reported no changes in 3HK levels in AD patients compared to controls, in either central or peripheral levels (Baran, Jellinger et al 1999, Gulaj, Pawlak et al 2010, Jacobs, Lim et al 2019, Sorgdrager, Vermeiren et al 2019). KMO enzyme requires NADPH as a coenzyme (Hughes, Guner et al 2022) and, therefore, the overactivity of NADPH oxidase enzyme consumes NADPH in AD patients (Fragoso-Morales, Correa-Basurto et al 2021), which may cause attenuated KMO enzyme activity.…”