Protection against Amyloid-β Oligomer Neurotoxicity by Small Molecules with Antioxidative Properties: Potential for the Prevention of Alzheimer’s Disease Dementia

Abstract

Soluble oligomeric assemblies of amyloid β-protein (Aβ), called Aβ oligomers (AβOs), have been recognized as primary pathogenetic factors in the molecular pathology of Alzheimer’s disease (AD). AβOs exert neurotoxicity and synaptotoxicity and play a critical role in the pathological progression of AD by aggravating oxidative and synaptic disturbances and tau abnormalities. As such, they are important therapeutic targets. From a therapeutic standpoint, it is not only important to clear AβOs or prevent their formation, it is also beneficial to reduce their neurotoxicity. In this regard, recent studies have reported that small molecules, most with antioxidative properties, show promise as therapeutic agents for reducing the neurotoxicity of AβOs. In this mini-review, we briefly review the significance of AβOs and oxidative stress in AD and summarize studies on small molecules with AβO-neurotoxicity-reducing effects. We also discuss mechanisms underlying the effects of these compounds against AβO neurotoxicity as well as their potential as drug candidates for the prevention and treatment of AD.

Proteostasis Deregulation in Neurodegeneration and Its Link with Stress Granules: Focus on the Scaffold and Ribosomal Protein RACK1

“…Together with the aforementioned link between tau aggregation and protein synthesis disruption, RNA oxidation has been reported to play a role in neurodegeneration. The analysis of oxidized RNA species detected in the brains of Alzheimer’s disease and amyotrophic lateral sclerosis patients revealed significant damage of mRNA and rRNA [ 162 ], which suggests a potentially beneficial antioxidant approach, both pharmacological and nutraceutical, to ameliorate these conditions [ 163 , 164 , 165 , 166 ].…”

Aβ Oligomer Toxicity-Reducing Therapy for the Prevention of Alzheimer’s Disease: Importance of the Nrf2 and PPARγ Pathways

“…Among the small molecules capable of reducing AβO-mediated toxicity highlighted in my previous review were the natural compounds tyrosol, honokiol, and rhynchophylline (Rhy). Notably, almost all of these molecules have potent antioxidative activity, underscoring the central role of oxidative stress in the pathophysiological cascade of AβO toxicity, as described above [17]. In reviewing the signaling pathways involved in the AβO toxicityreducing activity of these molecules, it became apparent that most of these molecules have the capacity to activate the Nrf2 pathway and initiate antioxidant defense responses.…”

“…In addition to these approaches, reducing the intrinsic toxicity of AβOs using certain small molecules is also a potential strategy. Indeed, a number of recent preclinical studies have suggested the viability of this latter approach [17]. Since Aβ accumulation has reached a substantial level by the prodromal stage of AD, it is particularly important to start therapeutic intervention as early as possible to prevent the clinical progression to AD dementia.…”

“…In a previous review, I discussed potential mechanisms underlying the action of AβO neurotoxicity-reducing small molecules [17]. Notably, almost all of these small molecules possess antioxidative properties, and most can stimulate the activity of Nrf2 (nuclear factor erythroid 2-related factor 2) [18], which is essential in antioxidative defense mechanisms.…”

Oxidative Stress, Neuroinflammation and Neurodegeneration: The Chicken, the Egg and the Dinosaur

“…Among the review articles, three of them focused on the involvement of oxidative stress in eye disorders, such as vitreoretinal diseases [ 8 ], diseases associated with retinal ganglion cells degeneration [ 9 ] and on the role of bisretinoids of the retina in photo-oxidation, iron-catalyzed oxidation and disease consequences [ 10 ]. The other four review papers summarized the major causes of central nervous system (CNS) redox homeostasis imbalance [ 11 ], the significance of amyloid β-protein oligomers (AβOs) and oxidative stress in AD [ 12 ], the role of TRAP1 in oxidative stress and neurodegeneration [ 7 ] and how PON2 controls oxidative stress, inhibits apoptosis and contributes to the progression of various types of malignancies [ 13 ].…”