Exploring the Therapeutic Potential of Phytochemicals in Alzheimer's Disease: Focus on Polyphenols and Monoterpenes

Abstract

Alzheimer's disease (AD) is a chronic, complex neurodegenerative disorder mainly characterized by the irreversible loss of memory and cognitive functions. Different hypotheses have been proposed thus far to explain the etiology of this devastating disorder, including those centered on the Amyloid-β (Aβ) peptide aggregation, Tau hyperphosphorylation, neuroinflammation and oxidative stress. Nonetheless, the therapeutic strategies conceived thus far to treat AD neurodegeneration have proven unsuccessful, probably due to the use of single-target drugs unable to arrest the progressive deterioration of brain functions. For this reason, the theoretical description of the AD etiology has recently switched from over-emphasizing a single deleterious process to considering AD neurodegeneration as the result of different pathogenic mechanisms and their interplay. Moreover, much relevance has recently been conferred to several comorbidities inducing insulin resistance and brain energy hypometabolism, including diabetes and obesity. As consequence, much interest is currently accorded in AD treatment to a multi-target approach interfering with different pathways at the same time, and to life-style interventions aimed at preventing the modifiable risk-factors strictly associated with aging. In this context, phytochemical compounds are emerging as an enormous source to draw on in the search for multi-target agents completing or assisting the traditional pharmacological medicine. Intriguingly, many plant-derived compounds have proven their efficacy in counteracting several pathogenic processes such as the Aβ aggregation, neuroinflammation, oxidative stress and insulin resistance. Many strategies have also been conceived to overcome the limitations of some promising phytochemicals related to their poor pharmacokinetic profiles, including nanotechnology and synthetic routes. Considering the emerging therapeutic potential of natural medicine, the aim of the present review is therefore to highlight the most promising phytochemical compounds belonging to two major classes, polyphenols and monoterpenes, and to report the main findings about their mechanisms of action relating to the AD pathogenesis.

Keywords: Alzheimer’s disease; amyloid-β aggregation; monoterpenes; multi-target therapy; neurodegeneration; neuroinflammation; phytochemicals; polyphenols.

FIGURE 1

An overview of the main mechanisms involved in Alzheimer’s disease pathogenesis and their interplay according to a multi-factorial hypothesis. The figure depicts the role of the amyloidogenic processing of the Amyloid Precursor Protein (APP) induced by genetic factors or aging, in the formation of Amyloid-β (Aβ) oligomers and extracellular amyloid plaques. Small Aβ aggregates contribute to reactive oxygen species (ROS) production and mitochondrial dysfunction, formation of Tau aggregates and neurofibrillary tangles (NFTs). In addition, the activation of astrocytes and microglia, resulting in the release of cytokines, ROS, and nitric oxide, contribute to neuronal oxidative stress and mitochondrial dysfunction. Mitochondrial damage caused by a neuroinflammatory milieau, aging or metabolic disorders such as Type 2 diabetes mellitus and obesity induces the accumulation of free radicals and impairs the energetic efficiency of the neuron.

FIGURE 2

Chemical structures of the approved drugs for Alzheimer’s disease treatment.

FIGURE 3

Chemical structures of the main polyphenolic compounds with a therapeutic potential for Alzheimer’s disease treatment.

FIGURE 4

Chemical structure of the main monoterpenes with a therapeutic potential for Alzheimer’s disease treatment.

FIGURE 5

Polyphenols and monoterpenes as potential bioactive agents in Alzheimer’s disease (AD) multi-target therapy. Phytochemicals may serve as therapeutic agents to combat AD neurodegeneration owing to their antioxidant and anti-inflammatory activities, which may be useful in counteracting oxidative stress and neuroinflammation. In addition, they may modulate the Amyloid-β (Aβ) aggregation and accumulation hence reducing brain Aβ burden. The improvement of insulin-sensitivity by phytochemicals may also be beneficial for reversing the detrimental progression of AD. The combination of the biological activities of phytochemicals with nanotechnology and/or synthetic strategies may improve their pharmacokinetic profile and their therapeutic potential.