Flavonoids as an Intervention for Alzheimer’s Disease: Progress and Hurdles Towards Defining a Mechanism of Action1

Abstract

Attempts to develop a disease modifying intervention for Alzheimer’s disease (AD) through targeting amyloid β (Aβ) have so far been unsuccessful. There is, therefore, a need for novel therapeutics against alternative targets coupled with approaches which may be suitable for early and sustained use likely required for AD prevention. Numerous in vitro and in vivo studies have shown that flavonoids can act within processes and pathways relevant to AD, such as Aβ and tau pathology, increases in BDNF, inflammation, oxidative stress and neurogenesis. However, the therapeutic development of flavonoids has been hindered by an ongoing lack of clear mechanistic data that fully takes into consideration metabolism and bioavailability of flavonoids in vivo. With a focus on studies that incorporate these considerations into their experimental design, this review will evaluate the evidence for developing specific flavonoids as therapeutics for AD. Given the current lack of success of anti-Aβ targeting therapeutics, particular attention will be given to flavonoid-mediated regulation of tau phosphorylation and aggregation, where there is a comparable lack of study. Reflecting on this evidence, the obstacles that prevent therapeutic development of flavonoids will be examined. Finally, the significance of recent advances in flavonoid metabolomics, modifications and influence of the microbiome on the therapeutic capacity of flavonoids in AD are explored. By highlighting the potential of flavonoids to target multiple aspects of AD pathology, as well as considering the hurdles, this review aims to promote the efficient and effective identification of flavonoid-based approaches that have potential as therapeutic interventions for AD.

A Rapidin vivoPipeline to Identify Small Molecule Inhibitors of Amyloid Aggregation

“…A second common suppressor class are the flavonoids, which are a large class of polyphenolic secondary metabolites synthesized by plants (Panche et al, 2016). Many flavonoid structures have been shown to antagonize amyloid formation in vitro (Akaishi et al, 2008; Choi et al, 2020; Yin et al, 2011), in culture (Kimura et al, 2018), and in vivo (Ahmad et al, 2017; Kim et al, 2010; Wei et al, 2014a) (see (Hole and Williams, 2021) for a comprehensive and recent review). Poor bioavailability may contribute to a lack of flavonoid-based therapies in the clinic, although converting anti-amyloid flavonoids into prodrugs may circumvent absorption barriers (Chen et al, 2018).…”

Oral (−)-Epicatechin Inhibits Progressive Tau Pathology in rTg4510 Mice Independent of Direct Actions at GSK3β

“…While GSK3β is a prominent tau kinase, many other kinases contribute to tau phosphorylation ( Noble et al, 2013 ) such as CDK5 ( Kimura et al, 2014 ), microtubule associated protein kinases ( Drewes et al, 1995 ; Gu et al, 2013 ) and MAPKs ( Drewes et al, 1992 ). Likewise, GSK3β is not the only tau-associated kinase that can be modulated by flavonoids ( Hole and Williams, 2020 ). Further investigation is needed to establish which other kinase pathways may have been affected by EC intervention in this study.…”

“…The polyphenol (−)-Epicatechin (EC) is a dietary flavonoid of the flavan-3-ol subgroup, found in relatively high concentrations as a monomer in cocoa beans and more widely distributed in oligomeric form as a proanthocyanidin. EC has well characterized signaling actions in neural cells ( Schroeter et al, 2007 ; Bahia et al, 2008 ) and is a promising intervention for AD due to its low toxicity profile ( Ottaviani et al, 2015 ) and potential for multi-modal targeting ( Hole and Williams, 2020 ). EC has been shown to improve vascular function and cognition in humans ( Bernatova, 2018 ; Haskell-Ramsay et al, 2018 ), reduce oxidative stress and up-regulate neuroprotective pathways ( Schroeter et al, 2001 ; Spencer et al, 2001 ; Shah et al, 2010 ; Rendeiro et al, 2013 ; Zhang et al, 2016 ; Navarrete-Yañez et al, 2020 ).…”

Brain-Derived Neurotrophic Factor Signaling in the Pathophysiology of Alzheimer’s Disease: Beneficial Effects of Flavonoids for Neuroprotection

“…Oral administration of Hex increased the concentration of Hex in the hippocampus and upregulated the BDNF and its downstream plasticity-associated molecules, resulting in improved synaptic plasticity and memory/learning in AD model mice [ 78 ]. Flavonoids are a large family of dietary polyphenol compounds, are found almost ubiquitously in plants, and some of them have ability to activate BDNF signaling [ 79 ]. As shown above, 7,8-DHF, a derivate of flavone, was identified as a selective small-molecular TrkB agonist that mimics the physiological actions of the BDNF [ 10 ].…”