Brain-Targeted Proanthocyanidin Metabolites for Alzheimer's Disease Treatment

Abstract

While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as limited knowledge regarding their bioavailability, metabolism and bioactivity, especially in the brain. We recently demonstrated that dietary supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimer’s disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric (Po) forms. In this study we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ~400 nM. Most importantly we report for the first time that a biosynthetic epicatechin metabolite, 3’-O-methyl-epicatechin-5-O-β-glucuronide (3’-O-Me-EC-Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3’-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in Alzheimer’s disease and other forms of dementia.

Paired Helical Filaments from Alzheimer Disease Brain Induce Intracellular Accumulation of Tau Protein in Aggresomes

“…Grape-derived bioactive GSE preparations comprising proanthocyanidins have been demonstrated to exert a wide scope of neuroprotective biological activities in animal models of tauopathy and neurodegeneration (33)(34)(35)(36)65). More complex proanthocyanidins, however, including dimers, trimers, and oligomers have a reduced bioavailability in the rat brain when compared with monomers (66).…”

“…Typically, GSE contains ϳ8% monomers, 75% oligomers, and 17% polymers (35). For the present studies, GSE was fractionated into monomer-enriched (monomeric GSE) and polymer-enriched fractions through solvent fractionation followed by chromatography on Toyopearl resin (36). The monomeric GSE fraction was used to treat cultured cells.…”

Natural Phenolic Compounds as Therapeutic and Preventive Agents for Cerebral Amyloidosis

“…Reductions of amyloid deposition, A" oligomer levels, inflammation, or oxidative stress in the brain with attenuation of cognitive deterioration have been reported in transgenic mouse models treated with: Cur (Lim et al 2001;Yang et al 2005;Hamaguchi et al 2009;Ray et al 2011), EGCG (Rezai-Zadeh et al 2005, Myr (Hamaguchi et al 2009), RA (Hamaguchi et al 2009), resveratrol (Karuppagounder et al 2009;Capiralla et al 2012;Solberg et al 2014;Porquet et al 2014), tannic acid (Mori et al 2012), FA (Mori et al 2013), rutin (a glycone of quercetin) (Xu et al 2014), oleuropein (Grossi et al 2013), hopeahainol A , grape seed polyphenolic extract (GSPE) Liu et al 2011), proanthocyanidins of GSPE (Wang et al 2012), red wine/its polyphenolic contents (Wang et al 2006;Ho et al 2009a), anthocyanin-enriched blueberry and blackcurrant 3)] exert inhibitory effects through different binding to A". Details of the studies were described in the reference (Ono et al 2012) extracts (Vepsäläinen et al 2013), pomegranate juice containing high levels of polyphenols (Hartman et al 2006), and a natural diet rich in polyphenols and polyunsaturated fatty acids (LMN diet) (Fernández-Fernández et al 2012).…”

Brain metabolism and Alzheimer's disease: The prospect of a metabolite-based therapy

“…As ketoacids and L-carnitine have been shown to reverse the mitochondrial dysfunction evoked by these toxins, these metabolites are potentially excellent candidates to remedy AD (52). As the dyslipidemia observed in astrocytes due to Al toxicity has been shown to be arrested by ketoacids, supplementation with pyruvate, acetoacetate and αKG may aid in the alleviation of the symptoms associated with AD (53,54,55). These natural metabolites are relatively inexpensive and may be devoid of any side-effects associated with pharmaceutical products.…”