Research to prevent and treat Alzheimer's disease (AD) is now focused on the development of novel therapeutic approaches that target multiple mechanisms simultaneously. Polyphenols, comprising multiple bio-available, active metabolites, are now being studied as novel therapeutics for strategies targeting the primary and secondary prevention of AD. Giulio Maria Pasinetti, MD, PhD, Saunders Family Chair and Professor of Neurology, Icahn School of Medicine, Mount Sinai, New York, New York, USA, presented work from his group examining the effects of cocoa polyphenols in AD.

Select cocoa polyphenol metabolites promote synaptic plasticity through mechanisms that include a reduction in amyloid-β (Aβ) production. At the secondary prevention level, cocoa polyphenols may decrease the burden associated with the accumulation of Aβ plaques and delay the onset of cognitive impairment in individuals with AD [Sperling RA et al. Sci Transl Med 2011].

The primary dietary flavan-3′-ol derivatives found in cocoa, as well as in grapes, are catechin, epicatechin, catechin gallate, and epicatechin gallate. In experimental studies using a transgenic mouse model of AD, the group of investigators led by Prof. Pasinetti found that grape seed-derived polyphenols are associated with improved Aβ neuropathology, which, in turn, led to improved synaptic plasticity and slowed cognitive deterioration in these mice [Wang J et al. Front Aging Neurosci 2014].

The effect of cocoa polyphenols on mood disorders and depression—the most common psychiatric comorbidities associated with the onset and progression of AD [Pellegrino et al. Curr Psychiatry Rep 2013]—is currently being examined. Data from animal studies has been encouraging, and has shown that the reduction in depression-related immobility [Messaoudi M et al. Nutr Neurosci 2008] may be attributable to the monoamine oxidase inhibition properties of cocoa flavanols [Xu Y et al. Pharmacol Biochem Behav 2010]. Prof. Pasinetti stated that more experimental studies into AD are required to determine the role of cocoa extracts in preserving synaptic plasticity, perhaps through the attenuation of Aβ conformational changes and prevention Aβ neurotoxicity, to determine whether this may change the relationship between depression and AD.

The polyphenol compositions of cocoa extracts vary due to the different methods used to obtain the extracts. Natural, Dutched, and Lavado cocoa extracts have different levels of total polyphenol gallic acid equivalents and oxygen radical absorbance capacity. Prof. Pasinetti reports that Lavado cocoa was shown to prevent globin transcription factor-1 (GATA1) -mediated repression of presynaptic genes in three independent experiments (Pasinetti, data not yet published). Furthermore, Lavado cocoa extract better attenuates Ab oligomerization, followed by Natural and Dutch cocoa extracts (Wang et al. 2014 in press). In ex vivo hippocampal slices from wild-type mice, Lavado, but not Dutch, cocoa extract prevented the impairment of long-term potentiation induced by oligomeric-Ab. Long-term potentiation is a key cellular mechanism underlying synaptic plasticity and is essential to learning and memory (Wang et al. 2014 in press).

The hypothetical role of cocoa flavan-3′-ol metabolites in synaptic plasticity has been reviewed elsewhere [Spencer JP. Chem Soc Rev 2009]. In brief, synapse growth and increased receptor density, resulting from the activation of the CREB (cyclic adenosine monophosphate (cAMP) response element-binding protein) pathway, leads to an increase in the expression of brain-derived neurotrophic factor (BDNF), which binds to pre- and postsynaptic tyrosine kinase B (TrkB) receptors, thereby triggering glutamate release, phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling, and synthesis of Arc, an immediate-early gene (IEG). PI3K and mTOR are important cellular regulatory pathways. Ongoing studies in Prof. Pasinetti's laboratory recently identified a novel role for cocoa polyphenols in influencing CREB pathways and the activation of IEGs, which are two independent but complementary molecular mechanisms influencing memory consolidation and synaptic plasticity.

Based on the neuroprotective effects of dietary cocoa polyphenols, Prof. Pasinetti and colleagues have undertaken a multi-faceted research strategy, with the ultimate goal to accelerate translational applications in the clinical setting for the primary and secondary prevention of AD. This includes the isolation of cocoa-derived bioactive polyphenol metabolites, their structural characterization and biosynthesis, the testing of bioactive polyphenols for AD disease-modifying activity in vivo, and elucidation of the mechanisms of this bioactivity, including the role of molecular pathways involved in Aβ generation, conformational changes, and clearance from the brain.