Eicosanoyl-5-hydroxytryptamide (EHT) prevents Alzheimer’s disease-related cognitive and electrophysiological impairments in mice exposed to elevated concentrations of oligomeric beta-amyloid

Abstract

Soluble forms of oligomeric beta-amyloid (Aβ) are thought to play a central role in Alzheimer’s disease (AD). Transgenic manipulation of methylation of the serine/threonine protein phosphatase, PP2A, was recently shown to alter the sensitivity of mice to AD-related impairments resulting from acute exposure to elevated levels of Aβ. In addition, eicosanoyl-5-hydroxytryptamide (EHT), a naturally occurring component from coffee beans that modulates PP2A methylation, was shown to confer therapeutic benefits in rodent models of AD and Parkinson’s disease. Here, we tested the hypothesis that EHT protects animals from the pathological effects of exposure to elevated levels of soluble oligomeric Aβ. We treated mice with EHT-containing food at two different doses and assessed the sensitivity of these animals to Aβ-induced behavioral and electrophysiological impairments. We found that EHT administration protected animals from Aβ-induced cognitive impairments in both a radial-arm water maze and contextual fear conditioning task. We also found that both chronic and acute EHT administration prevented Aβ-induced impairments in long-term potentiation. These data add to the accumulating evidence suggesting that interventions with pharmacological agents, such as EHT, that target PP2A activity may be therapeutically beneficial for AD and other neurological conditions.

Reduced Expression of the PP2A Methylesterase, PME-1, or the PP2A Methyltransferase, LCMT-1, Alters Sensitivity to Beta-Amyloid-Induced Cognitive and Electrophysiological Impairments in Mice

“…The pattern of immunoreactivity observed is consistent with that originally reported by Stine et al (2003) and in subsequent publications (Puzzo et al, 2008;L. Lee et al, 2014;Asam et al, 2017).…”

“…Multiple lines of evidence suggest a role for the serine/threonine phosphatase, PP2A, in Alzheimer's disease (AD). Among these are the observations that (1) PP2A expression and activity are reduced in brains from AD patients (Gong et al, 1993(Gong et al, , 1995Vogelsberg-Ragaglia et al, 2001;Sontag et al, 2004); (2) reducing PP2A activity in animal models results in AD-like pathology and cognitive deficits (Kins et al, 2001;Sun et al, 2003;Schild et al, 2006;Wang et al, 2010;Yin et al, 2010;Louis et al, 2011;Bolognin et al, 2012); (3) PP2A is the principal phosphatase for phosphorylated forms of microtubule-associated binding protein, tau, that are linked to AD (Martin et al, 2013); and (4) pharmacological activators of PP2A have been found to reduce cognitive impairment and pathology in AD-related mouse models (Corcoran et al, 2010;van Eersel et al, 2010;Vitek et al, 2012;Basurto-Islas et al, 2014;Asam et al, 2017;Van der Jeugd et al, 2018).…”

Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson's disease and DLB

“…Our present results, therefore, raise the possibility of similar synergy between EHT and CAF in both classes of chronic neurodegenerative diseases. Several epidemiologic studies have shown that greater consumption of coffee or CAF is associated with reduced risk of AD (56), and dietary supplementation with EHT is efficacious in two rodent models of AD: mice exposed to oligomeric beta-amyloid injections into the hippocampus (57) and rats injected in the lateral ventricle with viral vector expressing the endogenous PP2A inhibitor SET that exhibit tau hyperphosphorylation, elevated levels of cytoplasmic amyloid-β protein, and cognitive impairment (58). Additionally, in AβPPsw+PS1 transgenic mice, administration of caffeinated coffee increased plasma levels of cytokines, while neither CAF alone nor decaffeinated coffee had this effect, raising the likelihood that CAF synergizes with another component of coffee (59).…”

Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration

“…Evidence of PP2A dysfunction has prompted researchers to investigate therapeutic responses to PADs in experimental models of AD. Cognitive impairment driven by amyloid β aggregates was reduced following treatment of animals with the novel PP2A-activating compound EHT (Asam et al, 2017; Basurto-Islas et al, 2014) or FTY720 (Asle-Rousta, Kolahdooz, Dargahi, Ahmadiani, & Nasoohi, 2014; Asle-Rousta, Kolahdooz, Oryan, Ahmadiani, & Dargahi, 2013; Hemmati et al, 2013). Sodium selenate, which increases PP2A activity, reduced cognitive impairment in a PP2A-dependent manner in AD models based on dysregulated tau phosphorylation (Corcoran et al, 2010; van Eersel et al, 2010).…”