With the rapid growth of aging populations worldwide, cognitive decline and dementia are becoming an increasing burden not only on patients and their families, but also on national healthcare systems. Because of the lack of a disease therapy for dementia, preventive approaches are receiving increasing attention. Dementia is a collective term, encompassing Alzheimer-type dementia, vascular dementia, Lewy body dementia and frontotemporal dementia, and approximately 60% of dementia is classified as Alzheimer-type dementia. In Alzheimer’s disease, β-amyloid (Aβ) becomes aggregated and gets deposited as the affected individual ages. The Aβ deposits induce inflammation and neurologic deficits in the brain and result in cognitive decline [1,2]. Because Aβ is slowly produced in the brain for more than 10-20 years before cognitive decline are manifest, preventive approaches before rather than remedy after disease onset represents a promising therapeutic avenue.

Etiological reports suggest that low-to-moderate consumption of alcoholic beverages, such as wine and beer, reduce the risk of dementia. Individuals who consume low-to-moderate levels of alcoholic beverages on a daily basis have been shown to have a significantly lower risk of the development of cardiovascular and neurodegenerative disease relative to those who abstain from alcohol beverages or drink heavily [3-5]. Aside from the effects of alcohol itself, various reports have shown that resveratrol, a polyphenol in red wine, has a preventive effect on dementia and cognitive decline [6-8]. On the other hand, even though it is the most-consumed alcoholic beverage, no constituents of beer had been demonstrated to have preventive effects on dementia. However, a recent study using a rodent model has now shown that intake of ingredients in beer has preventive effects on Alzheimer’s disease pathology [9]. These ingredients are iso-α-acids, the hop-derived bitter components of beer.

Hops, the female inflorescences of the hop plant (Humulus lupulus L. Figure 1A), are essential materials in brewing that give beer its fresh bitterness and bright flavor. Hops have also been traditionally used as a medicinal plant, and several health benefits have been reported including appetite improvement, induction of sound sleep, stress relief, osteoporosis prevention, suppressing high-blood pressure, and obesity improvement. Various ingredients contained in hops or beer, such as humulone, lupulon, xanthohumol and eudesmol, in addition to iso-α- acids derived from α-acids (humulone, Figure 1B), are well known to impart the bitter taste to beer. α-Acids from hops are isomerized into iso-α-acids during the brewing process (Figure 1C and 1D). The concentrations of iso-α-acids are dependent on the type of beer; for example, ordinal beer contains iso-α-acids at 10-30 ppm. Iso-α-acids are especially rich in India Pale Ale (IPA)-type beers and are present in non-alcoholic beverages with a beer flavor. A previous study using rodents and humans demonstrated the effects of iso-α-acids on anti-obesity and metabolic syndrome improvement [10,11].

Figure 1: Chemical structures of α-acids and iso-α-acids. -Acids contained in hop (Humulus lupulus L.) plants (A). Structures of α- acids: cohumulone (B-a), humulone (B-b), and adhumulone (B-c) (B). Structures of cis-iso-α-acids: cis-isocohumulone (C-a), cis-isohumulone (C-b), and cis-isoadhumulone (C-c). Structures of trans-iso-α-acids: trans-isocohumulone (D-a), trans-isohumulone (D-b), and trans-isoadhumulone (D-c).

More recently, iso-α-acids were identified as novel components regulating microglia [9], a type of immune cell in the nervous systems. As a regulator of the immune response in the brain, microglia have been recently attracting increasing attention because numerous reports suggest that inflammation in the brain severely induces cognitive decline and exacerbates Alzheimer’s disease pathology. Microglia play an important role in removing waste products such as Aβ, but their function declines alongside the aging process, when, in contrast, they can induce inflammation in the brain. Iso-α-acids were identified as a component in beer that can enhance microglial phagocytic activity (Figure 2A and 2B) and suppress microglial inflammatory responses [9]. Iso-α-acids enhanced both microglial phagocytosis of Aβ and expression of CD36, a scavenger receptor for Aβ (Figure 2C) [12]. Simultaneously, iso-α-acids suppressed the production of TNF-α in response to LPS stimulation and induce microglia towards a CD206- positive M2 anti-inflammatory cell type (Figure 2D) [13].

Figure 2: Effect of in vitro treatment with iso-α-acids on murine microglial phagocytic and anti-inflammatory activity. Immunofluorescent image of cultured primary murine microglia without or with iso-α-acids showing CD11b-positive microglia (red) engulfing microbeads (green). DAPI-stained nuclei are shown in blue (A and B, respectively). Effects of iso-α-acids (0.1 to 5 μM) on in vitro phagocytosis of Aβ-FAM by CD11b-positive microglia (C). Concentration of TNF-α in microglial cultural supernatant after pretreatment with 0, 2.5, and 10 μM iso-α-acids, and treatment with 5 ng/ml of LPS and 0.5 ng/ml of IFN-γ. Data are means ± SE of 3-5 wells per sample. *p<0.05 and **p<0.01. Data are cited and modified from [7].

After the evaluation in primary microglia, the preventive effects of iso-α-acids on Alzheimer’s disease were evaluated by using a rodent model. Iso-α-acids were fed to 5xFAD transgenic mice overexpressing mutant human APP (695) with the Swedish (K670N, M671L), Florida (I716V), and London (V717I) Familial Alzheimer's Disease (FAD) mutations, along with human PS1 harboring two FAD mutations, M146L and L286V. These model mice rapidly develop severe amyloid pathology [14]. Immunohistochemical analysis revealed that intake of iso-α-acids reduced Aβ deposition by 30%-50% in the cerebral cortex and hippocampus. Quantification by ELISA showed that iso-α-acids also suppressed the accumulation of soluble and insoluble Aβ (Figure 3). The levels of inflammatory cytokines and chemokines such as TNF-α, IL-1β, and MIP-1α, which are induced after Aβ accumulation, were also significantly reduced. Analysis of phagocytic activity and cell-surface marker expression in microglia in the brain of 5xFAD mice also demonstrated that intake of iso-α-acids significantly ameliorated the decline in phagocytosis of Aβ in 5xFAD mice and enhanced CD36 expression. In addition, a novel object recognition test, a standard behavioral pharmacological evaluation [15], revealed that iso-α-acids prevent cognitive decline and memory impairment in 5xFAD mice. Collectively, these results demonstrate that iso-α-acids have preventive effects on Alzheimer’s disease pathology and cognitive decline by improving microglial phagocytic activity and inflammatory response.

Figure 3: Effect of oral iso-α-acids on deposition of Aβ in the brain of Alzheimer’s disease model mice. Immunohistochemistry of Aβ1-42 distribution in 5xFAD transgenic mice fed with an iso-α- acids (-) or iso-α-acids (+) diet for 2.5 months. Soluble Aβ1-42 in mice fed with an iso-α-acids (-) or iso-α-acids (+) diet quantified by ELISA (A). Data in the ELISA assay are represented as the means ± SEM of 13 mice. *p<0.05. Data are cited and modified from [7].

In summary, a new beneficial aspect of iso-α-acids, hop-derived bitter components in beer, has been identified. It is widely known that alcoholic beverages should be consumed in moderation; in addition, more elderly individuals tend to refrain from alcoholic intake. Thus, a new tool making it possible to consume iso-α-acids comfortably in daily life is desired.