foods Review Fermented Soy Products: Beneficial Potential in Neurodegenerative Diseases Chan Ho Jang 1,†, Jisun Oh 2,†, Ji Sun Lim 2, Hyo Jung Kim 3 and Jong-Sang Kim 1,2,4,* 1 School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Korea; [email protected] 2 Institute of Agricultural Science and Technology, Kyungpook National University, Daegu 41566, Korea; [email protected] (J.O.); [email protected] (J.S.L.) 3 Department of Korean Medicine Development, National Institute for Korean Medicine Development, Gyeongsan 38540, Korea; [email protected] 4 Department of Integrative Biotechnology, Kyungpook National University, Daegu 41566, Korea * Correspondence: [email protected]; Tel.: +82-53-950-5752; Fax: +82-53-950-6750 † These authors contributed equally to this work. Abstract: Fermented soybean products, such as cheonggukjang (Japanese natto), doenjang (soy paste), ganjang (soy sauce), and douchi, are widely consumed in East Asian countries and are major sources of bioactive compounds. The fermentation of cooked soybean with bacteria (Bacillus spp.) and fungi (Aspergillus spp. and Rhizopus spp.) produces a variety of novel compounds, most of which possess health benefits. This review is focused on the preventive and ameliorative potential of fermented soy foods and their components to manage neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Keywords: fermented soybean products; Parkinson’s disease; Alzheimer’s disease; isoflavones; gut microbiota Citation: Jang, C.H.; Oh, J.; Lim, J.S.; Kim, H.J.; Kim, J.-S. Fermented Soy Products: Beneficial Potential in Neurodegenerative Diseases. Foods 1. Introduction 2021, 10, 636. https://doi.org/ 10.3390/foods10030636 Population aging is a global demographic trend. According to the “2019 Revision of World Population Prospects” [1,2], the proportion of people aged 65 years or over world- Academic Editor: Juan E. Andrade wide is projected to reach nearly 16% by 2050, and 23% by 2100. However, this extended life expectancy is closely associated with a vulnerability to age-related disorders, such as Received: 9 February 2021 neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease Accepted: 15 March 2021 (PD) [3]. Unfortunately, there is currently no effective treatment for these devastating Published: 18 March 2021 diseases. Recently, an increasing number of studies have focused on the development of dietary measures as well as preventive regimens for these conditions [4,5]. For instance, Publisher’s Note: MDPI stays neutral the root of Angelica gigas and Platycodon grandiflorus, as well as Lactobacillus helveticus and with regard to jurisdictional claims in phosphatidylserine, have been approved regarding the claim of cognition improvement published maps and institutional affil- by the Korean government, which allowed them to be processed and marketed as health iations. functional foods. The nutritional values and medicinal effects of soybean or its constituents are well documented [6–11]. In several Asian countries, including China, Indonesia, Japan, and Korea, fermented soybean products, such as doenjang (soybean paste and Japanese miso), Copyright: © 2021 by the authors. ganjang (soy sauce), natto, and tempeh, have been extensively consumed since ancient times. Licensee MDPI, Basel, Switzerland. Numerous studies published in the past decades have revealed that fermented soy products This article is an open access article have multifarious health benefits, such as serum cholesterol-lowering, anti-diabetic, anti- distributed under the terms and hypertensive, anti-cardiovascular, and anti-neuroinflammatory effects [10,12–14]. Recently, conditions of the Creative Commons soybean and its fermented products have received much attention regarding their effects on Attribution (CC BY) license (https:// the gut microbiota, which are linked to the pathogenesis of various neurological disorders, creativecommons.org/licenses/by/ including depression, anxiety, autism, AD, and PD [15–17]. 4.0/). Foods 2021, 10, 636. https://doi.org/10.3390/foods10030636 https://www.mdpi.com/journal/foods Foods 2021, 10, x FOR PEER REVIEW 2 of 18 Foods 2021, 10, 636 2 of 17 This review article discusses the protective effects of popular fermented soy foods and theirThis reviewcomponents article in discusses the context the protective of neurodegenerative effects of popular diseases, fermented with a soy focus foods on andAD theirand PD, components and describes in the the context possible of neurodegenerativemechanisms underlying diseases, the beneficial with a focus effects on AD of these and PD,foods. and describes the possible mechanisms underlying the beneficial effects of these foods. 2.2. Types ofof FermentedFermented SoySoy ProductsProducts SoybeanSoybean hashas been processed intointo numerous typestypes ofof products, suchsuch as soymilk, tofu, sprouts,sprouts, andand fermentedfermented productsproducts (Figure(Figure1 1).). The The fermented fermented products products of of soybean soybean include include doenjangdoenjang (soybean(soybean paste), paste),ganjang ganjang(soy (soy sauce), sauce), Korean Koreancheonggukjang cheonggukjang, Japanese, Japanesenatto natto, Korean, Ko‐ gochujangrean gochujang, Indonesian, Indonesiantempeh ,tempehsieng (Cambodia,, sieng (Cambodia, Laos), pepok Laos),(Myanmar), pepok (Myanmar),thua nao (Thailand), thua nao and(Thailand),knema (India, and knema Nepal, (India, and Bhutan)Nepal, and [18 ].Bhutan) [18]. FigureFigure 1.1. ExamplesExamples ofof KoreanKorean fermentedfermented soysoy products.products. Korean cheonggukjang and Japanese natto are both produced via two main steps, i.e., Korean cheonggukjang and Japanese natto are both produced via two main steps, i.e., cooking and fermentation. In the first step, soybean is soaked in water at room temperature cooking and fermentation. In the first step, soybean is soaked in water at room tempera‐ for 18 h, followed by steaming at 121 ◦C for 30 min. The second step consists in the ture for 18 h, followed by steaming at 121 °C for 30 min. The second step consists in the fermentation of cooked soybean with airborne Bacillus species, including Bacillus subtilis, fermentation of cooked soybean with airborne Bacillus species, including Bacillus subtilis, originating from the ambient environment or from inoculation for 48 h (Figure1)[19]. originating from the ambient environment or from inoculation for 48 h (Figure 1) [19]. While most of these products, including cheonggukjang and natto, are fermented with While most of these products, including cheonggukjang and natto, are fermented with Bacillus spp., some products, such as doenjang, soy sauce, and tempeh, are manufactured Bacillus spp., some products, such as doenjang, soy sauce, and tempeh, are manufactured by fermenting cooked soybean with fungi, such as Aspergillus and Rhizopus, resulting inby the fermenting extensive cooked breakdown soybean of with soy components fungi, such as and Aspergillus the production and Rhizopus of novel, resulting bioactive in compoundsthe extensive [18 breakdown]. of soy components and the production of novel bioactive com‐ pounds [18]. Foods 2021, 10, 636 3 of 17 Douchi, which is a traditional Chinese food that is prepared using fermented and salted black soybeans, has been a popular seasoning in foods and a folk medicine in China for centuries [20]. Sufu or furu is one of the fermented soybean products, which has been consumed as a side dish in China over the centuries [21,22]. Sufu is a cheese-like product that is made by Aspergillus oryzae in solid-state fermentation of salted and ripened tofu through activities of hydrolytic enzymes, such as protease, α-amylase, β-amylase, and lipase [21,22]. 3. Bioactive Components of Fermented Soy Products Soybean contains a variety of biologically functional components that can be grouped into isoflavones, soyasaponins, lignans, cinnamic acid derivatives, terpenes, and sterols. The fermentation process results in the chemical modification and reduction of soy com- ponents. Although soybean is known to contain anti-nutritional factors, such as phytates, trypsin inhibitors and lectins [23], most fermented soy products have been analyzed to contain very small amounts of these factors, when compared with raw soybean [24]. In par- ticular, lactic acid bacteria (LAB)-mediated fermentation can reduce phytates and trypsin inhibitors [25], and hydrolyze tannic acid via their tannase activities [26,27]. Almost all lectins in soybeans are destroyed during fermentation processes over 72 h [28]. Moreover, various novel compounds are generated during the fermentation process not originally present in raw soybean (Table1). Table 1. Fermented soy products and phytochemicals. Fermented Soy Products Phytochemicals Biological Functions References Free isoflavones, levan, γPGA, Antioxidant, anti-hypertension, Cheonggukjang (natto) [29–31] natto kinase, vitamin K fibrinolysis, bone health Free isoflavones, Antioxidant, anti-obesity, anti-tumorigenic, non-DDMP-conjugated anti-hypertension, anti-sarcopenia, skin Doenjang (miso) soyasaponins (I, III, Be), whitening, immune modulation, [32–43] peptides, amino acids, MRPs, sympathetic nerve activity, anti-diabetic kojic acid activity Amino acids, peptides, MRPs, 1-methyl-1,2,3,4-tetrahydro-β- Anti-platelet activity, anti-allergenicity, Ganjang [34,44–47] carboline and anti-hypertension 1-methyl-β-carboline Antioxidant, fibrinolysis, α-amylase Subtilisin DFE, isoflavones, Douchi inhibition, ACE inhibition,