A large area of research in the field of neurodegeneration has been focused on the role of specific foods and food components in the neurodegenerative process. Luchsinger et al. [
65,
66] posited that taking nutritional supplements alone (e.g., carotenoids versus carrots) might not be as effective as whole foods in providing nutrients, perhaps because the
interaction of nutrients within whole foods or certain dietary patterns might contribute largely to any food's benefit. As an example, one study [
83] demonstrated that plant-based low-fat diets might be superior to low-fat diets containing little plant-based food intake (e.g., lower consumption of fruits, vegetables, nuts, etc.), even if the two diets have identical contents of fat, protein, carbohydrates, and cholesterol. The authors further noted that the beneficial effect of low-density lipoprotein (LDL) cholesterol in one's diet should not be underestimated.
One food of high interest in the AD prevention field has been fish. For example, researchers have investigated the benefits of certain omega-3 fatty acids found in fish and fish oils, specifically docosohexaenoic acid (DHA) and eicosapentaenoic acid, which have been shown to affect psychiatric and behavioral symptoms in AD, as demonstrated in animal studies and in human epidemiological studies [
84,
85]. In this line of research, Lim and colleagues [
86] demonstrated that DHA-enriched diets significantly reduced AD-type amyloid neuropathology by approximately 70%, including a decrease in A
β1–42 levels, compared to low-DHA or control diets, in a mouse model of AD. Moreover, Hashimoto and colleagues [
87] studied the effects of DHA on AD-type pathology following 12 weeks of DHA administration and found that DHA treatment led to a decreased number of working memory errors in A
β-infused rats in addition to an increase in corticohippocampal DHA levels and in the molar ratio of DHA/arachidonic acid, suggesting that DHA treatment attenuated impaired spatial cognition and learning abilities. They further demonstrated that DHA suppressed increases in levels of lipid peroxide and reactive oxygen species in the cerebral cortex and hippocampus of these A
β-infused rats, which suggested that DHA may also increase antioxidative defenses. These findings collectively demonstrated DHA's potential as a therapeutic agent in AD.
Another area of interest to researchers has been the benefits of certain plant extracts and spices in AD. In traditional Asian medicine, various leaves, fruits, barks, roots, and so forth have been used as agents to improve memory functions. In Ayurvedic medicine (a traditional system of Indian medicine), for example,
Bacopa monnieri, Centella asiatica, Withania somnifera, Glycrrhiza glabra, Acorus calamus, and
Emblica officinalis have been considered to enhance one's memory. Based on this notion, various laboratories have tested some of these memory-enhancing compounds in mouse models of AD. Mulberry leaf, for example, has been shown to inhibit A
β1–42 fibril formation and protect hippocampal neurons from A
β1–42-induced cell death in a concentration-dependent manner [
88]. Additionally, in a screening of 27 herbs for their ability to protect A
β1–42-induced neuronal death,
Curcuma aromatia and
Zingiber officinale (ginger) extracts were found to most effectively protect neurons. Several other herbs were also found to be neuroprotective (such as
Ginkgo biloba (Ginkgo),
Polygonatum sp. (King Solomon's seal),
Cinnamum cassia (Chinese cinnamon), and
Rheum coreanum (Korean rhubarb)), but did not exert as potent effects [
89].
Ginkgo biloba extract in particular has been heavily investigated for its use as a preventive and therapeutic agent in AD. It has been shown to exhibit neuroprotective effects in several mouse models [
90] and improve cognitive function in AD patients [
91,
92]. Several studies have demonstrated the mechanisms by which Ginkgo biloba extract may benefit AD. For example, it has been shown to improve age-related memory deficits and A
β-peptide burden, act as a nitric oxide scavenger [
93,
94], and regulate APP metabolism toward the
α-secretase pathway [
95]. Ginkgo biloba extract has also been shown to inhibit A
β-induced free radical generation in a dose-dependent manner [
96]. Further, Yao and colleagues [
97] examined a specific Ginkgo biloba extract EGb761 in relation to cholesterol and amyloidogenesis and found that EGb761 treatment reduced APP and A
β generation coincidental with decreased levels of free circulating cholesterol in
in vivo (in rats) and
in vitro studies. Moreover, Lee and colleagues [
98] investigated ginkgolides A and B for their effect on A
β-modulated acetylcholine release from hippocampal brain slices and found that ginkgolide B may produce antiamnestic effects by mitigating A
β peptides' inhibitory effect on cholinergic transmission. These studies have provided evidence supporting further investigation of Ginkgo biloba extract in AD.
Another plant extract, curcumin, a polyphenolic yellow pigment in the turmeric spice used in Indian curries and in Indian herbal medicine, has been investigated for its potential use in AD prevention and therapy. Epidemiological studies demonstrated that the prevalence of AD in individuals 70–79 years of age is 4.4-fold less in the India compared to the U.S. [
99]. The curcumin compound (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6 heptadiene-2,5 dione) has been shown to be neuroprotective against A
β toxicity
in vitro [
100], antiamyloidogenic [
101,
102], and capable of reducing brain amyloid load and plaque burden [
103]. Spectrophotometric studies have suggested that curcumin binds to the more readily redox-reactive metals Cu and Fe, but does not bind to Zn, and, in turn, acts as an antioxidant by chelating the redox active metal ions in the body [
104]. Lim and colleagues [
105] found that dietary curcumin treatment in AD mice significantly lowered levels of oxidized proteins, interleukin-1
β (a proinflammatory cytokine elevated in these mice), and insoluble and soluble A
β in the brain and reduced amyloid plaque burden by 43%–50%.
Several other spices have been investigated for their role in AD. For example, aged garlic extract has been shown
in vitro to suppress the generation of reactive oxygen species, which are known to be involved in apoptosis as a result of A
β-mediated neurotoxicity [
106], suggesting that garlic compounds may enhance antioxidant defenses in the brain. Additional
in vitro evidence demonstrated that garlic treatment inhibits caspase-3 in a dose-dependent manner, which indicates that garlic may inhibit apoptotic neuronal death in the brain [
107]. Another spice of interest to researchers as been
Crocus sativus, or saffron, due to its unusually polar carotenoid components. Notable, certain saffron extracts have been shown to inhibit A
β fibrillogenesis [
108]. Further research on these extracts may illuminate precise mechanisms of action on AD neuropathology and their potential as preventive or therapeutic agents in AD.
6.1. Fruit Juices and Wine
Polyphenols, the most abundant dietary antioxidants, have been heavily investigated for their ability to provide neuroprotection against oxidative damage in the brain. One study that propagated research on polyphenols in AD, conducted by Dai and colleagues [
109], revealed that long-term fruit juice consumption can reduce one's risk for AD. The investigators suggested that the neuroprotective effects of fruit juices can be enhanced by consuming a combination of juices that are rich in phenolic compounds, which include juices derived from purple grapes, grapefruit, cranberries, and apples.
Several studies have examined the effects of certain fruit juices and extracts on AD. For example, apple juice was shown to prevent A
β-induced oxidative damage
in vitro [
110], and blueberry treatment has been found to reverse the effects of aging on motor behavior and neuronal signaling in animal models [
111], possibly through mechanisms involving signal transduction, neuronal communication, and enhancement of hippocampal plasticity [
112,
113]. Moreover, treatment with antioxidant-rich pomegranate juice has been shown to reduce A
β1–42 content and amyloid deposition in the hippocampus by approximately 50% in mice. A study conducted by Mullen and colleagues [
114] examined 13 different fruit juices and reported that purple grape juice contained the highest number of individual phenolic compounds in addition to the highest concentration of total phenolics. The main components found in purple grape juice, accounting for 93% of the total phenolic conent, were flavan-3-ols, anthocyanins, and hydroxycinnamates. White grape juice, on the contrary, containing mainly hydroxycinnamates, had the lowest phenolic content of the juices examined.
Resveratrol is a naturally occurring polyphenol, found in the skin of grapes and red wine as a result of exposure to fungi or bacteria, which has been investigated for its ability to neuroprotect. Resveratrol has been demonstrated to maintain cell viability, exert antioxidant activity, exert proteasome-dependent antiamyloidogenic activity, and attenuate A
β-induced cytotoxicity in PC12 cells
in vitro [
115–
117]. Importantly, resveratrol is also understood to activate the expression of sirtuins, often referred to as the “longevity gene,” in yeast [
118] and in mammalian animal models of neurodegeneration [
119,
120]—this resveratrol-induced sirtuin activation has been shown to promote neuroprotective activities against neuronal apoptosis. However, given recent evidence suggesting that resveratrol may not directly activate sirtuins [
121], it is not quite clear if sirtuin activation plays a role in resveratrol's observed benefits in AD-type neuropathology. Further research will certainly illuminate resveratrol's bioactivity and the mechanisms through which it benefits AD.
Several studies have suggested that moderate red wine consumption reduces the incidence of AD clinical dementia [
65,
66,
115,
122–
124] and may even benefit the course of AD [
125]. Derived from red grapes, red wine is rich in antioxidants and holds neuroprotective properties. Studies in our laboratory, using an AD mouse model, examined whether moderate consumption of the red wine cabernet sauvignon (the most polyphenol-rich red wine, likely due to increased inclusion of grape skins) reduces AD-type neuropathology and cognitive deterioration. We found that cabernet sauvignon treatment was capable of attenuating AD-type cognitive deterioration and A
β neuropathology by mechanisms involving nonamyloidogenic processing of APP, ultimately inhibiting A
β generation [
126,
127].
6.2. Grape Seed Polyphenolic Extract
Another area of investigation of high interest in the AD field has been the potential beneficial role of grape seed polyphenolic extract (GSPE) in attenuating AD-type neuropathology and cognitive impairments. Studies in our laboratory have investigated a specific GSPE (MegaNatural), which is comprised primarily of catechin and epicatechin in monomeric, oligomeric, and polymeric forms, is readily absorbed through the intestinal mucosua due to modification of the constituent polyphenols in its preparation and has been demonstrated to be safe in animal models [
128–
131] and in humans with pre-hypertensive conditions [
132]. In an initial investigation in a mouse model of AD [
129], mice were treated for 5 months with 200
mg/kg/day GSPE in drinking water (equivalent to 1
g/day in humans, according to Food and Drug Administration criteria for converting drug dosages across species), after which
in vitro and
in vitro assessments were conducted at 6 (for behavior) and 10 (for neuropathology) months.
In vitro studies revealed that GSPE prevented A
β peptides from aggregating into high molecular weight (HMW) oligomers, and
in vivo studies showed that GSPE treatment significantly reduced A
β1–40 and A
β1–42 peptide and HMW A
β oligomer levels and amyloid plaque burden in the brain, relative to age- and gender-matched water-treated mice. Moreover, GSPE-treated mice also performed significantly better tests of cognitive function compared to age- and gender-matched water treated mice. A follow-up mechanistic study [
130] investigated
in vitro GSPE's ability to alter the assembly of A
β1–40 and A
β1–42 oligomers and A
β-induced cytotoxicity in A
β-treated PC12 cells; these studies revealed that GSPE blocked A
β protofibril formation, preprotofibrillar oligomerization, and the structure transition from initial coil to
α-helix/
β-sheet. Additionally, GSPE exerted protective activities in assays of A
β-induced cytoxicity (prior to peptide assembly, following assembly, and just prior to peptide addition in cells). These studies collectively suggest a neuroprotective and possibly therapeutic role of GSPE in AD-type A
β neuropathology and cognitive deterioration.
To follow this line of work, we also investigated
in vitro the potential beneficial role of GSPE on AD-type tau neuropathology [
133], another major hallmark of AD. Using an
in vitro model system, we found that GSPE treatment significantly inhibited the aggregation of tau peptides into filaments and was also capable of dissociating preformed tau aggregates. This finding suggests that GSPE treatment may attenuate deposits of tau aggregates in the AD brain.
In light of our evidence that GSPE was capable of attenuating A
β and tau pathology, we next explored GSPE bioavailability [
131] to further assess its potential as an AD treatment. We found that acute oral administration of GSPE in Sprague Dawley rats led to detectable contents of catechin, epicatechin and their metabolites in the brain. Following repeated GSPE exposure, we detected accumulations of catechin, epicatechin, and gallic acid and their metabolites in the blood and similarly, catechin and epicatechin and their metabolites in the brain.
These studies, which demonstrate GSPE's ability to attenuate AD-type Aβ pathology in vivo and in vitro and tau pathology in vitro, combined with its demonstrated safety and bioavailability, support the continued development of GSPE as a treatment for Aβ- and tau-mediated neurodegeneration and cognitive impairments.
