Review Article - Journal of Public Health and Nutrition (2018) Volume 1, Issue 2
Current Alzheimers management with berries fruits therapy.
Department of Bioinformatics, Integral University, Uttar Pradesh, India
- *Corresponding Author:
- Singh R
Department of Bioinformatics
Uttar Pradesh, India
Email: [email protected]
Accepted date: March 26, 2018
Citation: Singh R. Current Alzheimer’s management with berries fruits therapy. J pub health catalog. 2018;1(1):17-24.
Nature has lots of flora-bearing fruits, vegetables with human beings. Berries contain a powerful source of natural antioxidants. Berries plays an essential role in prevention and therapy of various neurodegenerative diseases, like Alzheimer’s disease (AD), Parkinson’s disease and other neuronal dysfunctions as they are a diverse source of a large variety of nutritive, nonnutritive and bioactive compounds. Polyphenolic antioxidants present in different varieties of berries present in phyto-compounds which are present in nature may be used as a cure to delay neuro-degeneration, improvement of memory and cognitive function of frontal lobes. Berries such as Strawberry, Blueberry, Blackberry etc., have also confirmed neuroprotective effect against the AD. The molecular mechanism behind this therapeutic effect is the association of discrete signalling pathways by the work of phytonutrients which results in protein folding and neuro-inflammation. In Alzheimer’s, the neuroprotective properties of the diversely occurring bioactive components of the berries have been used and tabulated in this review.
Alzheimer’s disease, Antioxidant, Neurodegeneration, Wnt signalling, Flavonoids
Increased adequate amount consumption of fruits and vegetables is recommended in dietary guidelines worldwide and intake of fruits like berries are rich in vital nutrients and phyto-nutraceuticals can prevent various diseases and disorders and more Neurodegenerative disorders. Fruits and vegetables may have noticeable long-term physiological effects due to their metabolic bioactivity and also enhance remarkable effect in the laboratory and epidemiological studies have been associated with a variety of nutrient and non-nutrient constituents, being many of them characterized by their antioxidant properties [1-5]. Compounds like ascorbic acid, tocopherols, β-carotene and phenolic compounds, flavonoids have high antioxidant capacity and promising potential against current therapeutic neuroproteins . The colorful berries fruits such as blackberry (Rubus species), black raspberry (Rubus occidentalis), blueberry (Vaccinium corymbosum), cranberry (Vaccinium macrocarpon), red raspberry (Rubus idaeus), and strawberry (Fragaria ananassa) are remarkably good source countered to therapeutic neuro targets of neurological disorders. Researchers analyzed berry fruits extracts for most common abnormalities and obtained significant results and have suggested that consumption of colored fruits and vegetables are associated with reduced risk of human breast cancer [7,8], human melanoma cancer [9,10], human ovarian cancer, and also help in the prevention of Alzheimer’s disease [11-13]. The majority of the compounds examined to date with a direct relevance to the AD are primarily from plants, from animal, marine and microbial sources. The review focuses on the berries compounds that might underlie the purported beneficial improvements in memory and cognition, neurovascular function, and in neuro-protection.
Occurrence and Season
Berries are used worldwide since ancient times and still popular in Europe and North America today. The industries dealing with berry varies from country to country because of different cultivation and growth condition. Some berries such as raspberries and strawberries have been bred for hundreds of years and are distinct from their wild counterparts, while other berries, such as lingonberries and cloudberries, grow almost exclusively in the wild. Besides of their different growing season, they also differ in temperature and time duration. For example, many soft fruit berries require a period of temperatures between 0°C and 10°C for breaking dormancy. Generally, strawberries require 200-300 hours, blueberries 650- 850 hours, blackberries 700 hours, raspberries 800-1700 hours, currants and gooseberries 800-1500 hours, and cranberries 2000 hours . Moreover, temperature regimes also severely affect growth and productivity of berries. The tolerable temperatures range from -29°C to -31°C, depending on variety .
Major Classes of Berries
The word “berry” meets the true botanical nomenclature as a fruit. For example Wild rose, Grapes, Elderberry, Currant, Barberry, Rosehips, Gooseberry etc. are true berry. "Stone fruits" is a drupe berry fruit with a fleshy fruit having a small stone. Acai, Hackberry, Sugarberry, Persimmon, Barbados cherry, Acerola, Indian plum, West Indian cherry, Goji berries do not meet the botanical classification but come under the category of berries. The botanical classification is not met by a few Epignyous types. Lingonberry, Cranberry, Bearberry, Crowberry, Blueberry, Bilberry, Juniper berries, Cowberry, Foxberry, Mountain cranberry, Red chokeberry, Black chokeberry, Purple chokeberry, etc. are the example of epignyous fruits. Rasberry, Strawberry, Blackberry, Dewberry, Salmonberry, Bayberry, Boysenberry, Mulberry, Cloudberry, Chehalm Berry, Loganberry, Thimbleberry, Wineberry, Youngberry, Juneberries etc contain multiple fruit seeds which are present in compound fruits.
Classification of berries found in nature is of two types mildy poisonous (causing gastric upset) and extremely poisonous (dangerous). Example-Holly berries, Yew berries, Rivet berries, Pokeberry, Daphne berries, Elderberry, Baneberry, Actea pachypoda, Jerusalem cherry, Green nightshade, Red nightshade, etc.
Besides being delicious in nature, berries contain an excessive amount of various nutrients, minerals vitamins, and other bioactive compound . This review will be an effort to explore the medicinal property of different berries in neurodegenerative diseases mainly Alzheimer’s disease.
Blackcurrant is a strong candidate fruit to provide neuroprotection in the AD where anthocyanin, a major group of polyphenols account for about 80% of the total amount of quantified compounds and have been shown to inhibit the formation and extension of Aβ fibrils and to destabilize the preformed Aβ fibrils in vitro [16,17]. Flavonoids by blackcurrant inhibit formation of induced β-Amyloid (Aβ). investigated the effects of anthocyanin-rich blackcurrant extracts on neuroprotection and amyloid precursor protein (APP) expression in human SH-SY5Y neuroblastoma cells overexpressing APP751 isoform under AD-related stress conditions [17,18]. Moreover, the cells also experienced significantly reduced ROS production. Promising antioxidant activity is shown by blackcurrant extracts rich in anthocyanin which is beneficial as depicted in the observations made.
Anticancer, antibacterial/antiviral, antiseptic, antioxidative, anti-hyperglycemic are some of the biological properties shown by Blackberry fruits [19,20]. They are also rich sources of antioxidants, polyphenols maganese, folate, fibers, cyaniding-3-0 glucoside, vitamin C, salicylate and high tannin possessing compounds. Boosting blood circulation reducing pains, preventing anti-aging, reducing blood cholesterol levels are some more functions [21,22].
Attainable neuroprotective effects like reducing intracellular ROS levels, modulating gluthathione levels and inhibition of the caspases occurance during treatments is displayed by Wild blackberries, bringalies and vagabundus that are collected from Braganca that lies in Northeast of Portugal . These effects protected neuronal cells against oxidative injury, one of the most important features of neurodegeneration. In vitro studies have also reported that blackberries have potent anti-inflammatory and antiproliferative properties [24,25]. In addition, the antioxidants present in these fruits improved behavioural performance in motor neuron tests in aged rats. Demonstration of the measurers of spatial working memory and learning is due to the balance and fine motor coordination in the cognitive test that also showed improvement in the Moris water maze .
Flavonoids, notably Anthocyanin, caffeic acid, flavanols, and hydroxycinnamates are a rich source for Bluberries [27-31]. A recent study has demonstrated that blueberry supplementation can alleviate age-related behavioural deficits and high-fat diet-related behavioural declines, besides helping in prevention and inhibition of oxidative stress, inflammation, kidney injury, as well as improving vascular health [32-35].
A preclinical study has demonstrated that blueberry supplementation enhances motor and memory performance in aged animals [36,37]. Changes that occur in brain-derived neurotrophic factor-mediated protein synthesis, such as Arc/ Arg3.1, are directly related to blueberry consumption. Inhibition of CREB/brain-derived neurotrophic factor pathway effectively blocks the changes in spatial memory in the blueberrysupplemented animals .
Anthocyanin distribution in the hippocampus might be related to increase neuronal signaling in this region . A study involving psychopharmacological screening to evaluate potential effects of a lyophilized extract of different cultivars from Vaccinium ashei, Reade (Ericaceae) berries, which are commonly known as rabbiteye blueberries and are shown to have memory-enhancing, anxiolytic and locomotion increasing properties in mice, as well as the protective effects against free radical-induced DNA damage in the brain Barros et al. (2006) . These results are reliable with the hypothesis that flavonoids (including Anthocyanin) can show beneficial effects on cell signaling and decrease oxidative damage. These results also suggest that flavonoids might directly act on cognitive function, which may help prevent age-related and pathological degenerative processes in the brain.
Strawberry tree (Arbutus unedo) is a shrub, belonging to Ericaceae family and prevalent in most of Europe. The polyphenols such as Anthocyanin, gallic acid, tannins, vitamin C, vitamin E, and carotenoids makes it an important part of the normal diet. Oxidative stress due to Ab protein is one of the major reasons for the pathogenesis of AD . The antioxidative effect of strawberry has been evaluated using PC12 cells. Pre-treatment with strawberry extract showed improved cell viability in H2O2 induced neurotoxicity induced PC12 cells which may be due to the presence of Ellagitannins [42- 44]. Notably, the strawberry extract has proven its potential to attenuate undesirable behavioural changes caused by 56Fe irradiation.
Grape seed extract (GSE) is abundant in phenolic antioxidants and proanthocyanidins. The accumulation of Ab is the major causative factor for the pathogenesis of AD . Several studies have shown that the polyphenol-enriched grape seed extract can reduce amyloid beta accumulation and protect against neurotoxicity and oxidative stress in vitro . Another important causative factor of the AD is inflammation by microglia activation that was significantly reduced by 70% due to the polyphenol content in the GSE diet [47,48]. Resveratrol (trans-3, 40, 5-trihydroxystilbene) is the nonflavonoid polyphenol abundant in grapes and red wine and has the potential to reduce accumulation of amyloid protein in cell culture by enhancing proteolytic cleavage . The mechanism behind the neuroprotective effects of resveratrol is due to its allosteric activity on the sirtuin proteins.
Alzheimer’s disease associated with berries fruits
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the world, exerting an escalating socioeconomic burden on modern society [50,51]. Most often, the AD is diagnosed in people over 65 years of age , who develop a progressive pattern of cognitive and functional impairments [53,54] that gradually increase as the disease advances. Memory impairment, in particular, the loss of the ability to form and retain new episodic memories, is a hallmark of the early AD and may help in differentiating AD from common age-related cognitive decline. This impairment is often attributed to synaptic dysfunction and neuronal loss in the perforant path connecting the medial temporal lobe, entorhinal cortex, and hippocampus [50,55]. Accordingly, cognitive changes in AD start with specific difficulties in the encoding and storage of new information, also indicative of a deficiency in semantic memory [56-58] and executive function impairment . The etiology of the AD is not well understood, except in 1 to 5% of cases in which genetic differences can be identified . It is increasingly recognized that AD is a proteinopathy characterized by specific neuropathological markers: amyloid deposits, tau-laden tangles and the loss of neurons and synapses in the cerebral cortex and subcortical regions, associated with gross atrophy of the affected regions [61-68]. The accumulation of amyloid beta (Aβ) fragments is thought to be due to the uncontrolled cleavage and defective clearance of amyloid precursor protein . Current treatments only partly alleviate symptoms but cannot stop or reverse the progression of the disease. Due to their favorable safety profile and availability, dietary approaches, in particular using polyphenol-enriched diets [69-71], are drawing attention as tools to prevent AD development [72-77]. The use of cheap and widely available compounds, like polyphenols, a nutraceutical or pharmaceutical tools in brain disorders such as AD may provide new strategies for the prevention or delay of cognitive decline.
Types of Alzheimer ’s Disease
A minority (less than 1%) of those affected with the AD is dominant familial forms , caused by mutations in one of three genes and having an early age of onset before 65 years [78,79]. The more common sporadic version has no commonly acknowledged causes and the risks pertaining to the disease are not well understood.
Genetic differences of less than 1% cases have been identified and the major cause of Alzheimer’s is still unknown. Many things have been attributed to trigger the AD, but as with many complex diseases, it may require a certain threshold to be surpassed before actual disease manifestation occurs. Multiple factors including genetic, environmental, dietary, or a combination of these could determine disease initiation, as well as disease progression.
The root cause of the disease can be explained by various competing hypotheses that exist:
• Amyloid hypothesis
• Cholinergic hypothesis
• Tau hypothesis
• GSK3β hypothesis
• Other hypothesis
People suffering from Down syndrome having entire gene copy in their chromosome have the universal chance of getting AD by the age of 40 [80-82] as the gene being located on chromosome 21 for amyloid precursor protein. The extracellular amyloid beta (AB) deposits are the root cause of this disease [83,84] as postulated in 1991.
The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis . According to this hypothesis, Alzheimer’s disease is caused by reduced synthesis of the neurotransmitter acetylcholine that is accountable for the transmittance of a neuronal message from one neuron to another that are associated by synapses [86,87].
Cell death and malfunctioning of biochemical communication of neurons result as abnormalities occurring in the tau protein, initiating the disease cascade . The pairing which occurs between hyper-phosphorylated tau with other threads of tau results in collapsing the neuron’s transport system due to the emmitment of cytoskeleton from the disintegration of microtubules [88-91].
Aβ peptides and hyperphosphorylated tau play a considerable role in the pathogenesis of Alzheimer’s disease. According to this hypothesis, Neurofibrillary tangles and Aβ sensible plaques are produced by two different mechanisms causing Alzheimer’s disease. A key enzyme GSK3β regulates cellular metabolism along with including phosphorylation of tau protein . Wnt signaling leads to the inactivation of GSK3β. usually, GSK3β has been found in a hyperactive state that is accountable for hyperphosphorylation of TAU . But in several cases GSK3β also regulates the metabolism of amyloid precursor beta protein, and assist in amyloidogenic cleavage leads to overproduction 12 of Aβ, condensed neurogenesis and increased apoptosis . Activation of GSK3β leads to neuronal changes and loss of neuronal cells that are observed in the AD. But the inhibition of GSK3β activity protects in opposition to neuronal degeneration and death induced by Aβ and Tau hyperphosphorylation .
Berries derived phyto-nutraceuticals with special relevance to Alzheimer’s disease
Berries contain abundant vitamins such as A, C, E, and B complex, also considered as antioxidants that help to boost the immune system, reduce inflammation, and help to fight the effects of oxidative stress leading to chronic diseases such as heart disease, diabetes, and certain cancers. Berries contain ascorbic acid, a water-soluble compound that performs numerous functions in living systems among all the berry fruit species reported .
The components present in berries are reported to protect against damage induced by ROS, known to be implicated in the development of neurological conditions such as Alzheimer’s disease. The increased production of reactive oxygen species (ROS) is one of the major cause in the development of neurodegenerative diseases [97,98] crucial role, Because of low activity of antioxidant defense systems, the brain is susceptible to oxidative stress more than other organs [99,100]. Moreover, many neurotransmitters are autoxidized to generate ROS . The neuroprotective effects  and chelation of metal ions is performed by the polyphenols which have the ability to cross the blood brain barrier and to directly mimic high concentration of ROS and nitrogen species. A special ability to activate key oxidant enzymes in the brain and scavage activity, resisting the oxidative stress (viscous cycle) and tissue damage was shown by a large number of Polyphenolic compounds [101,103]. A number of berries show beneficial effects and act as a promising agent of neuro-protection in this article.
More than one hydroxyl group along with a large heterogeneous group of chemical components containing few aromatic rings in a conjugated aromatic construct being present in the Phenolic Compounds. Phenolic compounds occur in free and conjugated forms with sugars, acids, and other biomolecules as water-soluble (phenolic acids, flavonoids, and quinones) or water-insoluble compounds (condensed tannins). They possess the ability to donate an electron or a hydrogen atom to a free radical and convert it into an inoffensive molecule. Consequently, phenolics have significant in vitro and in vivo antioxidant activities . That Furthermore, phenolic compounds include flavonoids, such as Anthocyanin (i.e., cyanidin glucosides and pelargonidin glucosides), flavonols (quercetin, kaempferol, myricetin), flavanols (catechins and epicatechin) and phenolic acids (hydroxybenzoic acids and hydroxycinnamic acids) and hydrolyzable tannins, such as ellagitannins, act as important BAC.
Flavonoids (FL) represent the most diverse group of phenolics, with two aromatic (A and B), rings associated via C-C bonds by a 3 C oxygenated heterocycle. On the basis of the oxidation state of the central ring, FLs are further divided into Anthocyanin, flavonols, flavanols, flavones, flavanones, and isoflavonoids. Berries are particularly rich in Anthocyanin, which are responsible for their typically vibrant colours . Anthocyanin are colored pigments that act as powerful antioxidants; they are especially abundant in berries with red, blue, or purple pigments.
Tannins are classified into hydrolyzable and condensed (or nonhydrolyzable) forms. Hydrolysable tannins are multiple esters of gallic or ellagic acid with glucose and products of their oxidative reactions and are known as galloyl tannins and ellagitannins, respectively [106,107] and are found in strawberry, raspberry, and blackberry but are less common in other berry fruits[108,109]. Together with Anthocyanin, ellagitannins are the major antioxidant phytochemicals in raspberries .
Stilbenes are another subgroup of phenolic compounds with a particular carbon skeleton, viz. C6-C2-C6 . Resveratrol is the best-known stilbene. Small quantities of resveratrol, pterostilbene, and piceatannol have been found in blueberry, bilberry, cranberry, and strawberry [112-115].
Berries have been implicated in health benefits relevant to a number of disease conditions. Much of the evidence has focused on the polyphenol components but other components (such as carotenoids, fibers, and terpenes) may also have roles to play. A number of natural antioxidant and anti-inflammatory compounds are found in plant food matrix.
- Muselik J, Garcia-Alonso M, Martin-Lopez MP, et al. Measurement of antioxidant activity of wine catechins, procyanidins, anthocyanins and pyranoanthocyanins. International Journal of Molecular Sciences. 2007;8(8):797-809.
- Li J, Jiang Y. Litchi flavonoids: Isolation, identification and biological activity. Molecules. 2007 Apr 11;12(4):745-58.
- Philpott M, Lim CC, Ferguson LR. Dietary protection against free radicals: a case for multiple testing to establish structure-activity relationships for antioxidant potential of anthocyanic plant species. International journal of molecular sciences. 2009 Mar 11;10(3):1081-103.
- Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. Journal of the american dietetic association. 1996 Oct 1;96(10):1027-39.
- Pietta PG. Flavonoids as antioxidants. Journal of natural products. 2000 Jul 28;63(7):1035-42.
- Drewnowski A, Gomez-Carneros C. Bitter taste, phytonutrients, and the consumer: a review-. The American journal of clinical nutrition. 2000 Dec 1;72(6):1424-35.
- Adlercreutz H. Epidemiology of phytoestrogens Baillieres Clin Endocrinol Metab 12 (4): 605-623. Find this article online. 1998.
- Fung TT, Chiuve SE, Willett WC, et al. Intake of specific fruits and vegetables in relation to risk of estrogen receptor-negative breast cancer among postmenopausal women. Breast cancer research and treatment. 2013 Apr 1;138(3):925-30.
- Serafino A, Sinibaldi-Vallebona P, Lazzarino G, et al. Differentiation of human melanoma cells induced by cyanidin-3-O-β-glucopyranoside. The FASEB journal. 2004 Dec;18(15):1940-2.
- Huang HP, Shih YW, Chang YC, et al. Chemoinhibitory effect of mulberry anthocyanins on melanoma metastasis involved in the Ras/PI3K pathway. Journal of agricultural and food chemistry. 2008 Sep 4;56(19):9286-93.
- Akim AM, Ling LC, Rahmat A, et al. Antioxidant and anti-proliferative activities of roselle juice on caov-3, mcf-7, mda-mb-231 and hela cancer cell lines. African Journal of Pharmacy and Pharmacology. 2011 Jul 31;5(7):957-65.
- Yi W, Fischer J, Krewer G, et al. Phenolic compounds from blueberries can inhibit colon cancer cell proliferation and induce apoptosis. Journal of agricultural and food chemistry. 2005 Sep 7;53(18):7320-9.
- Faria A, Oliveira J, Neves P, et al. Antioxidant properties of prepared blueberry (Vaccinium myrtillus) extracts. Journal of Agricultural and Food Chemistry. 2005 Aug 24;53(17):6896-902.
- Pritts M, Heidenreich C, McDermott L, et al. Berry Soil and Nutrient Management-A Guide for Educators and Growers.
- Nile SH, Park SW. Edible berries: Bioactive components and their effect on human health. Nutrition. 2014 Feb 1;30(2):134-44.
- Ghosh D, Konishi T. Anthocyanins and anthocyanin-rich extracts: role in diabetes and eye function. Asia Pacific journal of clinical nutrition. 2007 Jun 1;16(2):200-8.
- Vepsäläinen S, Koivisto H, Pekkarinen E, et al. Anthocyanin-enriched bilberry and blackcurrant extracts modulate amyloid precursor protein processing and alleviate behavioral abnormalities in the APP/PS1 mouse model of Alzheimer's disease. The Journal of nutritional biochemistry. 2013 Jan 1;24(1):360-70.
- Subash S, Essa MM, Al-Adawi S, et al. Neuroprotective effects of berry fruits on neurodegenerative diseases. Neural regeneration research. 2014 Aug 15;9(16):1557.
- Kaume L, Gilbert WC, Brownmiller C, et al. Cyanidin 3-O-β-D-glucoside-rich blackberries modulate hepatic gene expression, and anti-obesity effects in ovariectomized rats. Journal of Functional Foods. 2012 Apr 1;4(2):480-8.
- Stefanut MN, Cata A, Pop R, et al. Anti-hyperglycemic effect of bilberry, blackberry and mulberry ultrasonic extracts on diabetic rats. Plant foods for human nutrition. 2013 Dec 1;68(4):378-84.
- Jiao H, Wang SY. Correlation of antioxidant capacities to oxygen radical scavenging enzyme activities in blackberry. Journal of agricultural and food chemistry. 2000 Nov 20;48(11):5672-6.
- Siriwoharn T, Wrolstad RE, Durst RW. Identification of ellagic acid in blackberry juice sediment. Journal of food science. 2005 Apr 1;70(3).
- Tavares L, Figueira I, McDougall GJ, et al. Neuroprotective effects of digested polyphenols from wild blackberry species. European journal of nutrition. 2013 Feb 1;52(1):225-36.
- Wang SY, Jiao H. Scavenging capacity of berry crops on superoxide radicals, hydrogen peroxide, hydroxyl radicals, and singlet oxygen. Journal of Agricultural and Food Chemistry. 2000 Nov 20;48(11):5677-84.
- Dai J, Patel JD, Mumper RJ. Characterization of blackberry extract and its antiproliferative and anti-inflammatory properties. Journal of medicinal food. 2007 Jun 1;10(2):258-65.
- Shukitt-Hale B, Cheng V, Joseph JA. Effects of blackberries on motor and cognitive function in aged rats. Nutritional neuroscience. 2009 Jun 1;12(3):135-40.
- Gavrilova V, Kajdzanoska M, Gjamovski V, et al. Separation, Characterization and Quantification of Phenolic Compounds in Blueberries and Red and Black Currants by HPLC− DAD− ESI-MS n. Journal of agricultural and food chemistry. 2011 Mar 14;59(8):4009-18.
- Prior RL, Lazarus SA, Cao G, et al. Identification of procyanidins and anthocyanins in blueberries and cranberries (Vaccinium spp.) using high-performance liquid chromatography/mass spectrometry. Journal of agricultural and food chemistry. 2001 Mar 19;49(3):1270-6.
- Wu X, Gu L, Prior RL, et al. Characterization of anthocyanins and proanthocyanidins in some cultivars of Ribes, Aronia, and Sambucus and their antioxidant capacity. Journal of agricultural and food chemistry. 2004 Dec 29;52(26):7846-56.
- You Q, Wang B, Chen F, et al. Comparison of anthocyanins and phenolics in organically and conventionally grown blueberries in selected cultivars. Food Chemistry. 2011 Mar 1;125(1):201-8.
- Cao G, Shukitt-Hale B, Bickford PC, et al. Hyperoxia-induced changes in antioxidant capacity and the effect of dietary antioxidants. Journal of Applied Physiology. 1999 Jun 1;86(6):1817-22.
- Carey AN, Gomes SM, Shukitt-Hale B. Blueberry supplementation improves memory in middle-aged mice fed a high-fat diet. Journal of agricultural and food chemistry. 2014 Jan 30;62(18):3972-8.
- Sweeney MI, Kalt W, MacKinnon SL, et al. Feeding rats diets enriched in lowbush blueberries for six weeks decreases ischemia-induced brain damage. Nutritional neuroscience. 2002 Jan 1;5(6):427-31.
- Nair AR, Masson GS, Ebenezer PJ, et al. Role of TLR4 in lipopolysaccharide-induced acute kidney injury: protection by blueberry. Free Radical Biology and Medicine. 2014 Jun 1;71:16-25.
- Erlund I, Koli R, Alfthan G, et al. Favorable effects of berry consumption on platelet function, blood pressure, and HDL cholesterol-. The American journal of clinical nutrition. 2008 Feb 1;87(2):323-31.
- Youdim KA, Shukitt-Hale B, Martin A, et al. Short-term dietary supplementation of blueberry polyphenolics: beneficial effects on aging brain performance and peripheral tissue function. Nutritional Neuroscience. 2000 Jan 1;3(6):383-97.
- Casadesus G, Shukitt-Hale B, Stellwagen HM, et al. Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutritional neuroscience. 2004 Oct 1;7(5-6):309-16.
- Williams CM, El Mohsen MA, Vauzour D, et al. Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radical Biology and Medicine. 2008 Aug 1;45(3):295-305.
- Casadesus G, Shukitt-Hale B, Joseph JA. Qualitative versus quantitative caloric intake: are they equivalent paths to successful aging? Neurobiology of aging. 2002 Sep 1;23(5):747-69.
- Barros D, Amaral OB, Izquierdo I, et al. Behavioral and genoprotective effects of Vaccinium berries intake in mice. Pharmacology Biochemistry and Behavior. 2006 Jun 1;84(2):229-34.
- Pappolla MA, Chyan YJ, Omar TR, et al. Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer's disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. The American journal of pathology. 1998 Apr;152(4):871.
- Heo HJ, Lee CY. Strawberry and its anthocyanins reduce oxidative stress-induced apoptosis in PC12 cells. Journal of agricultural and food chemistry. 2005 Mar 23;53(6):1984-9.
- McDonald RJ, White NM. Parallel information processing in the water maze: evidence for independent memory systems involving dorsal striatum and hippocampus. Behavioral and neural biology. 1994 May 1;61(3):260-70.
- Shukitt-Hale B, Carey AN, Jenkins D, et al. Beneficial effects of fruit extracts on neuronal function and behavior in a rodent model of accelerated aging. Neurobiology of aging. 2007 Aug 1;28(8):1187-94.
- Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. science. 2002 Jul 19;297(5580):353-6.
- Bastianetto S, Zheng WH, Quirion R. Neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide‐related toxicity in cultured hippocampal neurons. British journal of pharmacology. 2000 Oct 1;131(4):711-20.
- Von Bernhardi R. Glial cell dysregulation: a new perspective on Alzheimer disease. Neurotoxicity research. 2007 Dec 1;12(4):215-32.
- Wang YJ, Thomas P, Zhong JH, et al. Consumption of grape seed extract prevents amyloid-β deposition and attenuates inflammation in brain of an Alzheimer’s disease mouse. Neurotoxicity research. 2009 Jan 1;15(1):3-14.
- Essa MM, Vijayan RK, Castellano-Gonzalez G, et al. Neuroprotective effect of natural products against Alzheimer’s disease. Neurochemical research. 2012 Sep 1;37(9):1829-42.
- Bensalem J, Dal-Pan A, Gillard E, et al. Protective effects of berry polyphenols against age-related cognitive impairment. Nutrition and Aging. 2015 Jan 1;3(2-4):89-106.
- Wimo A, Jonsson L, Bond J, et al. The worldwide economic impact of dementia 2010. Alzheimer's & dementia: the journal of the Alzheimer's Association. 2013 Jan 1;9(1):1-1.
- Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. American journal of public health. 1998 Sep;88(9):1337-42.
- Khan ZU, Martin-Montañez E, Navarro-Lobato I, et al. Memory deficits in aging and neurological diseases. InProgress in molecular biology and translational science 2014 Jan 1 (Vol. 122, pp. 1-29). Academic Press.
- Forstl H, Kurz A. Clinical features of Alzheimer’s disease. European archives of psychiatry and clinical neuroscience. 1999 Dec 1;249(6):288-90.
- Celone KA, Calhoun VD, Dickerson BC, et al. Alterations in memory networks in mild cognitive impairment and Alzheimer's disease: an independent component analysis. Journal of Neuroscience. 2006 Oct 4;26(40):10222-31.
- Gainotti G, Quaranta D, Vita MG, et al. Neuropsychological predictors of conversion from mild cognitive impairment to Alzheimer's disease. Journal of Alzheimer's disease. 2014 Jan 1;38(3):481-95.
- Pena-Casanova J, Sanchez-Benavides G, de Sola S, et al. Neuropsychology of Alzheimer's disease. Archives of medical research. 2012 Nov 1;43(8):686-93.
- Jak AJ, Bangen KJ, Wierenga CE, et al. Contributions of neuropsychology and neuroimaging to understanding clinical subtypes of mild cognitive impairment. International review of Neurobiology. 2009 Jan 1;84:81-103.
- Molinuevo JL, Gomez-Anson B, Monte GC, et al. Neuropsychological profile of prodromal Alzheimer's disease (Prd-AD) and their radiological correlates. Archives of gerontology and geriatrics. 2011 Mar 1;52(2):190-6.
- Rao AT, Degnan AJ, Levy LM. Genetics of Alzheimer disease. Am. J. Neuroradiol. 2014; 35, 457-458.
- Prakasam A, Muthuswamy A, Ablonczy Z, et al. Differential accumulation of secreted AβPP metabolites in ocular fluids. Journal of Alzheimer's Disease. 2010 Jan 1;20(4):1243-53.
- Hooper NM. Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein.
- Wenk GL. Neuropathologic changes in Alzheimer's disease. Journal of Clinical Psychiatry. 2003 Jul 1;64:7-10.
- Heredia L, Lin R, Vigo FS, et al. Deposition of amyloid fibrils promotes cell-surface accumulation of amyloid β precursor protein. Neurobiology of disease. 2004 Aug 1;16(3):617-29.
- Utsuki T, Yu QS, Davidson D, et al. Identification of novel small molecule inhibitors of amyloid precursor protein synthesis as a route to lower Alzheimer's disease amyloid-β peptide. Journal of Pharmacology and Experimental Therapeutics. 2006 Aug 1;318(2):855-62.
- Sambamurti K, Pappolla MA, Rao KJ. Value in Development of a TAPIR-like mouse monoclonal antibody to Aβ. Journal of Alzheimer's disease: JAD. 2008 Jun;14(2):175.
- Barrio JR, Kepe V, Satyamurthy N, et al. Amyloid and tau imaging, neuronal losses and function in mild cognitive impairment. The Journal of Nutrition Health and Aging. 2008 Jan 1;12(1):S61-5.
- Padmaraju V, Indi SS, Rao KS. New evidences on Tau-DNA interactions and relevance to neurodegeneration. Neurochemistry international. 2010 Aug 1;57(1):51-7.
- Solfrizzi V, Capurso C, D’Introno A, et al. Lifestyle-related factors in predementia and dementia syndromes. Expert Review of Neurotherapeutics. 2008 Jan 1;8(1):133-58.
- Nehlig A. The neuroprotective effects of cocoa flavanol and its influence on cognitive performance. British journal of clinical pharmacology. 2013 Mar 1;75(3):716-27.
- Sofi F, Macchi C, Abbate R, et al. Effectiveness of the Mediterranean diet: can it help delay or prevent Alzheimer's disease?. Journal of Alzheimer's Disease. 2010 Jan 1;20(3):795-801.
- Luchsinger JA, Noble JM, Scarmeas N. Diet and Alzheimer’s disease. Curr. Neurol. Neurosci. Rep 2007;7:366-372.
- Kawas CH. Medications and Diet Protective Factors for AD?. Alzheimer disease and associated disorders. 2006 Jul;20( 2):S89.
- Vauzour D. Effect of flavonoids on learning, memory and neurocognitive performance: relevance and potential implications for Alzheimer's disease pathophysiology. Journal of the Science of Food and Agriculture. 2014 Apr 1;94(6):1042-56.
- Calon F. Omega-3 polyunsaturated fatty acids in Alzheimer's disease: key questions and partial answers. Current Alzheimer Research. 2011 Aug 1;8(5):470-8.
- Calon F, Cole G. Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2007 Nov 1;77(5-6):287-93.
- Calon F, Lim GP, Yang F, et al. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron. 2004 Sep 2;43(5):633-45.
- van der Flier WM, Pijnenburg YA, Fox NC, et al. Early-onset versus late-onset Alzheimer's disease: the case of the missing APOE ɛ4 allele. The Lancet Neurology. 2011 Mar 1;10(3):280-8.
- Miyoshi K. What is ‘early onset dementia’?. Psychogeriatrics. 2009 Jun 1;9(2):67-72.
- Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends in pharmacological sciences. 1991 Jan 1;12:383-8.
- Mudher A, Lovestone S. Alzheimer's disease-do tauists and baptists finally shake hands?. Trends in neurosciences. 2002 Jan 1;25(1):22-6.
- Lott IT, Head E. Alzheimer disease and Down syndrome: factors in pathogenesis. Neurobiology of aging. 2005 Mar 1;26(3):383-9.
- Nistor M, Don M, Parekh M, et al. Alpha-and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain. Neurobiology of aging. 2007 Oct 1;28(10):1493-506.
- Francis PT, Palmer AM, Snape M, et al. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. Journal of Neurology, Neurosurgery & Psychiatry. 1999 Feb 1;66(2):137-47.
- Masliah E, Terry R. Thalamic nuclei in Alzheimer disease: evidence against the cholinergic hypothesis of plaque formation. Brain research. 1989 Jul 31;493(2):240-6.
- Sayeed S, Akhtar S, Mohammad Q, et al. Multiple targets for the management of Alzheimer’s disease. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2016 Dec 1;15(10):1279-89.
- Leon R, Garcia AG, Marco‐Contelles J. Recent advances in the multitarget‐directed ligands approach for the treatment of Alzheimer's disease. Medicinal research reviews. 2013 Jan 1;33(1):139-89.
- Goedert M, Spillantini MG, Crowther RA. Tau proteins and neurofibrillary degeneration. Brain pathology. 1991 Jul 1;1(4):279-86.
- Iqbal K, Alonso AD, Chen S, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2005 Jan 3;1739(2-3):198-210.
- Chun W, Johnson GV. The role of tau phosphorylation and cleavage in neuronal cell death. Frontiers in bioscience: a journal and virtual library. 2007;12:733-56.
- Chin PC, Majdzadeh N, D'Mello SR. Inhibition of GSK3β is a common event in neuroprotection by different survival factors. Molecular Brain Research. 2005 Jun 13;137(1-2):193-201.
- Gong EJ, Park HR, Kim ME, et al. Morin attenuates tau hyperphosphorylation by inhibiting GSK3β. Neurobiology of disease. 2011 Nov 1;44(2):223-30.
- Samudralwar DL, Diprete CC, Ni BF, et al. Elemental imbalances in the olfactory pathway in Alzheimer's disease. Journal of the neurological sciences. 1995 Jun 1;130(2):139-45.
- Kumar YV. Screening natural product database for identification of potential inhibitors of beta Secretase; a key enzyme of Alzheimer’s disease. 2013;1:58-92.
- Pantelidis GE, Vasilakakis M, Manganaris GA, et al. Antioxidant capacity, phenol, anthocyanin and ascorbic acid contents in raspberries, blackberries, red currants, gooseberries and Cornelian cherries. Food chemistry. 2007 Jan 1;102(3):777-83.
- Zheng Z, Lee JE, Yenari MA. Stroke: molecular mechanisms and potential targets for treatment. Current Molecular Medicine. 2003 Jun 1;3(4):361-72.
- Schaffer S, Eckert GP, Schmitt-Schillig S, et al. Plant foods and brain aging: a critical appraisal. InLocal Mediterranean Food Plants and Nutraceuticals 2006 (Vol. 59, pp. 86-115). Karger Publishers.
- Rahman K. Studies on free radicals, antioxidants, and co-factors. Clinical interventions in aging. 2007 Jun;2(2):219.
- Uttara B, Singh AV, Zamboni P, et al. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Current neuropharmacology. 2009 Mar 1;7(1):65-74.
- Liu R, Liu IY, Bi X, et al. Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics. Proceedings of the National Academy of Sciences. 2003 Jul 8;100(14):8526-31.
- Aquilano K, Baldelli S, Rotilio G, et al. Role of nitric oxide synthases in Parkinson’s disease: a review on the antioxidant and anti-inflammatory activity of polyphenols. Neurochemical research. 2008 Dec 1;33(12):2416-26.
- Esposito E, Rotilio D, Di Matteo V, et al. A review of specific dietary antioxidants and the effects on biochemical mechanisms related to neurodegenerative processes. Neurobiology of aging. 2002 Sep 1;23(5):719-35.
- Robards K, Prenzler PD, Tucker G, et al. Phenolic compounds and their role in oxidative processes in fruits. Food chemistry. 1999 Sep 1;66(4):401-36.
- Del Rio D, Borges G, Crozier A. Berry flavonoids and phenolics: bioavailability and evidence of protective effects. British Journal of Nutrition. 2010 Oct;104(S3):S67-90.
- Barbehenn RV, Constabel CP. Tannins in plant-herbivore interactions. Phytochemistry. 2011 Sep 1;72(13):1551-65.
- Arapitsas P. Hydrolyzable tannin analysis in food. Food chemistry. 2012 Dec 1;135(3):1708-17.
- Hassimotto N, Lajolo FM. Antioxidant status in rats after long‐term intake of anthocyanins and ellagitannins from blackberries. Journal of the Science of Food and Agriculture. 2011 Feb 1;91(3):523-31.
- Josuttis M, Verrall S, Stewart D, et al. Genetic and environmental effects on tannin composition in strawberry (Fragaria× ananassa) cultivars grown in different European locations. Journal of agricultural and food chemistry. 2013 Jan 18;61(4):790-800.
- Rao AV, Snyder DM. Raspberries and human health: a review. Journal of Agricultural and Food Chemistry. 2010 Feb 24;58(7):3871-83.
- Bravo L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutrition reviews. 1998 Nov 1;56(11):317-33.
- Szajdek A, Borowska EJ. Bioactive compounds and health-promoting properties of berry fruits: a review. Plant Foods for Human Nutrition. 2008 Dec 1;63(4):147-56.
- Paredes-Lopez O, Cervantes-Ceja ML, Vigna-Pérez M, et al. Berries: improving human health and healthy aging, and promoting quality life—a review. Plant foods for human nutrition. 2010 Sep 1;65(3):299-308.
- Rimando AM, Kalt W, Magee JB, et al. Resveratrol, pterostilbene, and piceatannol in vaccinium berries. Journal of agricultural and food chemistry. 2004 Jul 28;52(15):4713-9.
- Ehala S, Vaher M, Kaljurand M. Characterization of phenolic profiles of Northern European berries by capillary electrophoresis and determination of their antioxidant activity. Journal of Agricultural and Food Chemistry. 2005 Aug 10;53(16):6484-90.