Prevention of Neurodegeneration for Alzheimer’s Disease by Lycium barbarum

Fig. 7.1
Potential effects of Wolfberry on the prevention of AD. The development of AD is affected by various risk factors, which can increase the level of oxidative stress, neuroinflammation and induce AD-related pathological changes. Wolfberry can antagonize some of these changes hence may play a protective role for AD. SOD superoxide dismutase, CAT catalase, GSH-Px glutathione peroxidase, Ab β-amyloid peptide

7.2.2 Diabetes Mellitus

Diabetes has been associated with an increased risk of AD and dementia. Several prospective, population-based studies reported an increased risk of AD in patients with diabetes (Kopf and Frolich 2009). While the worldwide prevalence of diabetes is about 6.4 %, it has been estimated that a 10 % reduction of the prevalence of diabetes would result in 81,000 less AD cases (Barnes and Yaffe 2011). Animal studies have shown that impair glucose metabolism can affect synaptic plasticity, causing deficits in long-term potentiation and long-term depression (Artola et al. 2005; Kamal et al. 2006). A number of possible mechanisms explain how diabetes can promote degeneration in the brain. The most well discussed one is insulin resistance. In AD patients, the levels of insulin were found to decrease in the CSF and increase in plasma. The observed changes were greater for patients with advanced AD, suggesting a possible correlation between insulin and disease severity (Craft et al. 1998). Another piece of supporting evidence is that AD patients and normal subjects react to insulin differentially. When insulin is administrated, the levels of plasma Aβ reduced in the normal subjects while that increased in the AD patients (Kulstad et al. 2006). On the other hand, animal models of AD showed that increased productions of Aβ promote insulin dysregualtion. Amyloid precursor protein (APP)/presenilin 2 (PS2) coexpression in diabetes-positive (db/+) mice results in hyperinsulinemia, hyperglycemia, and hypercholesterolemia together with augmented β-cell mass in the pancreas (Jimenez-Palomares et al. 2012). These data suggest a vicious cycle form between Aβ production and insulin dysregulation. The intracellular signaling cascade of insulin also affects the phosphorylation of tau. Insulin is known to activate phosphatidylinositol 3-kinase (PI3K), which phosphorylates and activates protein kinase B (Akt). Activated Akt can inactivate glycogen synthase kinase-3β, which is a major kinase to phosphorylate tau in the brain. Besides, poor glycemic control in diabetes increases the levels of advanced glycation products (AGE) and oxidative stress in the brain, which can promote neurodegeneration in the central nervous system (CNS; Wrighten et al. 2009).

The hypoglycemic effect of Wolfberry has been documented in several studies (Jing et al. 2009; Luo et al. 2004; Zhu et al. 2013). In the study conducted by Luo and colleagues, feeding of LBP reduced blood glucose level and serum total cholesterol and triglyceride levels in alloxan-induced diabetic rats. They reported that the blood glucose levels decreased in all alloxan-treated rabbits fed with Wolfberry water extract, crude LBP and LBP-X (a fraction of total LBP); and these animals had improved glucose tolerance (Luo et al. 2004). Similar findings were also reported by Jing and colleagues, who found that 28 days LBP treatment significantly reduced the fasting blood glucose levels, total cholesterol, and triglyceride levels in diabetic mice (Jing et al. 2009). The hypoglycemic effect of LBP was further confirmed in a high-fat diet + streptozotocin mice diabetes model (Zhu et al. 2013). In the same study, researchers found that LBP-enhanced glucose consumption in HepG2 cells and 3TE-L1 cells, and stimulated the secretion of insulin from pancreatic β cell. The dual actions of LBP on the pancreatic cells and peripheral tissue may explain the hypoglycemic action of LBP. In a pilot study, healthy human subjects received Wolfberry juice found to have increased caloric expenditure after a single bolus of the juice intake and a reduction of waist circumference after 14 days consumption (Amagase and Nance 2011). All these data support that Wolfberry is likely to have beneficial effects on diabetes patients and thus be potential to reduce the risk of neurodegeneration in AD.

7.2.3 Depression

Neuropsychiatric symptoms are often observed throughout the course of AD and they may severely impair quality of life. Depression is frequently found in AD patients. Meta-analysis found that people with depression had about a two times increased risk of dementia and AD compared with those without a history of the disease (Jorm 2001; Ownby et al. 2006). Anxiety and depression have been shown to accelerate cognitive decline in AD patients (Starkstein et al. 2008). However, the use of traditional antidepressant in elderly with depression does not always results in improved cognitive functions (Butters et al. 2000; Knegtering et al. 1994). Therefore, it seems that prevention of depression is important for reducing the risk of cognitive impairment. Moreover, it has been estimated that more than 10 % of AD (nearly 3.6 million) worldwide are potentially attributable to depression, which further support the important role of depression in AD (Barnes and Yaffe 2011). Several pathological and biological linkages of depression and AD have been proposed (Wong et al. 2013; Wuwongse et al. 2010, 2013). For instance, in animal models of depression and postmortem brains of depressed subjects, decrease in antiapoptotic markers was observed. This can make neurons more vulnerable to the degenerative factors in AD. The levels of pro-inflammatory cytokines also increased in depression subjects. These pro-inflammatory cytokines influence neuronal functions in the prefrontal cortex and hippocampus by modulating the transmission of neurotransmitters and growth factors (Leonard and Myint 2006; Poon et al. 2013).

Wolfberry has demonstrated antidepressant effect in a depression animal model conducted by Zhang and colleagues (Zhang et al. 2012). They first fed the rats with LBP for 7 days and then corticosterone was injected subcutaneously for 14 days to induce depressive-like behavior. The group found that corticosterone treatment significantly increased the rats’ immobility period during force swimming test, which is widely used for detecting depressive symptoms in rodents. Rats fed with LBP had significantly shorter immobility period, suggesting lesser degree of depressive-like symptoms. Furthermore, LBP restored the impairment of neurogenesis in the hippocampus of corticosterone-injected rats, although it was found that it is not directly related to the observed behavioral changes. LBP also restored spine density and the decreased level of PSD-95 (a postsynaptic protein which is important in neuronal plasticity) in the hippocampus, suggesting that LBP enhanced synaptic plasticity in the region. Data from this animal study support the notion that Wolfberry has a preventive or even a therapeutic role in depression. Further studies are required to elucidate the exact mechanism or to confirm the effects of LBP in different depression animal models. Recently, a US health product company conducted some studies on the effects of their Wolfberry juice. Although larger scale of experiment is required before definite conclusion is drawn, their pilot findings demonstrated that human subjects who drink Wolfberry juice had additional improvements in fatigue, depression, and sleeping quality (Paul Hsu et al. 2012). It is hoped that more in-depth studies can be conducted to verify the effects of Wolfberry on human.

7.2.4 Hyperhomocysteinemia

Homocysteine is a nonessential amino acid whose metabolism depends on folate, vitamin B6, and vitamin B12. Elevated plasma levels of total homocysteine are associated with increased risk for dementia and AD (McIlroy et al. 2002; Morris 2003). It is one of the nongenetic risk factors that scientist are interested to target for the prevention of AD. A randomized controlled study showed that high homocysteine levels at baseline are associated with faster gray matter atrophy in elderly subjects. Supplement of vitamin B as treatment can reduce homocysteine level and attenuate the cerebral atrophy in those grey matter regions specifically vulnerable to the AD process by as much as sevenfold (Douaud et al. 2013). Autopsy findings also confirm the pathological linkage between homocysteine level and AD. In a population aged ≥ 85 years, elevated baseline homocysteine has been shown to associate with increased neurofibrillary tangles in their postmortem brains. There is also an association between Aβ accumulation and elevated homocysteine. In the same time, those with homocysteine levels in the highest quartile also had more severe medial temporal atrophy and periventricular and deep white matter hyperintensities, which is associated with increased risk of dementia (Hooshmand et al. 2013; Debette and Markus 2010). Together with several in vitro and in vivo studies, it is believed that high levels of homocysteine promote the production of Aβ and the generation of oxidative stress, enhance tau phosphorylation, and even affects normal cell cycle states (Morris 2003).

Data from our laboratory showed that Wolfberry could antagonize homocysteine neurotoxicity in vitro (Ho et al. 2010). Primary cultures of cortical neurons are susceptible to the toxicity of homocysteine, which can lead to apoptosis and cell death. LBP significantly attenuated homocysteine-induced neuronal cell death and the activation of caspase-3. LBP also reduced homocysteine-induced tau pathology. It is known that hyperphosphorylation of tau can affect normal neuronal functions. With LBP treatment, the increased levels of tau phosphorylation at Ser198/199/202, Ser396, and Ser214 by homocysteine were marked reduced. Moreover, the level of toxic truncated-tau was also decreased accordingly. It was found that LBP could reduce the phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK) but not the phosphorylation of glycogen synthase kinase 3 beta (GSK3β). These changes in tau kinases might partly explain the protective effects of LBP. Research from our group also proved that tau phosphorylation is highly regulated by endoplasmic reticulum stress (ER stress) during neurodegeneration and blocking of ER stress could reduce tau hyperhosphorylation (Ho et al. 2012). Our previous findings showed that LBP could reduce dithiothreitol (DTT)-induced neurotoxicity (Yu et al. 2006). We, therefore, further investigate if LBP can also reduce homocysteine-induced phosphorylation of tau through modulating the ER stress signaling.

7.3 Direct Protective Action of Wolfberry on the AD Brain

7.3.1 Aβ Neurotoxicity

Aβ is the major component found in senile plaques and its CSF levels has been considered as a biomarker for AD. Numerous studies prove that Aβ is toxic to neurons (please refer to Cavallucci et al. 2012 for a detailed review). Dysfunction of synapse is found in all stages of AD. The amount of presynaptic vesicles protein is reduced throughout the disease progression. It was found that Aβ accumulated at synapses and induces a progressive toxicity. It increases N-methyl-D-aspartate receptor (NMDAR)-mediated Ca2+ influx, thus disrupts neuronal transmission. This can lead to subsequent pathological events such as the generation of reactive oxygen species. It also impairs the normal function of mitochondria and triggers the activation of caspase-3 and apoptosis. The activation of capsase-3 can impair NMDAR-dependent long-term depression.

Our laboratory found that LBP could attenuate the activation of caspase-3 and neuronal cell death induced by Aβ1–42 and Aβ25–35, which is a shorter synthetic fragment. Interestingly, this protective effect was only provided by the polysaccharide fraction of Wolfberry but not other fractions including betaine and β-sitosterol (Ho et al. 2007, Yu et al. 2005). We also compared the protective effects of LBP with a well-known Western neuroprotective medicine, lithium chloride (LiCl), and discovered that LBP even has a wider effective and safety dosage (Yu et al. 2005, 2007). Our data supported that different fractions of LBP protected neurons through distinct mechanisms. The water extract of Wolfberry contained LBP fractions that could inhibit some proapoptotic signaling pathways, including the JNK and double-stranded RNA-dependent protein kinase (PKR; Yu et al. 2005, 2007); while the alkaline extract contains LBP that could upregulate the pro-survival Akt pathway (Ho et al. 2007). In fact, Wolfberry was found to promote the expression of genes related to cell survival in mouse spleen. In mice that received 7 days of oral feeding of micronized Wolfberry, the gene expression of tumor necrosis factor (TNF), NF-kappaB, and Bcl-2 were upregulated, while that of APAF-1 and caspase-3 were downregulated (Lin et al. 2011). This indirect evidence suggested that Wolfberry could affect multiple gene expression and these changes might explain how it helps our body to cope with stress and reduces damages.

7.3.2 Glutamate Neurotoxicity

Glutamatergic NMDA receptors are important for learning and memory. However, overactivation of the NMDA receptors can lead to Ca2+ overload and excitotoxicity, which disturb neuroplasticity and cause neuronal cell death. Glutamate excitotoxicity is involved in the pathogenesis of AD. Apart from the excitotoxicity, high concentrations of glutamate can induce oxidative stress by inhibiting the uptake of cysteine thus the synthesis of glutathione (Murphy et al. 1990). Therefore, reducing glutamate excitotoxicity or restoring the homeostatsis in the glutamatergic system is one of the available strategies for the treatment of AD. Currently, the noncompetitive NMDA receptor antagonist memantine has been approved by the European Medicines Agency (EMEA) and Food and Drug Administration (FDA) for the treatment of moderate-to-severe AD (Ho et al. 2009; Hynd et al. 2004).

It has been reported that LBP from Wolfberry antagonized the toxicity of glutamate in primary cultures of cortical neurons (Ho et al. 2009). Pretreatment of neurons with LBP significantly reduced the necrosis and apoptosis following subsequent glutamate exposure. The protective effects of LBP were even comparable to that provided by memantine, which further support the potential of LBP as neuroprotective drug for AD. Interestingly, the LBP used in this study had no antioxidant effects and it could not reduce the levels of reactive oxygen species triggered by hydrogen peroxide. It was suggested that LBP might mediate its protection by attenuating the phosphorylation of the apoptotic kinase JNK. Since glutamate toxicity is also involved in other diseases such as glaucoma and stroke, it is worth to conduct further studies on Wolfberry.

7.4 Wolfberry Preserves Memory Functions in Various Animal Models

Cognitive impairment remains the major clinical symptoms in AD. Cognitive performance is always used as the primary and almost the most important parameter for the diagnosis of AD. It is, therefore, important to evaluate the efficacy of potential drugs by observing if there are cognitive improvements after intake. Two animal studies proved that Wolfberry could improve cognition (Chen et al. 2014; Zhang et al. 2013).

In the first study, Wolfberry water extract was fed to APP/PS double transgenic mice for 2 weeks, and then their cognitive performance was measured by Morris water maze test. In this test, mice were put in a water tank and they were trained to find a hidden platform with visual cues. The time they spent in searching the hidden platform during the training period and the final stage (probe trial) indicated their learning and memory functions. APP/PS double transgenic mice are used commonly as animal model for AD. These mice have spontaneous increase in Aβ production and memory loss when they grow up. The researchers found that mice fed with Wolfberry water extract took shorter time to find the hidden platform and they spent longer time in the memorized zone during the probe trial when compared to those just fed with saline, indicating these APP/PS1 mice had better learning and memory. ELISA experiment confirmed that the Wolfberry water extract reduced the levels of Aβ1–42 in these mice, which explained the observed beneficial effects (Zhang et al. 2013).

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Jun 28, 2017 | Posted by in PHARMACY | Comments Off on Prevention of Neurodegeneration for Alzheimer’s Disease by Lycium barbarum

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