Current Alzheimer Research - Volume 14, Issue 8, 2017

Background: Amyloid-beta (Aβ) induced mitochondrial dysfunction is one of the major causes of neuronal toxicity in Alzheimer’s disease. A number of recent reports suggest involvement of mitochondrial alterations through intracellular accumulation of oligomeric Aβ. These mitochondrial alterations include increased Reactive Oxygen Species (ROS), mt-DNA depletion, decreased oxidative phosphorylation and ATP production, membrane depolarization, reduced number of mitochondria etc. All these defects cumulatively caused neural toxicity and alterations in cellular energy homeostasis. On the other hand, anti-inflammatory drug aspirin is reported to promote both mitochondrial biogenesis and improvement in cellular energy status. Methods: Taking altogether the mentioned clues, we evaluated protective effect of aspirin, if any on oligomeric Aβ42 induced toxicity and mitochondrial alterations in differentiated neuronal cells. Results: A significant reduction in neuronal viability and increased apoptosis was observed in Aβ42 treated cells, as evident by MTT assay, apoptosis ELISA and immunofluorescence from β-III tubulin antibody staining of neuronal cells. A concomitant decrease was also observed in the intensity of mitotracker red FM staining and mt-DNA to nDNA ratio, suggesting mitochondrial membrane depolarization and/or reduced number of mitochondria along with depletion in mt-DNA. However, simultaneous treatment of 5 μM aspirin to oligomeric Aβ42 treated cells protected them from mitochondrial dysfunction and neurotoxicity. Conclusion: We suggest mitochondrial biogenesis, changes in mitochondrial membrane potential and / or inhibition of Aβ42 aggregation by aspirin as possible underlying mechanism(s).

Background: Vitamin D (VD) and resveratrol (RSV) are two nutritional molecules that have reported neuroprotective effects, and findings from cellular models suggest that resveratrol could potentiate vitamin D's effects. The senescence-accelerated mouse-prone 8 (SAMP8) is a useful model of Alzheimer's disease (AD)-related memory impairment. Objective: We aimed to explore how the combination of vitamin D with resveratrol would affect memory impairments shown by SAMP8 mice, as well as the potential mechanisms. Method: SAMP8 mice and their control senescence-accelerated mouse resistant 1 (SAMR1) mice (10 weeks old) were divided into 5 groups, i.e. SAMR1 group, SAMP8 group, SAMP8 mice supplemented with VD group, SAMP8 mice supplemented with RSV group and SAMP8 mice supplemented with both VD and RSV group. At the end of the intervention, Morris water maze (MWM) test was used to assess cognitive function. Hippocampus and parietal cortex were dissected for further analysis. Results: The combination of VD and RSV significantly increased time spent in target quadrant and the number of crossing via MWM test. In hippocampus, the combined intervention significantly reduced soluble Aβ42 level and BACE1 protein expression. In cortex, the combined treatment significantly reduced phosphorylation of tau at serine404 and p-p53, as well as enhanced p-CREB protein expression. The combination also significantly reduced GFAP and p-NFΚB p65 in both hippocampus and cortex. Conclusion: The combined intervention might exert greater neuroprotective effects in SAMP8 mice, this might be associated with the fact that the combined intervention could positively affect amyloidogenic pathways, neuroinflammation, tau phosphorylation and probably apoptosis markers.

Background: Symptoms of psychosis is one of the common clinical manifestations of Alzheimer’s disease (AD). However, the pathophysiology behind psychosis is unknown. Objective: The aim of the present study was to explore the relationship between Apolipoprotein E (APOE) genotype, Lewy body pathology, and psychosis in AD. Method: The data was obtained from the National Alzheimer’s disease Coordinating Centre (NACC), using the Uniform Data Set and the Neuropathology Data Set. Subjects with frequent neuritic plaque on CERAD, and Braak Stage of V or VI, corresponding to high probability of AD based on the NIA-AA Regan criteria were included in the analysis. Results: Subjects with two copies of 4 alleles were significantly more likely to develop psychosis, both delusions and/or hallucinations, during the course of their illness. This association was gender-specific, only reaching significance in females. Our findings further showed that presence of two copies of 4 allele was positively associated with the formation of Lewy bodies. Only in females with Lewy bodies was the effect of two copies of 4 allele significant, reaching an odd ratio of 4.5. Conclusion: The APOE 4 allele has a female-specific effect in inducing psychosis in AD through the formation of Lewy bodies.

Background: Nutrition is important for the fetal developmental programming. Nutritional deficiency in early life could increase the susceptibility to many aging-related disorders including cognitive decline. Objective: Our study aims to investigate the effect of early famine exposure on aging-associated cognitive function. Methods: We recruited 6790 subjects born between 1956 to 1964 during which the Great Chinese Famine occurred (1959-1961). Cognitive function of these subjects were evaluated using the Mini-Mental State Examination (MMSE), the Activities of Daily Living scale (ADL), the Instrumental Activities of Daily Living scale (IADL) and the Clinical Dementia Rating (CDR). Results: Our study identified that early exposure to the famine significantly increased the risk of cognitive impairments in later life, leading to higher prevalence of Mild Cognitive Impairment (MCI) and dementia. We also found the sex and rural-urban differences in this malnutrition-induced effect. Illiteracy, history of stroke or diabetes mellitus are great risk factors to facilitate the cognitive decline. Conclusion: These findings demonstrate that exposure to famine during early life including prenatal period and early childhood facilitates aging-associated cognitive deficits.

Background: In addition to cognitive decline, Alzheimer’s Disease (AD) is also characterized by agitation and disruptions in activity and sleep. These symptoms typically occur in the evening or night and have been referred to as ‘sundowning’. They are especially difficult for carers and there are no specific drug treatments. There is increasing evidence that these symptoms reflect pathology of circadian rhythm generation and transmission. Objective: We investigated whether a transgenic mouse model relevant to AD (APPswe/PS1dE9) exhibits circadian alterations in locomotor activity in their home cage and whether expression of clock genes involved in the regulation of the circadian cycle is abnormal in the hippocampus and medulla-pons brain regions isolated from these mice. Results: In 2month old female mice the APPswe/PS1dE9 transgene alters levels and patterns in circadian rhythm of locomotor activity. Expression of the clock genes Per1, Per2, Cry1 and Cry2 was found to increase at night compared to day in wild-type control mice in the medulla/pons. This effect was blunted for Cry1 and Cry2 gene expression in APPswe/PS1dE9. Conclusion: This study suggests altered circadian regulation of locomotor activity is abnormal in female APPswe/ PS1dE9 mice and that this alteration has biomolecular analogies in a widely available model of AD. The early age at which these effects are manifest suggests that these circadian effects may precede plaque development. The APPswe/PS1dE9 mouse genetic model may have potential to serve as a tool in understanding the neuropathology of circadian abnormalities in AD and as a model system to test novel therapeutic agents for these symptoms.

Tannic acid (TA) is a naturally occurring plant-derived polyphenol found in several herbaceous and woody plants, including legumes, sorghum, beans, bananas, persimmons, rasberries, wines and a broad selection of teas. Clinically, TA has strong antioxidant/free radical scavenging, antiinflammatory, anti-viral/bacterial, and anti-carcinogenic properties. While the aetiology of Alzheimer’s disease (AD) remains unclear, this complex multifactorial neurodegenerative disorder remains the most common form of dementia, and is a growing public health concern worldwide. The neuroprotective effects of TA against AD have been shown in several in vitro and in vivo models of AD. Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that TA is also a natural inhibitor of β-secretase (BACE1) activity and protein expression. BACE1 is the primary enzyme responsible for the production and deposition of Aβ peptide. TA also destabilises neurotoxic amyloid beta (Aβ) fibrils in vitro. Apart from its effects on the Aβ cascade, TA can also inhibit the in vitro aggregation of tau peptide, a core component of intracellular neurofibrillary tangles (NFTs). This review summarizes the relevance of TA and TA-related vegetable extracts (tannins) in the pathogenesis of AD and its enzymatic targets. It also highlights the significance of TA as an important lead compound against AD.

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, neuropathologically characterized by aggregates of β-amyloid peptides, which deposit as senile plaques, and of TAU protein, which forms neurofibrillary tangles. It is now widely accepted that neuroinflammation is implicated in AD pathogenesis. Method: Indeed, inflammatory mediators, such as cytokines and chemokines (chemotactic cytokines) can impact on the Alzheimer´s amyloid precursor protein by affecting its expression levels and amyloidogenic processing and/or β -amyloid aggregation. Additionally, cytokines and chemokines can influence kinases’ activities, leading to abnormal TAU phosphorylation. To date there is no cure for AD, but several therapeutic strategies have been directed to prevent neuroinflammation. Anti-inflammatory, but also anti-amyloidogenic compounds, such as flavonoids were shown to favourably modulate some pathological events associated with neurodegeneration. Conclusion: This review focuses on the role of cytokines and chemokines in AD-associated pathologies, and summarizes the potential anti-inflammatory therapeutic approaches aimed at preventing or slowing down disease progression.

Background: Cancer and Alzheimer's disease (AD) are both associated with aging, but do not often occur together. Obesity is a shared risk factor for both diseases and may be involved in this curious clinical observation. Fat cells produce many active substances, including leptin and adiponectin; leptin has cancer stimulating and AD inhibiting properties, while adiponectin can inhibit cancer but stimulate AD. Objective: To describe the opposing effects of leptin and adiponectin on cancer and AD, to outline signaling pathways involved in these effects and to suggest new research on effective control strategies for both diseases. Methods: A review was conducted to document the inverse cancer/AD relationship and the role of excess body fat as a common risk factor. Previous studies have suggested the involvement of p53, Wnt and other cell signaling pathways in this inverse relationship. The opposing effects of leptin and adiponectin on these signaling pathways in cancer and AD were evaluated. Results: The inverse cancer/AD relationship is well documented, as is the role of excess body fat, especially central obesity, in increasing risk for both diseases. Leptin and adiponectin have opposing effects in cancer and AD mediated by signaling factors that influence apoptosis, angiogenesis, and other cell growth controls. Wnt and p53 are prominent among these signaling factors. Conclusion: Opposing effects of leptin and adiponectin, mediated by specific cell signaling pathways, are involved in the inverse cancer/Ad relationship. Future research aimed at modifying the leptin/adiponectin ratio may lead to important treatment and control approaches in both cancer and AD.

Background: Recent evidence suggests that obesity, besides being a risk factor for cardiovascular events, also increases the risk of Alzheimer’s disease. Insulin resistance is common in all cases of obesity and appears to be the linkage between both diseases. Obesity, often associated with excessive fat and sugar intake, represents a preclinical stage toward insulin resistance during which nutrition intervention is likely to have maximum effect. Objective: In this way, healthy lifestyles lifetime to prevent obesity-related modifiable risk factors such as inflammation, oxidative stress and metabolic disorders could be simultaneously beneficial for preserving cognition and controlling the Alzheimer’s disease. Method: This review relates extensive research literature on facts linking nutrients and dietary patterns to obesity and Alzheimer’s disease. In addition briefly presents molecular mechanisms involved in obesity- induced insulin resistance and the contribution of peripheral inflammatory and defective insulin signalling pathways, as well as ectopic lipids accumulation to Alzheimer’s development through brain inflammation, neuronal insulin resistance, and cognitive dysfunction seen in Alzheimer’s disease. Results: The work relates current and emerging pharmacological and non-pharmacological therapies for the management of obesity, insulin resistance and Alzheimer’s considering them as disorders with common molecular features. Conclusion: The findings of this review validate the importance of some nutritional interventions as possible approach to prevent or delay simultaneously progression of Alzheimer’s disease and obesity.