Anorexigenic neuropeptides as anti-obesity and neuroprotective agents: exploring the neuroprotective effects of anorexigenic neuropeptides.

Since 1975, the incidence of obesity has increased to epidemic proportions, and the number of patients with obesity has quadrupled. Obesity is a major risk factor for developing other serious diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular diseases. Recent epidemiologic studies have defined obesity as a risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and other types of dementia. Despite all these serious comorbidities associated with obesity, there is still a lack of effective antiobesity treatment. Promising candidates for the treatment of obesity are anorexigenic neuropeptides, which are peptides produced by neurons in brain areas implicated in food intake regulation, such as the hypothalamus or the brainstem. These peptides efficiently reduce food intake and body weight. Moreover, because of the proven interconnection between obesity and the risk of developing AD, the potential neuroprotective effects of these two agents in animal models of neurodegeneration have been examined. The objective of this review was to explore anorexigenic neuropeptides produced and acting within the brain, emphasizing their potential not only for the treatment of obesity but also for the treatment of neurodegenerative disorders.

[Role of NLRP3 inflammasome in prevention and treatment of cognitive impairment-related diseases and traditional Chinese medicine intervention: a review].

Alzheimer's disease(AD), vascular dementia(VD), and traumatic brain injury(TBI) are more common cognitive impairment diseases characterized by high disability and mortality rates, imposing a heavy burden on individuals and their families. Although AD, VD, and TBI have different specific mechanisms, their pathogenesis is closely related to the nucleotide-binding oligome-rization domain-like receptor protein 3(NLRP3). The NLRP3 inflammasome is involved in neuroinflammatory responses, mediating microglial polarization, regulating the reduction of amyloid ß-protein(Aß) deposition, neurofibrillary tangles(NFTs) formation, autophagy regulation, and maintaining brain homeostasis, and synaptic stability, thereby contributing to the development of AD, VD, and TBI. Previous studies have shown that traditional Chinese medicine(TCM) can alleviate neuroinflammation, promote microglial polarization towards the M2 phenotype, reduce Aß deposition and NFTs formation, regulate autophagy, and maintain brain homeostasis by intervening in NLRP3 inflammasome, hence exerting a role in preventing and treating cognitive impairment-related diseases, reducing psychological and economic pressure on patients, and improving their quality of life. Therefore, this article elucidated the role of NLRP3 inflammasome in AD, VS, and TBI, and provided a detailed summary of the latest research results on TCM intervention in NLRP3 inflammasome for the prevention and treatment of these diseases, aiming to inherit the essence of TCM and provide references and foundations for clinical prevention and treatment of cognitive impairment-related diseases with TCM. Meanwhile, this also offers insights and directions for further research in TCM for the prevention and treatment of cognitive impairment-related diseases.

Curcumin and omega-3 polyunsaturated fatty acids as bioactive food components with synergistic effects on Alzheimer's disease.

Curcumin and omega-3 polyunsaturated fatty acids (ω-3 PUFA) are multifunctional compounds which play an important role in Alzheimer's disease (AD) and little has been addressed about the role of these two compounds together in the progression of the disease. There is evidence of the beneficial effect of combined administration of ω-3 PUFA and other dietary supplements such as vitamins and polyphenols in the prevention of AD, although much remains to be understood about their possible complementary or synergistic activity. Therefore, the objective of this work is to review the research focused on studying the effect and mechanisms of action of curcumin, ω-3 PUFA, and the combination of these nutraceutical compounds, particularly on AD, and to integrate the possible ways in which these compounds can potentiate their effect. The most important pathophysiologies that manifest in AD will be addressed, in order to have a better understanding of the mechanisms of action through which these bioactive compounds exert a neuroprotective effect.

Harnessing Passive Pulsatile Shear Stress for Alzheimer's Disease Prevention and Intervention.

 Alzheimer's disease (AD) affects more than 40 million people worldwide and is the leading cause of dementia. This disease is a challenge for both patients and caregivers and puts a significant strain on the global healthcare system. To address this issue, the Lancet Commission recommends focusing on reducing modifiable lifestyle risk factors such as hypertension, diabetes, and physical inactivity. Passive pulsatile shear stress (PPSS) interventions, which use devices like whole-body periodic acceleration, periodic acceleration along the Z-axis (pGz), and the Jogging Device, have shown significant systemic and cellular effects in preclinical and clinical models which address these modifiable risks factors. Based on this, we propose that PPSS could be a potential non-pharmacological and non-invasive preventive or therapeutic strategy for AD. We perform a comprehensive review of the biological basis based on all publications of PPSS using these devices and demonstrate their effects on the various aspects of AD. We draw from this comprehensive analysis to support our hypothesis. We then delve into the possible application of PPSS as an innovative intervention. We discuss how PPSS holds promise in ameliorating hypertension and diabetes while mitigating physical inactivity, potentially offering a holistic approach to AD prevention and management.

[Exosome and prevention of Alzheimer's disease: based on theory of kidney storing essence].

The theory of kidney storing essence storage, an important part of the basic theory of traditional Chinese medicine(TCM), comes from the Chapter 9 Discussion on Six-Plus-Six System and the Manifestations of the Viscera in the Plain Questions, which says that "the kidney manages closure and is the root of storage and the house of Jing(Essence)". According to this theory, essence is the fundamental substance of human life activities and it is closely related to the growth and development of the human body. Alzheimer's disease(AD) is one of the common neurodegenerative diseases, with the main pathological features of Aß deposition and Tau phosphorylation, which activate neurotoxic reactions and eventually lead to neuronal dysfunction and cell death, severely impairing the patient's cognitive and memory functions. Although research results have been achieved in the TCM treatment of AD, the complex pathogenesis of AD makes it difficult to develop the drugs capable of curing AD. The stem cell therapy is an important method to promote self-repair and regeneration, and bone marrow mesenchymal stem cells(BMSCs) as adult stem cells have the ability of multi-directional differentiation. By reviewing the relevant literature, this paper discusses the association between BMSCs and the TCM theory of kidney storing essence, and expounds the material basis of this theory from the perspective of molecular biology. Studies have shown that TCM with the effect of tonifying the kidney in the treatment of AD are associated with BMSCs. Exosomes produced by such cells are one of the main substances affecting AD. Exosomes containing nucleic acids, proteins, and lipids can participate in intercellular communication, regulate cell function, and affect AD by reducing Aß deposition, inhibiting Tau protein phosphorylation and neuroinflammation, and promoting neuronal regeneration. Therefore, discussing the prevention and treatment of exosomes and AD based on the theory of kidney storing essence will provide a new research idea for the TCM treatment of AD.

Perinatal choline supplementation prevents learning and memory deficits and reduces brain amyloid Aß42 deposition in AppNL-G-F Alzheimer's disease model mice.

Alzheimer's disease (AD) is characterized by cognitive and memory impairments and neuropathological abnormalities. AD has no cure, inadequate treatment options, and a limited understanding of possible prevention measures. Previous studies have demonstrated that AD model mice that received a diet high in the essential nutrient choline had reduced amyloidosis, cholinergic deficits, and gliosis, and increased neurogenesis. In this study, we investigated the lifelong effects of perinatal choline supplementation on behavior, cognitive function, and amyloidosis in AppNL-G-F AD model mice. Pregnant and lactating mice were given a diet containing either 1.1 g/kg (control) or 5 g/kg (supplemented) of choline chloride until weaning and subsequently, all offspring received the control diet throughout their life. At 3, 6, 9, and 12 months of age, animals were behaviorally tested in the Open Field Test, Elevated Plus Maze, Barnes Maze, and in a contextual fear conditioning paradigm. Immunohistochemical analysis of Aß42 was also conducted on the brains of these mice. AppNL-G-F mice displayed hippocampal-dependent spatial learning deficits starting at 3-months-old that persisted until 12-months-old. These spatial learning deficits were fully prevented by perinatal choline supplementation at young ages (3 and 6 months) but not in older mice (12 months). AppNL-G-F mice also had impaired fearful learning and memory at 9- and 12-months-old that were diminished by choline supplementation. Perinatal choline supplementation reduced Aß42 deposition in the amygdala, cortex, and hippocampus of AppNL-G-F mice. Together, these results demonstrate that perinatal choline supplementation is capable of preventing cognitive deficits and dampening amyloidosis in AppNL-G-F mice and suggest that ensuring adequate choline consumption during early life may be a valuable method to prevent or reduce AD dementia and neuropathology.

Effects of the ApoE genotype on cognitive function in aging mice fed with a high-fat diet and the protective potential of n-3 polyunsaturated fatty acids.

The ApoE4 allele is the strongest genetic determinant for Alzheimer's disease (AD), while obesity is a strong environmental risk for AD. The modulatory effect of the ApoE genotype on aging-related cognitive function in tandem with a high-fat diet (HFD) remains uncertain. This study aimed to elucidate the effects of ApoE3/ApoE4 genotypes in aged mice exposed to a HFD, and the benefits of n-3 polyunsaturated fatty acids (PUFAs) from fish oil. Remarkably, the HFD led to weight gain and lipid accumulation, more pronounced in ApoE3 mice, while ApoE4 mice experienced exacerbated cerebral insulin resistance, neuroinflammation, and oxidative stress. Critically, n-3 PUFAs modulated the cerebral insulin signaling via the IRS-1/AKT/GLUT4 pathway, mitigated microglial hyperactivity, and reduced IL-6 and MDA levels, thereby counteracting cognitive deficits. These findings highlight the contrasting impacts of ApoE genotypes on aging mice exposed to a HFD, supporting n-3 PUFAs as a strategic nutritional intervention for brain health, especially for ApoE4 carriers.

Mendelian randomization to evaluate the effect of folic acid supplement on the risk of Alzheimer disease.

We conducted a study to evaluate the impact of folic acid supplementation on the risk of Alzheimer disease (AD). A Mendelian randomization (MR) analysis model assessed the causal effects of folic acid supplementation on AD, utilizing data from recent genome-wide association studies. Effect estimates were scrutinized using various methods: inverse-variance weighted (IVW), simple mode, weighted mode, simple median, weighted median, penalized weighted median, and the MR-Egger method. The sensitivity analysis assessed heterogeneity and pleiotropy of individual single nucleotide polymorphisms (SNPs) using the IVW method with Cochran Q statistics and MR Egger intercept, respectively. Additionally, a leave-one-out sensitivity analysis determined potential SNP-driven associations. Both fixed-effect and random-effect IVW models in the MR analysis revealed a reduced risk of AD associated with folic acid supplementation (odds ratio, 0.930; 95% CI, 0.903-0.958, P < .001; odds ratio, 0.930; 95% CI, 0.910-0.950, P < .001) based on 7 SNPs as instrumental variables. The reverse MR analysis indicated no causal association between AD and folic acid supplementation. This study, utilizing genetic data, suggests that folic acid supplementation may potentially reduce the risk of AD and provides novel insights into its etiology and preventive measures.

The associations of serum vitamin D status and vitamin D supplements use with all-cause dementia, Alzheimer's disease, and vascular dementia: a UK Biobank based prospective cohort study.

BACKGROUND: Prior studies on vitamin D and dementia outcomes yielded mixed results and had several important limitations. OBJECTIVES: We aimed to assess the associations of both serum vitamin D status and supplementation with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) incidence. METHODS: With a prospective cohort study design, we comprehensively assessed the associations of vitamin D and multivitamin supplementation, as well as vitamin D deficiency {25-hydroxyvitamin D [25(OH)D] <30 nmol/L}, and insufficiency [25(OH)D 30 to <50 nmol/L], with the 14-year incidence of all-cause dementia, AD, and VD in 269,229 participants, aged 55 to 69, from the UK Biobank. RESULTS: Although 5.0% reported regular vitamin D use and 19.8% reported multivitamin use, the majority of participants exhibited either vitamin D deficiency (18.3%) or insufficiency (34.0%). However, vitamin D deficiency was less prevalent among users of vitamin D (6.9%) or multivitamin preparations (9.5%) than among nonusers (21.5%). Adjusted Cox regression models demonstrated 19% to 25% increased risk of all 3 dementia outcomes for those with vitamin D deficiency [hazard ratio (HR) 95% confidence interval (CI)]: 1.25 (1.16, 1.34) for all-cause dementia; 1.19 (1.07-1.31) for AD; 1.24 (1.08-1.43) for VD] and 10% to 15% increased risk of those with vitamin D insufficiency [HR (95% CI): 1.11 (1.05, 1.18) for all-cause dementia; 1.10 (1.02-1.19) for AD; 1.15 (1.03-1.29) for VD]. Regular users of vitamin D and multivitamins had 17% and 14% lower risk of AD [HR (95% CI): 0.83 (0.71, 0.98)] and VD [HR (95% CI): 0.86 (0.75, 0.98)] incidence, respectively. CONCLUSIONS: Although our findings indicate the potential benefits of vitamin D supplementation for dementia prevention, randomized controlled trials are essential for definitive evidence.

Long-Term Krill Oil Administration Alleviated Early Mild Cognitive Impairment in APP/PS1 Mice.

SCOPE: Alzheimer's disease is an age-dependent neurodegenerative disorder. Mounting studies focus on the improvement of advanced cognitive impairment by dietary nutrients. Krill oil (KO), a rich source of DHA/EPA and astaxanthin, is effective in improving cognitive function. The study mainly investigates the protective effects of long-term KO administration on early cognitive impairment. METHODS AND RESULTS: Results show that 2 months KO administration (50 and 100 mg kg-1 BW) can dramatically promote learning and memory abilities. Mechanism studies demonstrate that KO reduces amyloid ß concentration by regulating the amyloidogenic pathway, inhibits neuro-inflammation via regulating TLR4-NLRP3 signaling pathway, and prevents neuron injure. KO supplementation also enhances gut barrier integrity, reduces serum lipopolysaccharide leakage, and alters the gut microbiota by reducing Helicobacteraceae, Lactobacillaceae proportion, increasing Dubosiella and Akkermansia relative abundance. Particularly, a significant increase of isovaleric acid, propionic acid, and acetic acid levels is observed after KO supplementation. Correlation analysis shows that short-chain fatty acids (SCFAs), gut microbiota, and cognitive function are strongly correlated. CONCLUSIONS: The results reveal that KO relieves early mild cognitive impairment possibly for its role in mediating the gut microbiome-SCFAs-brain axis. Thus, KO may provide potential intervention strategies to prevent cognitive impairment in the early stages through the microbiota-gut-brain axis.

Biotransformation of American Ginseng Stems and Leaves by an Endophytic Fungus Umbelopsis sp. and Its Effect on Alzheimer's Disease Control.

BACKGROUND: Common ginsenosides can be transformed into rare ginsenosides through microbial fermentation, and some rare ginsenosides can prevent Alzheimer's disease (AD). This study aimed to transform common ginsenosides into rare ginsenosides through solid-state fermentation of American ginseng stems and leaves (AGSL) by an endophytic fungus and to explore whether fermented saponin extracts prevent AD. METHODS: The powders of AGSL were fermented in a solid state by endophytic fungus. Total saponins were extracted from fermentation products using the methanol extraction method. The types of saponins were analyzed by liquid chromatography mass spectrometry (LC/MS). The Aß42 concentration and ß-secretase activity were measured by ELISA for the prevention of AD. RESULTS: After AGSL was fermented by an endophytic fungus NSJG, the total saponin concentration of the fermented extract G-SL was higher than the unfermented CK-SL. Rare ginsenoside Rh1 was newly produced and the yield of compound K (561.79%), Rh2 (77.48%), and F2 (40.89%) was increased in G-SL. G-SL had a higher inhibition rate on Aß42 concentration (42.75%) and ß-secretase activity (42.22%) than CK-SL, possibly because the rare ginsenoside Rh1, Rh2, F2, and compound K included in it have a strong inhibitory effect on AD. CONCLUSION: The fermented saponin extracts of AGSL show more inhibition effects on AD and may be promising therapeutic drugs or nutrients for AD.

Diet's Role in Modifying Risk of Alzheimer's Disease: History and Present Understanding.

Diet is an important nonpharmacological risk-modifying factor for Alzheimer's disease (AD). The approaches used here to assess diet's role in the risk of AD include multi-country ecological studies, prospective and cross-sectional observational studies, and laboratory studies. Ecological studies have identified fat, meat, and obesity from high-energy diets as important risk factors for AD and reported that AD rates peak about 15-20 years after national dietary changes. Observational studies have compared the Western dietary pattern with those of the Dietary Approaches to Stop Hypertension (DASH), Mediterranean (MedDi), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets. Those studies identified AD risk factors including higher consumption of saturated and total fats, meat, and ultraprocessed foods and a lower risk of AD with higher consumption of fruits, legumes, nuts, omega-3 fatty acids, vegetables, and whole grains. Diet-induced factors associated with a significant risk of AD include inflammation, insulin resistance, oxidative stress, elevated homocysteine, dietary advanced glycation end products, and trimethylamine N-oxide. The molecular mechanisms by which dietary bioactive components and specific foods affect risk of AD are discussed. Given most countries' entrenched food supply systems, the upward trends of AD rates would be hard to reverse. However, for people willing and able, a low-animal product diet with plenty of anti-inflammatory, low-glycemic load foods may be helpful.

Psychological Status of the Participants in Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Colombia.

BACKGROUND: The SARS-CoV2 global pandemic impacted participants in the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) clinical trial, who faced three stressors: 1) fear of developing dementia; 2) concerns about missing treatment; and 3) risk of SARS-CoV2 infection. OBJECTIVE: To describe the frequency of psychological disorders among the participants of the API ADAD Colombia clinical study, treated by a holistic mental health team during the COVID-19 pandemic. The extent of use of mental health team services was explored considering different risk factors, and users and non-users of these services were compared. METHODS: Participants had free and optional access to psychology and psychiatry services, outside of the study protocol. Descriptive statistics was used to analyze the frequency of the mental health difficulties. A multivariable logistic regression model has been used to assess associations with using this program. RESULTS: 66 participants were treated by the Mental Health Team from March 1, 2020, to December 31, 2020. Before and after the start of the pandemic, the most common psychological problems were anxiety (36.4% before, 63.6% after) and depression (34.8% before, 37.9% after). 70% of users assisted by psychology and 81.6% of those assisted by psychiatry felt that the services were useful for them. Female sex, depression, and anxiety before the pandemic were positively associated with being assisted by either psychology or psychiatry, while the association with hyperlipidemia was negative. CONCLUSIONS: A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19.

Potential Neuroprotective Effects of Dietary Omega-3 Fatty Acids on Stress in Alzheimer's Disease.

BACKGROUND: A large number of individual potentially modifiable factors are associated with risk for Alzheimer's disease (AD). However, less is known about the interactions between the individual factors. METHODS: In order to begin to examine the relationship between a pair of factors, we performed a pilot study, surveying patients with AD and controls for stress exposure and dietary omega-3 fatty acid intake to explore their relationship for risk of AD. RESULTS: For individuals with the greatest stress exposure, omega-3 fatty acid intake was significantly greater in healthy controls than in AD patients. There was no difference among those with low stress exposure. CONCLUSIONS: These initial results begin to suggest that omega-3 fatty acids may mitigate AD risk in the setting of greater stress exposure. This will need to be examined with larger populations and other pairs of risk factors to better understand these important relationships. Examining how individual risk factors interact will ultimately be important for learning how to optimally decrease the risk of AD.

Tea intake or consumption and the risk of dementia: a meta-analysis of prospective cohort studies.

Purpose: Dementia affects as many as 130 million people, which presents a significant and growing medical burden globally. This meta-analysis aims to assess whether tea intake, tea consumption can reduce the risk of dementia, Alzheimer's disease (AD) and Vascular dementia (VD). Patients and methods: Cochrane Library, PubMed and Embase were searched for cohort studies from inception to November 1, 2022. The Newcastle Ottawa Quality Assessment Scale (NOS) was applied to evaluate the risk of bias of the included studies. We extracted the data as the relative risks (RRs) for the outcome of the interest, and conducted the meta-analysis utilizing the random effect model due to the certain heterogeneity. Sensitivity analysis were performed by moving one study at a time, Subgroup-analysis was carried out according to different ages and dementia types. And the funnel plots based on Egger's and Begger's regression tests were used to evaluate publication bias. All statistical analyses were performed using Stata statistical software version 14.0 and R studio version 4.2.0. Results: Seven prospective cohort studies covering 410,951 individuals, which were published from 2009 and 2022 were included in this meta-analysis. The methodological quality of these studies was relatively with five out of seven being of high quality and the remaining being of moderate. The pooling analysis shows that the relationship between tea intake or consumption is associated with a reduced risk of all-cause dementia (RR = 0.71, 95% CI [0.57-0.88], I2 = 79.0%, p < 0.01). Further, the subgroup-analysis revealed that tea intake or consumption is associated with a reduced risk of AD (RR = 0.88, 95% CI [0.79-0.99], I2 = 52.6%, p = 0.024) and VD (RR = 0.75, 95% CI [0.66-0.85], I = 0.00%, p < 0.001). Lastly, tea intake or consumption could reduce the risk of all-cause dementia to a greater degree among populations with less physical activity, older age, APOE carriers, and smokers. Conclusion: Our meta-analysis demonstrated that tea (green tea or black tea) intake or consumption is associated with a significant reduction in the risk of dementia, AD or VD. These findings provide evidence that tea intake or consumption should be recognized as an independent protective factor against the onset of dementia, AD or VD.

Espresso Coffee Mitigates the Aggregation and Condensation of Alzheimer's Associated Tau Protein.

Espresso coffee is among the most consumed beverages in the world. Recent studies report a protective activity of the coffee beverage against neurodegenerative disorders such as Alzheimer's disease. Alzheimer's disease belongs to a group of disorders, called tauopathies, which are characterized by the intraneuronal accumulation of the microtubule-associated protein tau in fibrillar aggregates. In this work, we characterized by NMR the molecular composition of the espresso coffee extract and identified its main components. We then demonstrated with in vitro and in cell experiments that the whole coffee extract, caffeine, and genistein have biological properties in preventing aggregation, condensation, and seeding activity of the repeat region of tau. We also identified a set of coffee compounds capable of binding to preformed tau fibrils. These results add insights into the neuroprotective potential of espresso coffee and suggest candidate molecular scaffolds for designing therapies targeting monomeric or fibrillized forms of tau.

Tenuifolin in the prevention of Alzheimer's disease-like phenotypes: Investigation of the mechanisms from the perspectives of calpain system, ferroptosis, and apoptosis.

Polygala tenuifolia was documented to calm the mind and promote wisdom. However, its underlying mechanisms are still unclear. This study aimed to investigate the mechanisms underlying the effects of tenuifolin (Ten) on Alzheimer's disease (AD)-like phenotypes. We first applied bioinformatics methods to screen the mechanisms of P. tenuifolia in the treatment of AD. Thereafter, the d-galactose combined with Aß1-42 (GCA) was applied to model AD-like behaviors and investigate the action mechanisms of Ten, one active component of P. tenuifolia. The data showed that P. tenuifolia actioned through multi-targets and multi-pathways, including regulation of synaptic plasticity, apoptosis, and calcium signaling, and so forth. Furthermore, in vitro experiments demonstrated that Ten prevented intracellular calcium overload, abnormal calpain system, and down-regulation of BDNF/TrkB signaling induced by GCA. Moreover, Ten suppressed oxidative stress and ferroptosis in HT-22 cells induced by GCA. Calpeptin and ferroptosis inhibitor prevented the decrease of cell viability induced by GCA. Interestingly, calpeptin did not interrupt GCA-induced ferroptosis in HT-22 cells but blocked the apoptosis. Animal experiments further demonstrated that Ten prevented GCA-induced memory impairment in mice and increased synaptic protein expression while reducing m-calpain expression. Ten prevents AD-like phenotypes through multiple signaling by inhibiting oxidative stress and ferroptosis, maintaining the stability of calpain system, and suppressing neuronal apoptosis.

Caffeine for Prevention of Alzheimer's Disease: Is the A2A Adenosine Receptor Its Target?

Alzheimer's disease (AD) is the most prevalent kind of dementia with roughly 135 million cases expected in the world by 2050. Unfortunately, current medications for the treatment of AD can only relieve symptoms but they do not act as disease-modifying agents that can stop the course of AD. Caffeine is one of the most widely used drugs in the world today, and a number of clinical studies suggest that drinking coffee may be good for health, especially in the fight against neurodegenerative conditions such as AD. Experimental works conducted "in vivo" and "in vitro" provide intriguing evidence that caffeine exerts its neuroprotective effects by antagonistically binding to A2A receptors (A2ARs), a subset of GPCRs that are triggered by the endogenous nucleoside adenosine. This review provides a summary of the scientific data supporting the critical role that A2ARs play in memory loss and cognitive decline, as well as the evidence supporting the protective benefits against neurodegeneration that may be attained by caffeine's antagonistic action on these receptors. They are a novel and fascinating target for regulating and enhancing synaptic activity, achieving symptomatic and potentially disease-modifying effects, and protecting against neurodegeneration.

Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer's Disease.

Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pE3Aß) is a highly pathogenic molecule with increased neurotoxicity and propensity for aggregation. In the brains of Alzheimer's Disease (AD) cases, pE3Aß represents a major constituent of the amyloid plaque. The data show that pE3Aß formation is increased at early pre-symptomatic disease stages, while tau phosphorylation and aggregation mostly occur at later stages of the disease. This suggests that pE3Aß accumulation may be an early event in the disease pathogenesis and can be prophylactically targeted to prevent the onset of AD. The vaccine (AV-1986R/A) was generated by chemically conjugating the pE3Aß3-11 fragment to our universal immunogenic vaccine platform MultiTEP, then formulated in AdvaxCpG adjuvant. AV-1986R/A showed high immunogenicity and selectivity, with endpoint titers in the range of 105-106 against pE3Aß and 103-104 against the full-sized peptide in the 5XFAD AD mouse model. The vaccination showed efficient clearance of the pathology, including non-pyroglutamate-modified plaques, from the mice brains. AV-1986R/A is a novel promising candidate for the immunoprevention of AD. It is the first late preclinical candidate which selectively targets a pathology-specific form of amyloid with minimal immunoreactivity against the full-size peptide. Successful translation into clinic may offer a new avenue for the prevention of AD via vaccination of cognitively unimpaired individuals at risk of disease.

Plants of the Genus Mahonia as a Potential Traditional Chinese Medicine for the Prevention and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), a prevalent multiple neurodegenerative disease, has gained attention, particularly in the aging population. However, presently available therapies merely focus on alleviating the symptoms of AD and fail to slow disease progression significantly. Traditional Chinese medicine (TCM) has been used to ameliorate symptoms or interfere with the pathogenesis of aging-associated diseases for many years based on disease-modifying in multiple pathological roles with multi-targets, multi-systems and multi-aspects. Mahonia species as a TCM present potential for anti-inflammatory activity, antioxidant activity, anti-acetylcholinesterase activity, and antiamyloid- beta activity that was briefly discussed in this review. They are regarded as promising drug candidates for AD therapy. The findings in this review support the use of Mahonia species as an alternative therapy source for treating AD.