Pros and Cons of APOE4 Homozygosity and Effects on Neuroplasticity, Malnutrition, and Infections in Early Life Adversity, Alzheimer's Disease, and Alzheimer's Prevention.

Fortea et al.'s. (2024) recent data analysis elegantly calls attention to familial late-onset Alzheimer's disease (AD) with APOE4 homozygosity. The article by Grant (2024) reviews the factors associated with AD, particularly the APOE genotype and lifestyle, and the broad implications for prevention, both for individuals with the lifestyles associated with living in resource-rich countries and for those enduring environmental adversity in poverty settings, including high exposure to enteric pathogens and precarious access to healthcare. Grant discusses the issue of APOE genotype and its implications for the benefits of lifestyle modifications. This review highlights that bearing APOE4 could constitute an evolutionary benefit in coping with heavy enteric infections and malnutrition early in life in the critical formative first two years of brain development. However, the critical issue may be that this genotype could be a health concern under shifts in lifestyle and unhealthy diets during aging, leading to severe cognitive impairments and increased risk of AD. This commentary supports the discussions of Grant and the benefits of improving lifestyle for decreasing the risks for AD while providing further understanding and modelling of the early life benefits of APOE4 amidst adversity. This attention to the pathophysiology of AD should help further elucidate these critical, newly appreciated pathogenic pathways for developing approaches to the prevention and management in the context of the APOE genetic variations associated with AD.

The Relationship between Diet, Depression, and Alzheimer's Disease: A Narrative Review.

PURPOSE OF REVIEW: This narrative review evaluates the role of diet in the relationship between depression and Alzheimer's disease (AD). RECENT FINDINGS: AD and depression are often comorbid, and depression appears to independently increase the future risk of AD. Evidence suggests diet influences the risk of both conditions directly and indirectly. Diet impacts neurochemical and biological processes that may affect the development and progression of depression and cognitive dysfunction. The dietary components offering the greatest protection against depression and AD are yet to be determined. Current evidence highlights the importance of polyphenolic compounds, folate, B vitamins, and polyunsaturated fatty acids, along with adherence to dietary patterns like the Mediterranean diet, which includes multiple beneficial dietary factors. SUMMARY: The investigation of dietary factors in the prevention of depression and AD is a comparatively young field of research. Comprehensive highly characterised longitudinal datasets and advanced analytical approaches are required to further examine the complex relationship between diet, depression, and AD. There is a critical need for more research in this area to develop effective preventive strategies aimed at maintaining mental and physical health with advancing age.

Metformin beyond type 2 diabetes: Emerging and potential new indications.

Metformin is best known as a foundational therapy for type 2 diabetes but is also used in other contexts in clinical medicine with a number of emerging and potential indications. Many of its beneficial effects may be mediated by modest effects on weight loss and insulin sensitivity, but it has multiple other known mechanisms of action. Current clinical uses beyond type 2 diabetes include: polycystic ovarian syndrome; diabetes in pregnancy/gestational diabetes; prevention of type 2 diabetes in prediabetes; and adjunct therapy in type 1 diabetes. As metformin has been in clinical use for almost 70 years, much of the underpinning evidence for its use in these conditions is, by definition, based on trials conducted before the advent of contemporary evidence-based medicine. As a result, some of the above-established uses are 'off-label' in many regulatory territories and their use varies accordingly in different countries. Going forward, several current 'repurposing' investigational uses of metformin are also being investigated: prevention of cancer (including in Li Fraumeni syndrome), renal protection, Alzheimer's disease, metabolic dysfunction-associated steatotic liver disease and promotion of healthy ageing. Despite the longevity of metformin and its important current roles beyond type 2 diabetes in clinical medicine, it has further potential and much research is ongoing.

Nutrition guidance within a multimodal intervention improves diet quality in prodromal Alzheimer's disease: Multimodal Preventive Trial for Alzheimer's Disease (MIND-ADmini).

BACKGROUND: Multimodal lifestyle interventions can benefit overall health, including cognition, in populations at-risk for dementia. However, little is known about the effect of lifestyle interventions in patients with prodromal Alzheimer's disease (AD). Even less is known about dietary intake and adherence to dietary recommendations within this population making it difficult to design tailored interventions for them. METHOD: A 6-month MIND-ADmini pilot randomized controlled trial (RCT) was conducted among 93 participants with prodromal AD in Sweden, Finland, Germany, and France. Three arms were included in the RCT: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management, and social stimulation); 2) multimodal lifestyle intervention + medical food product; and 3) regular health advice (control group). Adherence to dietary advice was assessed with a brief food intake questionnaire by using the Healthy Diet Index (HDI) and Mediterranean Diet Adherence Screener (MEDAS). The intake of macro- and micronutrients were analyzed on a subsample using 3-day food records. RESULTS: The dietary quality in the intervention groups, pooled together, improved compared to that of the control group at the end of the study, as measured with by HDI (p = 0.026) and MEDAS (p = 0.008). The lifestyle-only group improved significantly more in MEDAS (p = 0.046) and almost significantly in HDI (p = 0.052) compared to the control group, while the lifestyle + medical food group improved in both HDI (p = 0.042) and MEDAS (p = 0.007) during the study. There were no changes in macro- or micronutrient intake for the intervention groups at follow-up; however, the intakes in the control group declined in several vitamins and minerals when adjusted for energy intake. CONCLUSION: These results suggest that dietary intervention as part of multimodal lifestyle interventions is feasible and results in improved dietary quality in a population with prodromal AD. Nutrient intakes remained unchanged in the intervention groups while the control group showed a decreasing nutrient density. TRIAL REGISTRATION: ClinicalTrials.gov NCT03249688, 2017-07-08.

Geroscience and the Fight Against Alzheimer's Disease: Between Myth and Reality.

 Aging is associated with a gradual decline in cellular stability, leading to a decrease in overall health. In the brain, this process is closely linked with an increased risk of neurodegenerative diseases, including Alzheimer's disease. Understanding the mechanisms of brain aging is crucial for developing strategies aimed at enhancing both lifespan and health span. Recent advancements in geroscience, the study of the relationship between aging and age-related diseases, have begun to redefine our understanding of Alzheimer's disease, guiding the development of preventive medical strategies that target the aging process itself rather than merely addressing the symptomatic manifestations of the disease.

Delaying Brain Aging or Decreasing Tau Levels as Strategies to Prevent Alzheimer's Disease: In Memoriam of Mark A. Smith.

Aging is the main risk for neurodegenerative disorders like Alzheimer's disease. In this short review, I will comment on how delaying brain aging through the addition of Yamanaka Factors or small compounds that bind to the folate receptor alpha, which promote the expression of the Yamanaka Factors or by the decrease tau levels in brain cells from older subjects could serve as strategies to prevent Alzheimer's disease.

Postbiotics as Molecules Targeting Cellular Events of Aging Brain-The Role in Pathogenesis, Prophylaxis and Treatment of Neurodegenerative Diseases.

Aging is the most prominent risk factor for neurodegeneration occurrence. The most common neurodegenerative diseases (NDs), Alzheimer's (AD) and Parkinson's (PD) diseases, are characterized by the incidence of proteinopathy, abnormal activation of glial cells, oxidative stress, neuroinflammation, impaired autophagy and cellular senescence excessive for the patient's age. Moreover, mitochondrial disfunction, epigenetic alterations and neurogenesis inhibition, together with increased blood-brain barrier permeability and gut dysbiosis, have been linked to ND pathogenesis. Since NDs still lack curative treatment, recent research has sought therapeutic options in restoring gut microbiota and supplementing probiotic bacteria-derived metabolites with beneficial action to the host-so called postbiotics. The current review focuses on literature explaining cellular mechanisms involved in ND pathogenesis and research addressing the impact that postbiotics as a whole mixture and particular metabolites, such as short-chain fatty acids (SCFAs), lactate, polyamines, polyphenols, tryptophan metabolites, exopolysaccharides and bacterial extracellular vesicles, have on the ageing-associated processes underlying ND occurrence. The review also discusses the issue of implementing postbiotics into ND prophylaxis and therapy, depicting them as compounds addressing senescence-triggered dysfunctions that are worth translating from bench to pharmaceutical market in response to "silver consumers" demands.

Pro-inflammatory protein S100A9 targeted by a natural molecule to prevent neurodegeneration onset.

Accumulation of the pro-inflammatory protein S100A9 has been implicated in neuroinflammatory cascades in neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). S100A9 co-aggregates with other proteins such as α-synuclein in PD and Aß in AD, contributing to amyloid plaque formation and neurotoxicity. The amyloidogenic nature of this protein and its role in chronic neuroinflammation suggest that it may play a key role in the pathophysiology of these diseases. Research into molecules targeting S100A9 could be a potential therapeutic strategy to prevent its amyloidogenic self-assembly and to attenuate the neuroinflammatory response in affected brain tissue. This work suggests that bioactive natural molecules, such as those found in the Mediterranean diet, may have the potential to alleviate neuroinflammation associated with the accumulation of proteins such as S100A9 in neurodegenerative diseases. A major component of extra virgin olive oil (EVOO), hydroxytyrosol (HT), with its ability to interact with and modulate S100A9 amyloid self-assembly and expression, offers a compelling approach for the development of novel and effective interventions for the prevention and treatment of ND. The findings highlight the importance of exploring natural compounds, such as HT, as potential therapeutic options for these complex and challenging neurological conditions.

Tea, coffee, and caffeine intake and risk of dementia and Alzheimer's disease: a systematic review and meta-analysis of cohort studies.

Background: Limited and conflicting evidence exists for the associations between tea, coffee, and caffeine intake and risk of dementia and Alzheimer's disease (AD). This meta-analysis aimed to elucidate these associations and quantify potential dose-response relationships. Methods: PubMed, EMBASE, and Web of Science were searched up to 11 June 2024 for cohort studies. Random effects models were used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs), with the dose-response relationship assessed using restricted cubic splines. The Grading of Recommendations Assessment Development and Evaluation (GRADE) tool was used to assess the risk of bias. Results: Our analysis encompassed 38 cohorts, totalling 751 824 participants and 13 017 dementia and 17 341 AD cases. For dementia, compared with the lowest category, the pooled RRs (95% CI) in the highest category of tea, coffee, and caffeine were 0.84 (0.74-0.96, n = 6), 0.95 (0.87-1.02, n = 9), and 0.94 (0.70-1.25, n = 5), with all rated as low certainty in GRADE. For AD, the pooled RRs (95% CI) in the highest category of tea, coffee, and caffeine compared to the lowest category were 0.93 (0.87-1.00, n = 6), 1.01 (0.90-1.12, n = 10), and 1.34 (1.04-1.74, n = 2), with certainty ratings of low, low, and very low, respectively. Dose-response analysis indicated a non-linear relationship between coffee intake (Poverall = 0.04 and Pnonlinear = 0.01) and dementia risk, showing the protective association of risk of dementia with 1 to 3 cups per day of coffee intake. There is a linear association between tea intake and risk of dementia, with a significantly decreased risk of dementia for each 1 cup per day increase in tea consumption (0.96, 95% CI 0.94-0.99, Poverall = 0.01 and Pnonlinear = 0.68). Conclusion: Increased tea consumption was associated with a decreased risk of dementia and AD, and a non-linear relationship was found between coffee and dementia, supporting public health recommendations for dementia prevention.

Optimizing the Implementation of a Lifestyle Dementia Prevention Intervention for Older Patients in an Academic Healthcare System.

Background: Interventions that promote healthy lifestyles are critical for the prevention of Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). However, knowledge of the best practices for implementing AD/ADRD prevention in healthcare settings remains limited. Objective: We aimed to qualitatively identify barriers and facilitators to implementing a clinical trial of a novel lifestyle intervention (My Healthy Brain) in our medical center for older patients with subjective cognitive decline who are at-risk for AD/ADRD. Methods: We conducted focus groups with 26 healthcare professionals (e.g., physicians, psychology, nursing) from 5 clinics that treat older patients (e.g., memory care, psychiatry). Our qualitative analysis integrated two implementation frameworks to systematically capture barriers and facilitators to AD/ADRD prevention (Consolidated Framework for Implementation Science Research) that impact implementation outcomes of acceptability, appropriateness, and feasibility (Proctor's framework). Results: We found widespread support for an RCT of My Healthy Brain and AD/ADRD prevention. Participants identified barriers related to patients (stigma, technological skills), providers (dismissiveness of "worried well," doubting capacity for behavior change), clinics (limited time and resources), and the larger healthcare system (underemphasis on prevention). Implementation strategies guided by Expert Recommendations for Implementing Change (ERIC) included: developing tailored materials, training staff, obtaining buy-in from leadership, addressing stigmatized language and practices, identifying "champions," and integrating with workflows and resources. Conclusions: The results will inform our recruitment, enrollment, and retention procedures to implement the first randomized clinical trial of My Healthy Brain. Our study provides a blueprint for addressing multi-level barriers to the implementation of AD/ADRD prevention for older patients in medical settings.

Caloric restriction leading to attenuation of experimental Alzheimer's disease results from alterations in gut microbiome.

BACKGROUND: Caloric restriction (CR) might be effective for alleviating/preventing Alzheimer's disease (AD), but the biological mechanisms remain unclear. In the current study, we explored whether CR caused an alteration of gut microbiome and resulted in the attenuation of cognitive impairment of AD animal model. METHODS: Thirty-week-old male APP/PS1 transgenic mice were used as AD models (AD mouse). CR was achieved by 30% reduction of daily free feeding (ad libitum, AL) amount. The mice were fed with CR protocol or AL protocol for six consecutive weeks. RESULTS: We found that with CR treatment, AD mice showed improved ability of learning and spatial memory, and lower levels of Aß40, Aß42, IL-1ß, TNF-α, and ROS in the brain. By sequencing 16S rDNA, we found that CR treatment resulted in significant diversity in composition and abundance of gut flora. At the phylum level, Deferribacteres (0.04%), Patescibacteria (0.14%), Tenericutes (0.03%), and Verrucomicrobia (0.5%) were significantly decreased in CR-treated AD mice; at the genus level, Dubosiella (10.04%), Faecalibaculum (0.04%), and Coriobacteriaceae UCG-002 (0.01%) were significantly increased in CR-treated AD mice by comparing with AL diet. CONCLUSIONS: Our results demonstrate that the attenuation of AD following CR treatment in APP/PS1 mice may result from alterations in the gut microbiome. Thus, gut flora could be a new target for AD prevention and therapy.

Vegan and Vegetarian Soups Are Excellent Sources of Cholinesterase Inhibitors.

BACKGROUND: The cholinesterase theory stands as the most popular worldwide therapy for Alzheimer's disease (AD). Given the absence of a cure for AD, a plant-based diet has been repeatedly shown as positive in the prevention of AD, including exploring ready-made products in stores and the development of new functional foods. GOAL: This study compared the anti-acetyl- and butyrylcholinesterase activity of thirty-two Polish market soups and five newly formulated soups intended to be functional. Additionally, the research aimed to assess the significance of animal content, distinguishing between vegan and vegetarian options, in cholinesterase inhibition. MATERIALS AND METHODS: The anticholinesterase activity was investigated using a spectrophotometric method, and the inhibitory activity was expressed as % inhibition of the enzyme. The study categorized soups into three groups based on ingredients: those containing animal-derived components, vegetarian soups and vegan soups. RESULTS: Soups exhibited varying levels of activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), indicating differences in their compositions. Composition appeared to be the primary factor influencing anticholinesterase activity, as soups within each group showed significant variability in activity levels. While some commercial soups demonstrated notable anticholinesterase activity, they did not surpass the effectiveness of the optimized soups developed in the laboratory. Certain ingredients were associated with higher anticholinesterase activity, such as coconut, potato, onion, garlic, parsley and various spices and herbs. CONCLUSIONS: Vegetarian and vegan soups exhibited comparable or even superior anticholinesterase activity compared to animal-derived soups, highlighting the importance of plant-based ingredients. The study underscores the need for further research to explore the mechanisms underlying the anticholinesterase activity of soups, including the impact of ingredient combinations and processing methods.

Resistance Exercise Training as a New Trend in Alzheimer's Disease Research: From Molecular Mechanisms to Prevention.

Alzheimer's disease is a pathology characterized by the progressive loss of neuronal connections, which leads to gray matter atrophy in the brain. Alzheimer's disease is the most prevalent type of dementia and has been classified into two types, early onset, which has been associated with genetic factors, and late onset, which has been associated with environmental factors. One of the greatest challenges regarding Alzheimer's disease is the high economic cost involved, which is why the number of studies aimed at prevention and treatment have increased. One possible approach is the use of resistance exercise training, given that it has been shown to have neuroprotective effects associated with Alzheimer's disease, such as increasing cortical and hippocampal volume, improving neuroplasticity, and promoting cognitive function throughout the life cycle. However, how resistance exercise training specifically prevents or ameliorates Alzheimer's disease has not been fully characterized. Therefore, the aim of this review was to identify the molecular basis by which resistance exercise training could prevent or treat Alzheimer's disease.

Quinic acid alleviates high-fat diet-induced neuroinflammation by inhibiting DR3/IKK/NF-κB signaling via gut microbial tryptophan metabolites.

With the increasing of aging population and the consumption of high-fat diets (HFD), the incidence of Alzheimer's disease (AD) has skyrocketed. Natural antioxidants show promising potential in the prevention of AD, as oxidative stress and neuroinflammation are two hallmarks of AD pathogenesis. Here, we showed that quinic acid (QA), a polyphenol derived from millet, significantly decreased HFD-induced brain oxidative stress and neuroinflammation and the levels of Aß and p-Tau. Examination of gut microbiota suggested the improvement of the composition of gut microbiota in HFD mice after QA treatment. Metabolomic analysis showed significant increase of gut microbial tryptophan metabolites indole-3-acetic acid (IAA) and kynurenic acid (KYNA) by QA. In addition, IAA and KYNA showed negative correlation with pro-inflammatory factors and AD indicators. Further experiments on HFD mice proved that IAA and KYNA could reproduce the effects of QA that suppress brain oxidative stress and inflammation and decrease the levels of of Aß and p-Tau. Transcriptomics analysis of brain after IAA administration revealed the inhibition of DR3/IKK/NF-κB signaling pathway by IAA. In conclusion, this study demonstrated that QA could counteract HFD-induced brain oxidative stress and neuroinflammation by regulating inflammatory DR3/IKK/NF-κB signaling pathway via gut microbial tryptophan metabolites.

Prediction of the 3D conformation of a small peptide vaccine targeting Aß42 oligomers.

The original etiology of Alzheimer's disease (AD) is the deposition of amyloid-beta (Aß) proteins, which starts from the aggregation of the Aß oligomers. The optimal therapeutic strategy targeting Aß oligomer aggregation is the development of AD vaccines. Despite the fact that positive progress has been made for experimental attempts at AD vaccines, the physicochemical and even structural properties of these AD vaccines remain unclear. In this study, through immunoinformatic and molecular dynamics (MD) simulations, we first designed and simulated an alternative of vaccine TAPAS and found that the structure of the alternative can reproduce the 3D conformation of TAPAS determined experimentally. Meanwhile, immunoinformatic methods were used to analyze the physicochemical properties of TAPAS, including immunogenicity, antigenicity, thermal stability, and solubility, which confirm well the efficacy and safety of the vaccine, and validate the scheme reliability of immunoinformatic and MD simulations in designing and simulating the TAPAS vaccine. Using the same scheme, we predicted the 3D conformation of the optimized ACI-24 peptide vaccine, an Aß peptide with the first 15 residues of Aß42 (Aß1-15). The vaccine was verified once to be effective against both full-length Aß1-42 and truncated Aß4-42 aggregates, but an experimental 3D structure was absent. We have also explored the immune mechanism of the vaccine at the molecular level and found that the optimized ACI-24 and its analogues can block the growth of either full-length Aß1-42 or truncated Aß4-42 pentamer by contacting the hydrophobic residues within the N-terminus and ß1 region on the contact surface of either pentamer. Additionally, residues (D1, D7, S8, H13, and Q15) were identified as the key residues of the vaccine to contact either of the two Aß oligomers. This work provides a feasible implementation scheme of immunoinformatic and MD simulations for the development of AD small peptide vaccines, validating the power of the scheme as a parallel tool to the experimental approaches and injecting molecular-level information into the understanding and design of anti-AD vaccines.

Network pharmacology study on fermented soybeans for the prevention of Alzheimer's disease in older individuals.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the disruption of synaptic communication among millions of neurons. Recent research has highlighted the potential therapeutic effectiveness of natural polyphenolic compounds in addressing AD. Soybeans are abundant in polyphenols, and their polyphenolic composition undergoes significant alteration through fermentation by Eurotium cristatum. Through comprehensive database searches, we identified active components within fermented soybean polyphenols and genes associated with AD. Subsequently, we utilized Venn diagrams to analyze the overlap between AD-related genes and these components. Furthermore, we visualized the network between intersecting targets and proteins using Cytoscape software. The anti-AD effects of soybeans were further explored through comprehensive analysis, including protein-protein interaction analysis, pathway enrichment analysis, and molecular docking studies. Our investigation unveiled 6-hydroxydaidzein as a major component of fermented soybean polyphenols, shedding light on its potential therapeutic significance in combating AD. The intersection between target proteins of fermented soybeans and disease-related targets in AD comprised 34 genes. Protein-protein interaction analysis highlighted key potential targets, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glycogen synthase kinase 3 beta (GSK3B), amyloid precursor protein (APP), cyclin-dependent kinase 5 (CDK5), and beta-site APP cleaving enzyme 1 (BACE1). Molecular docking results demonstrated a robust binding effect between major components from fermented soybeans and the aforesaid key targets implicated in AD treatment. These findings suggest that fermented soybeans demonstrate a degree of efficacy and present promising prospects in the prevention of AD.

New Value of Acorus tatarinowii/gramineus Leaves as a Dietary Source for Dementia Prevention.

The rhizomes of Acorus tatarinowii Schott and Acorus gramineus Solander are widely used for treating amnesia in traditional Chinese medicine. In contrast, their leaves are usually discarded without their medicinal properties being known. Here, we found that the hot water extract of leaves improved cognition and tau pathology in model mice of frontotemporal dementia, similar to or even better than that of rhizomes. To explore the optimal method of processing, we made three preparations from dried leaves: hot water extract, extraction residue, and non-extracted simple crush powder. Among them, the simple crush powder had the strongest effect on tauopathy in mice. The crush powder also ameliorated Aß and α-synuclein pathologies and restored cognition in mouse models of Alzheimer's disease and dementia with Lewy bodies. These findings suggest the potential of Acorus tatarinowii/gramineus leaves as a dietary source for dementia prevention and reveal that simple crushing is a better way to maximize their efficacy.

GlyT1 Inhibition by NFPS Promotes Neuroprotection in Amyloid-ß-Induced Alzheimer's Disease Animal Model.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-ß, leading to N-methyl-D-aspartate (NMDA) receptor-dependent synaptic depression, spine elimination, and memory deficits. Glycine transporter type 1 (GlyT1) modulates glutamatergic neurotransmission via NMDA receptors (NMDAR), presenting a potential alternative therapeutic approach for AD. This study investigates the neuroprotective potential of GlyT1 inhibition in an amyloid-ß-induced AD mouse model. C57BL/6 mice were treated with N-[3-([1,1-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine (NFPS), a GlyT1 inhibitor, 24 h prior to intrahippocampal injection of amyloid-ß. NFPS pretreatment prevented amyloid-ß-induced cognitive deficits in short-term and long-term memory, evidenced by novel object recognition and spatial memory tasks. Moreover, NFPS pretreatment curbed microglial activation, astrocytic reactivity, and subsequent neuronal damage from amyloid-ß injection. An extensive label-free quantitative UPLC-MSE proteomic analysis was performed on the hippocampi of mice treated with NFPS. In proteomics, KEGG enrichment analysis revealed increased in dopaminergic synapse, purine-containing compound biosynthetic process and long-term potentiation, and a reduction in Glucose catabolic process and glycolytic process pathways. The western blot analysis confirmed that NFPS treatment elevated BDNF levels, correlating with enhanced TRKB phosphorylation and mTOR activation. Moreover, NFPS treatment reduced the GluN2B expression after 6 h, which was associated with an increase on CaMKIV and CREB phosphorylation. Collectively, these findings demonstrate that GlyT1 inhibition by NFPS activates diverse neuroprotective pathways, enhancing long-term potentiation signaling and countering amyloid-ß-induced hippocampal damage.

hTERT Peptide Fragment GV1001 Prevents the Development of Porphyromonas gingivalis-Induced Periodontal Disease and Systemic Disorders in ApoE-Deficient Mice.

GV1001, an anticancer vaccine, exhibits other biological functions, including anti-inflammatory and antioxidant activity. It also suppresses the development of ligature-induced periodontitis in mice. Porphyromonas gingivalis (Pg), a major human oral bacterium implicated in the development of periodontitis, is associated with various systemic disorders, such as atherosclerosis and Alzheimer's disease (AD). This study aimed to explore the protective effects of GV1001 against Pg-induced periodontal disease, atherosclerosis, and AD-like conditions in Apolipoprotein (ApoE)-deficient mice. GV1001 effectively mitigated the development of Pg-induced periodontal disease, atherosclerosis, and AD-like conditions by counteracting Pg-induced local and systemic inflammation, partly by inhibiting the accumulation of Pg DNA aggregates, Pg lipopolysaccharides (LPS), and gingipains in the gingival tissue, arterial wall, and brain. GV1001 attenuated the development of atherosclerosis by inhibiting vascular inflammation, lipid deposition in the arterial wall, endothelial to mesenchymal cell transition (EndMT), the expression of Cluster of Differentiation 47 (CD47) from arterial smooth muscle cells, and the formation of foam cells in mice with Pg-induced periodontal disease. GV1001 also suppressed the accumulation of AD biomarkers in the brains of mice with periodontal disease. Overall, these findings suggest that GV1001 holds promise as a preventive agent in the development of atherosclerosis and AD-like conditions associated with periodontal disease.