Beta Amyloid Peptide: Research Paper : Metabolic reprogramming rejuvenates aged myeloid cells restoring cognition

Metabolic reprogramming rejuvenates aged myeloid cells restoring cognition

Abstract

Inflammaging is associated with aging-associated cognitive loss and neurodegeneration. Chronic NSAID use has been reported to reduce the incidence of Alzheimer's Disease (AD), presumably by inhibiting inflammation, although NSAIDs appear to not be good candidates for anti-AD therapeutics given disappointing clinical trial results. Prostaglandin E2 (PGE2) acts downstream of NSAID target COX-2, a cyclooxygenase, to activate several G-protein coupled receptors (GPCR) including EP2, which is now reported to reduce glycolysis and oxidative phosphorylation during aging by increasing glycogen synthesis and polarizing myeloid cells toward the M1 pro-inflammatory phenotype. Inhibiting EP2 using small molecule drugs, polarizes macrophages toward the anti-inflammatory phenotype, restores youthful metabolism and mitochondrial morphology as well as youthful hippocampus-based memory capability. EP2 may be a better target than cyclooxygenases for the development of drugs that improve age-associated mild cognitive impairment and possibly even for the development of drugs to treat dementias.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33487125/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Natural Marine and Terrestrial Compounds as Modulators of Matrix Metalloproteinases-2 (MMP-2) and MMP-9 in Alzheimer's Disease

Natural Marine and Terrestrial Compounds as Modulators of Matrix Metalloproteinases-2 (MMP-2) and MMP-9 in Alzheimer's Disease

Abstract

Several studies have reported neuroprotective effects by natural products. A wide range of natural compounds have been investigated, and some of these may play a beneficial role in Alzheimer's disease (AD) progression. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, have been implicated in AD. In particular, MMP-2 and MMP-9 are able to trigger several neuroinflammatory and neurodegenerative pathways. In this review, we summarize and discuss existing literature on natural marine and terrestrial compounds, as well as their ability to modulate MMP-2 and MMP-9, and we evaluate their potential as therapeutic compounds for neurodegenerative and neuroinflammatory diseases, with a focus on Alzheimer's disease.

Keywords: AD; Alzheimer's disease; MMP-2; MMP-9; marine compounds; natural compounds; neurodegeneration; neuroinflammation; nutraceuticals; terrestrial compounds.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33498927/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Screening of Synthetic Isoxazolone Derivative Role in Alzheimer's Disease: Computational and Pharmacological Approach

Screening of Synthetic Isoxazolone Derivative Role in Alzheimer's Disease: Computational and Pharmacological Approach

Abstract

Alzheimer's disease (AD) is age-dependent neurological disorder with progressive loss of cognition and memory. This multifactorial disease is characterized by intracellular neurofibrillary tangles, beta amyloid plaques, neuroinflammation, and increased oxidative stress. The increased cellular manifestations of these markers play a critical role in neurodegeneration and pathogenesis of AD. Therefore, reducing neurodegeneration by decreasing one or more of these markers may provide a potential therapeutic roadmap for the treatment of AD. AD causes a devastating loss of cognition with no conclusive and effective treatment. Many synthetic compound containing isoxazolone nucleus have been reported as neuroprotective agents. The aim of this study was to explore the anti-Alzheimer's potential of a newly synthesized 3,4,5-trimethoxy isoxazolone derivative (TMI) that attenuated the beta amyloid (Aβ1-42) and tau protein levels in streptozotocin (STZ) induced Alzheimer's disease mouse model. Molecular analysis revealed increased beta amyloid (Aβ1-42) protein levels, increased tau protein levels, increased cellular oxidative stress and reduced antioxidant enzymes in STZ exposed mice brains. Furthermore, ELISA and PCR were used to validate the expression of Aβ1-42. Pre-treatment with TMI significantly improved the memory and cognitive behavior along with ameliorated levels of Aβ1-42 proteins. TMI treated mice further showed marked increase in GSH, CAT, SOD levels while decreased levels of acetylcholinesterase inhibitors (AChEI's) and MDA intermediate. The multidimensional nature of isoxazolone derivatives and its versatile affinity towards various targets highpoint its multistep targeting nature. These results indicated the neuroprotective potential of TMI which may be considered for the treatment of neurodegenerative disease specifically in AD.

Keywords: AChEI's; Antioxidant; Beta amyloid; Hippocampus; Isoxazolones; Oxidative stress; Streptozotocin.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33486698/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Astrocyte subtype-specific approach to Alzheimer's disease treatment

Astrocyte subtype-specific approach to Alzheimer's disease treatment

Abstract

Astrocytes respond to any pathological condition in the central nervous system (CNS) including Alzheimer's disease (AD), and this response is called astrocyte reactivity. Astrocyte reaction to a CNS insult is a highly heterogeneous phenomenon in which the astrocytes undergo a set of morphological, molecular and functional changes with a characteristic secretome profile. Such astrocytes are termed as 'reactive astrocytes'. Controversies regarding the reactive astrocytes abound. Recently, a continuum of reactive astrocyte profiles with distinct transcriptional states has been identified. Among them, disease-associated astrocytes (DAA) were uniquely present in AD mice and expressed a signature set of genes implicated in complement cascade, endocytosis and aging. Earlier, two stimulus-specific reactive astrocyte subtypes with their unique transcriptomic signatures were identified using mouse models of neuroinflammation and ischemia and termed as A1 astrocytes (detrimental) and A2 astrocytes (beneficial) respectively. Interestingly, although most of the A1 signature genes were also detected in DAA, as opposed to A2 astrocyte signatures, some of the A1 specific genes were expressed in other astrocyte subtypes, indicating that these nomenclature-based signatures are not very specific. In this review, we elaborate the disparate functions and cytokine profiles of reactive astrocyte subtypes in AD and tried to distinguish them by designating neurotoxic astrocytes as A1-like and neuroprotective ones as A2-like without directly referring to the A1/A2 original nomenclature. We have also focused on the dual nature from a functional perspective of some cytokines depending on AD-stage, highlighting a number of them as major candidates in AD therapy. Therefore, we suggest that promoting subtype-specific beneficial roles, inhibiting subtype-specific detrimental roles or targeting subtype-specific cytokines constitute a novel therapeutic approach to AD treatment.

Keywords: Alzheimer's disease; Astrocyte reactivity; Astrocyte subtype; Central nervous system; Cytokine; Reactive astrocyte.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33503465/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Targeting the CB 2 receptor and other endocannabinoid elements to delay disease progression in amyotrophic lateral sclerosis

Targeting the CB 2 receptor and other endocannabinoid elements to delay disease progression in amyotrophic lateral sclerosis

Abstract

Cannabinoids form a singular group of plant-derived compounds, endogenous lipids and synthetic derivatives with multiple therapeutic effects exerted by targeting different elements of the so-called endocannabinoid system. One of their therapeutic applications is the preservation of neuronal integrity exerted by attenuating the multiple neurotoxic events that kill neurons in neurodegenerative disorders. In this review, we will address the potential of cannabinoids as neuroprotective agents in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder characterized by muscle denervation, atrophy and paralysis, and progressive deterioration in upper and/or lower motor neurons. The emphasis will be paid on the cannabinoid receptor type-2 (CB2 ), whose activation limits glial reactivity, but the potential of additional endocannabinoid-related targets will be also addressed. The evidence accumulated so far at the preclinical level supports the need to move soon towards the patients and initiate clinical trials to confirm the potential of cannabinoid-based medicines as disease modifiers in ALS.

Keywords: CB2 receptors; Cannabinoids; amyotrophic lateral sclerosis; endocannabinoid signaling system; neurodegeneration; neuroprotection.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33486755/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Sex-Dependent End-of-Life Mental and Vascular Scenarios for Compensatory Mechanisms in Mice with Normal and AD-Neurodegenerative Aging

Sex-Dependent End-of-Life Mental and Vascular Scenarios for Compensatory Mechanisms in Mice with Normal and AD-Neurodegenerative Aging

Abstract

Life expectancy decreases with aging, with cardiovascular, mental health, and neurodegenerative disorders strongly contributing to the total disability-adjusted life years. Interestingly, the morbidity/mortality paradox points to females having a worse healthy life expectancy. Since bidirectional interactions between cardiovascular and Alzheimer's diseases (AD) have been reported, the study of this emerging field is promising. In the present work, we further explored the cardiovascular-brain interactions in mice survivors of two cohorts of non-transgenic and 3xTg-AD mice, including both sexes, to investigate the frailty/survival through their life span. Survival, monitored from birth, showed exceptionally worse mortality rates in females than males, independently of the genotype. This mortality selection provided a "survivors" cohort that could unveil brain-cardiovascular interaction mechanisms relevant for normal and neurodegenerative aging processes restricted to long-lived animals. The results show sex-dependent distinct physical (worse in 3xTg-AD males), neuropsychiatric-like and cognitive phenotypes (worse in 3xTg-AD females), and hypothalamic-pituitary-adrenal (HPA) axis activation (higher in females), with higher cerebral blood flow and improved cardiovascular phenotype in 3xTg-AD female mice survivors. The present study provides an experimental scenario to study the suggested potential compensatory hemodynamic mechanisms in end-of-life dementia, which is sex-dependent and can be a target for pharmacological and non-pharmacological interventions.

Keywords: angiogenesis; anxiety; arterial properties; cerebral blood flow; cognition; gender medicine; healthy life expectancy (HALE); morbidity/mortality paradox; neurodegenerative disorders; systolic blood pressure.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33498895/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Global and Regional Changes in Perivascular Space in Idiopathic and Familial Parkinson's Disease

Global and Regional Changes in Perivascular Space in Idiopathic and Familial Parkinson's Disease

Abstract

Background: The glymphatic system, including the perivascular space (PVS), plays a critical role in brain homeostasis. Although mounting evidence from Alzheimer's disease has supported the potential role of PVS in neurodegenerative disorders, its contribution in Parkinson's disease (PD) has not been fully elucidated. Although idiopathic (IPD) and familial PD (FPD) share similar pathophysiology in terms of protein aggregation, the differential impact of PVS on PD subtypes remains unknown. Our objective was to examine the differences in PVS volume fraction in IPD and FPD compared to healthy controls (HCs) and nonmanifest carriers (NMCs).

Methods: A total of 470 individuals were analyzed from the Parkinson's Progression Markers Initiative database, including (1) IPD (n = 179), (2) FPD (LRRK2 [leucine-rich repeat kinase 2], glucocerebrosidase, or α-synuclein) (n = 67), (3) NMC (n = 101), and (4) HCs (n = 84). Total PVS volume fraction (%) was compared using parcellation and quantitation within greater white matter volume at global and regional levels in all cortical and subcortical white matter.

Results: There was a significant increase in global and regional PVS volume fraction in PD versus non-PD, particularly in FPD versus NMC and LRRK2 FPD versus NMC. Regionally, FPD and NMC differed in the medial orbitofrontal region, as did LRRK2 FPD versus NMC. Non-PD and PD differed in the medial orbitofrontal region and the banks of the superior temporal regions. IPD and FPD differed in the cuneus and lateral occipital regions.

Conclusions: Our findings support the role of PVS in PD and highlight a potentially significant contribution of PVS to the pathophysiology of FPD, particularly LRRK2. © 2021 International Parkinson and Movement Disorder Society.

Keywords: imaging; perivascular spaces; α-synuclein; leucine-rich repeat kinase 2; glucocerebrosidase.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33470460/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Classification of Mild Cognitive Impairment with Multimodal Data using both Labeled and Unlabeled Samples

Classification of Mild Cognitive Impairment with Multimodal Data using both Labeled and Unlabeled Samples

Abstract

Mild Cognitive Impairment (MCI) is a preclinical stage of Alzheimer's Disease (AD) and is clinical heterogeneity. The classification of MCI is crucial for the early diagnosis and treatment of AD. In this study, we investigated the potential of using both labeled and unlabeled samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to classify MCI through the multimodal co-training method. We utilized both structural magnetic resonance imaging (sMRI) data and genotype data of 364 MCI samples including 228 labeled and 136 unlabeled MCI samples from the ADNI-1 cohort. First, the selected quantitative trait (QT) features from sMRI data and SNP features from genotype data were used to build two initial classifiers on 228 labeled MCI samples. Then, the co-training method was implemented to obtain new labeled samples from 136 unlabeled MCI samples. Finally, the random forest algorithm was used to obtain a combined classifier to classify MCI patients in the independent ADNI-2 dataset. The experimental results showed that our proposed framework obtains an accuracy of 85.50% and an AUC of 0.825 for MCI classification, respectively, which showed that the combined utilization of sMRI and SNP data through the co-training method could significantly improve the performances of MCI classification.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33471765/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Relationship of Porphyromonas gingivalis and Alzheimer's disease: a systematic review of pre-clinical studies

Relationship of Porphyromonas gingivalis and Alzheimer's disease: a systematic review of pre-clinical studies

Abstract

Objectives: This study aimed to analyze the following PICO question: Are animals infected with Porphyromonas gingivalis (P. gingivalis) or bacterial lipopolysaccharide (Pg-LPS) more affected by neurodegeneration, similar to the pathogenesis generated by Alzheimer's disease (AD), compared with non-infected animals?

Methods: Databases PubMed, Lilacs, SciELO, Science Direct, Scopus, Web of Science, and Cochrane were searched for pre-clinical in vivo studies in which mice were infected with P. gingivalis or received Pg-LPS, in order to assess the brain tissue and cognitive impairment. No limit for date or publication language was imposed and this study was registered at the International Prospective Register of Systematic Reviews (PROSPERO), with nine articles included. Syrcle's protocol was used to evaluate bias in the selected studies.

Results: Nine articles were included. Infection by P. gingivalis or the administration of Pg-LPS increased the production of the inflammatory mediators, TNF-α (tumor necrosis factor-alpha), IL-6 (interleukin-6), and IL-1β (interleukin-1beta), augmented Aβ (amyloid beta) production, and activated the complement system, causing inflammation, brain tissue degeneration, and cognitive impairment, consistent with the damage in AD.

Conclusions: Infection by P. gingivalis and Pg-LPS administration appears to be in relation with the pathogenesis of AD by activating the complement cascade, increasing Aβ production and augmenting pro-inflammatory cytokine expression, causing age-dependent brain inflammation, neuroinflammation, and neurodegeneration.

Clinical relevance: Taking into account the importance of holistic treatment in the dental office, this study focuses on identifying highly prevalent oral diseases, such as periodontal disease, as risk factors for the aggravation of degenerative diseases in the elderly population.

Keywords: Alzheimer's disease; Porphyromonas gingivalis; cognition; inflammation; periodontal diseases; systematic review.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33469718/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS)

The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS)

Abstract

Background: Much progress has been made in mapping genetic abnormalities linked to amyotrophic lateral sclerosis (ALS), but the majority of cases still present with no known underlying cause. Furthermore, even in families with a shared genetic abnormality there is significant phenotypic variability, suggesting that non-genetic elements may modify pathogenesis. Identification of such disease-modifiers is important as they might represent new therapeutic targets. A growing body of research has begun to shed light on the role played by the gut microbiome in health and disease with a number of studies linking abnormalities to ALS.

Main body: The microbiome refers to the genes belonging to the myriad different microorganisms that live within and upon us, collectively known as the microbiota. Most of these microbes are found in the intestines, where they play important roles in digestion and the generation of key metabolites including neurotransmitters. The gut microbiota is an important aspect of the environment in which our bodies operate and inter-individual differences may be key to explaining the different disease outcomes seen in ALS. Work has begun to investigate animal models of the disease, and the gut microbiomes of people living with ALS, revealing changes in the microbial communities of these groups. The current body of knowledge will be summarised in this review. Advances in microbiome sequencing methods will be highlighted, as their improved resolution now enables researchers to further explore differences at a functional level. Proposed mechanisms connecting the gut microbiome to neurodegeneration will also be considered, including direct effects via metabolites released into the host circulation and indirect effects on bioavailability of nutrients and even medications.

Conclusion: Profiling of the gut microbiome has the potential to add an environmental component to rapidly advancing studies of ALS genetics and move research a step further towards personalised medicine for this disease. Moreover, should compelling evidence of upstream neurotoxicity or neuroprotection initiated by gut microbiota emerge, modification of the microbiome will represent a potential new avenue for disease modifying therapies. For an intractable condition with few current therapeutic options, further research into the ALS microbiome is of crucial importance.

Keywords: ALS; Amyotrophic lateral sclerosis; Disease modifiers; Microbial; Microbial metabolites; Microbiome.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33468103/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.