Background: Aging leads to alterations in electrolyte regulation mechanisms, increasing the risk of imbalances such as hyponatremia, hypochloremia, hypokalemia, and hypomagnesemia. These disturbances can cause severe complications, including renal dysfunction and increased morbidity. Objective: This study aims to analyze the prevalence of sodium, chloride, potassium, and magnesium imbalances based on age, gender, and geographic location in Western Cameroon. Methods: A cross-sectional study was conducted among 768 participants aged 50 years and above. Blood samples were analyzed to measure levels of sodium, chloride, potassium, and magnesium, classified into three categories: hypo-, normal, and hyper-. Results: The study revealed a high prevalence of electrolyte imbalances, especially among women and individuals over 60 years old, particularly in rural areas such as Baham and Bandjoun. Geographic differences, dietary habits, and age-related comorbidities appear to significantly influence these imbalances. Conclusion: Monitoring electrolytes in older adults is essential to prevent complications associated with aging.
Individuals with autism spectrum disorder (ASD) often face unique barriers in daily life, education, and social interactions. Family members also face challenges in caregiving, education, and social interactions, often contributing to heightened stress, depression, and trauma. This questionnaire-based survey study aimed to understand the roles of parental and prenatal conditions in ASD development. Data were collected through online questionnaires completed by families of individuals with clinically diagnosed ASD. The questionnaire consisted of multiple-choice questions and was distributed via email to families (n=123) affiliated with the Pan American Health Society. We found: 1) A significant association between paternal age and incidence of ASD. 2) A strong association between maternal stress levels during pregnancy and incidence of ASD. 3) An association between autism and male gender. This survey highlights several critical parental and prenatal factors associated with ASD. Paternal age and maternal stress during pregnancy emerged as contributors to ASD development, underscoring the need for awareness and preventative strategies. The observed association between autism status and male gender provides a basis for further investigation into biological and environmental mechanisms. These findings emphasize the importance of targeted interventions and enhanced support systems to address risk factors and improve outcomes for individuals with ASD and their families.
Background: This study investigates the relationship between creatine kinase (CK) levels and lymphocyte populations in elderly individuals across five localities in West Cameroon. CK, a muscle enzyme, may be associated with immune imbalances that contribute to premature aging. Methods: A cross-sectional study included 768 participants aged 50 years and older. CK and lymphocyte counts were measured and categorized as hypoCKaemia, normoCKaemia, and hyperCKaemia for CK, and lymphopenia, normal, and lymphocytosis for lymphocytes. Multivariate regression analyses were conducted to assess these associations, controlling for age, sex, socio-economic factors, and nutritional variables. Results: HypoCKaemia was significantly associated with lymphopenia, while hyperCKaemia correlated with lymphocytosis. Individuals aged ≥70 years exhibited higher prevalence rates of these imbalances. Socio-economic status, dietary habits, and geographic variations significantly influenced the observed patterns. Conclusions: Monitoring CK and lymphocyte levels is essential for identifying risks of premature aging and immune imbalances. Targeted interventions focusing on physical activity, nutrition, and addressing socio-economic disparities could improve muscle and immune health in elderly populations.
The Siddha system is one of the traditional systems which provide healthy life to humans through the natural sources in the form of herbals, minerals and animal products. Lavaņa kuḻambu is a Siddha herbo-mineral formulation mentioned in the Siddha text Aņupõka Vaittiyanavaṉītam. Kuḻambu is a semi solid preparation with the shelf life of 5 years. The drug is indicated for Pīlīkai kaṭṭi, Kavitai kaṭṭi, Pāņṭu, Kāmālai, Peruvayiṟu, Makōtaram All these symptoms are related to the dysfunction of the vital organ Liver. Liver inflammation and oxidative stress are commonly associated with development and progression of chronic liver disease. It is evident that the natural products with anti inflammatory and anti oxidant activities posses therapeutic effect against inflammation, fibrosis and metabolic disorders. This review is aimed to bring out scientific evidence for the therapeutic usage of Lavaņa kuḻambu and focused on the Hepato protective activity for the curative nature of the drug. It is unambiguous that the ingredients in the Lavaņa kuḻambu have Hepato protective activity as per the Siddha literature and scientific evidence.
Muscarinic acetylcholine M receptors (mAChRs) belong to the G protein-coupled receptor (GPCR) superfamily and play a crucial role in regulating and controlling the release of acetylcholine (ACh). This review aims to focus on M3 receptor (M3R) subtype distribution, function, efficacy, and clinical applications. Specifically, we will delve into the M3R, encoded by the CHMR3 gene, which is primarily found in the cerebral cortex, airway, digestive tract, and glands. Under normal healthy conditions, M3Rs participate in various significant physiological reactions. They are involved in regulating the release of second messengers and controlling the opening of ion channels. Such functions contribute to maintaining essential processes within the body. In pathological conditions, M3Rs become potential therapeutic targets. Pharmacological manipulation using M3R agonists or antagonists can be utilized in treating a range of diseases, including schizophrenia, Alzheimer's disease (AD), type Ⅱ diabetes (T2D), congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), acute pancreatitis (AR), and overactive bladder (OAB). These receptors hold promise as proven or potential targets for effective disease management. Therefore, understanding the pharmacological properties and molecular mechanisms of M3R is vital for developing multi-target drugs (MTAs) to treat diseases with complex pathogenesis. This approach can help avoid the decline in drug efficacy caused by drug resistance. Exploiting the unique three-dimensional structure of M3Rs and their selective preference for different ligands, selective or non-selective pharmaceutical reagents for targeted therapy can be designed. Understanding these characteristics can facilitate the design of drugs that interact optimally with the receptor, potentially enhancing therapeutic outcomes.
Introduction: Reproductive disorders in females as a result of exposure to heavy metals are considered an important public health and social problem. Aim: The study was to determine the level of influence of Xylopia aethiopica extract on the female reproductive hormone, and histological changes in the uterus following administration of Aluminum chloride (AICI3). Materials and methods: Twenty female Wistar rats were randomly divided into 4 groups of five rats. Group 1 served as normal control, groups 2, 3, 4 were administered 150mg/kg Aluminum chloride (AICI3). Group 2 served as positive control, while groups 3 and 4 were also administered 50 mg/kg and 100 mg/kg extract of Xylopia aethiopica respectively. Administration of extract was done through the oral route for 21 days, after which the animals were sacrificed. Hormonal assay such as Luteinizing hormone, Progesterone, Follicle Stimulating Hormone, Estradiol and histology of the uterus were evaluated. Results: This revealed that (AICI3) decreased the levels of FSH, LH, Estradiol and Progesterone. These results were further supported by histological observation that showed the thickenings and degeneration in the endometrial epithelial in the uterus caused by Aluminum chloride. Xylopia aethiopica treated groups showed significant (p<0.05) increase in FSH, LH and Progesterone levels, while the Estradiol level was increase but it was not significant. Histologically, Xylopia aethiopica reduced thickenings and degeneration in the endometrial epithelium of the uterus caused by Aluminum chloride. Conclusion: The finding demonstrated that treatment using Xylopia aethiopica may minimizes the toxic effect of Aluminum chloride on the female reproductive hormones and the uterus.
Work in our laboratory over the last 10 years has shown that prolonged brain calpain-2 activation following a variety of insults plays a critical role in brain pathology resulting from these insults, including neuronal damage, brain inflammation, and cognitive impairment. My laboratory is collaborating with NeurAegis, Inc, to develop selective calpain-2 inhibitors for the treatment of a number of neurological disorders, including traumatic brain injury and concussions. We have identified a lead clinical candidate, NA-184, which significantly inhibits neuronal damage in rodent models of TBI, as well as a blood biomarker, P13BP, which reflects brain calpain-2 activation. We will discuss our plans to bring NA-184 to the clinic in 2024.
The Wisniewski laboratory has helped develop novel biomarkers and therapeutic approaches to AD, particular immunotherapeutic approaches that affect both the adaptive and innate immune systems. We have developed a means to stimulate innate immunity to ameliorate AD pathology, which we have tested in aged squirrel monkeys, and now are conducting a phase I clinical trial. We have also developed both active and passive immunization that specifically targets the dominant β-sheet secondary structure of multiple toxic oligomers concurrently (including both Aβ and tau oligomers). Recently we have also documented the neurological manifestations of SARS-CoV-2 infection (in particular cognitive dysfunction) and associated biomarkers of neurodegeneration and neuroinflammation. We have also developed an unbiased proteomic methodology that produces robust data utilizing archival formalin, fixed paraffin embedded human tissue, using this method to perform the most extensive proteomic analysis of amyloid plaques and the phosphorylated tau interaction, as well as to characterize the amyloid proteome of distinct subtypes of AD including rapidly progressive AD and AD in Down syndrome. These studies have helped enhance the understanding of the pathogenesis of AD, and also with the development of novel therapies.
Late-onset Alzheimer’s disease (AD) and related dementia (ADRD) are serious neurodegenerative disorders among aging populations. The progress of AD/ADRD cultivates over years to decades in humans and several months in animal models. Ca2+ homeostasis is a core function of neurons where the N-methyl-D-aspartate (NMDA) receptor plays a major role in excitatory neuronal activities. The Ca2+ hypothesis of AD proposes that even slight but sustained Ca2+ dyshomeostasis in the brain is a critical pathophysiology or pathogenesis of AD. However, instigating factors like the trigger and time/duration of the Ca2+ dysregulation in AD progression have been largely obscure, while β-amyloid (Aβ) peptides are often indicated as the trigger. Hyperactivities of excitatory neurons and NMDARs have been implicated in AD as a main mediating mechanism caused by AD pathologies such as Aβ deposition. NMDAR overactivation is restrained by the unique regulatory GluN3 subunits (GluN3A and GluN3B; previously known as NR3A and NR3B). Expression of GluN3A in the receptor complex reduces NMDAR currents and Ca2+ influx, while deletion of GluN3A causes larger NMDA currents and elevated intracellular Ca2+. Significant GluN3A levels are detected in both rodent and human adult/aging brains. We hypothesized that the “gatekeeper” role of GluN3A is constantly required for Ca2+ homeostasis and normal aging; its deficiency can lead to slowly evolved “degenerative excitotoxicity”. Our in vitro, ex vivo, and in vivo studies using GluN3A knockout (KO) mice of young and older ages revealed neuronal hyperactivity, moderate but sustained elevation of cytosolic Ca2+, chronic inflammation, neuronal loss/apoptosis, synaptic impairments and progressive cognitive deficits. The AD hallmarks of Aβ and tau pathology were identified after, but not before, cognition decline. In the “gain of function” experiment, expression of GluN3A in the GluN3A KO brain prevented AD progression. Specific regional knockdown of GluN3A in the cortex and hippocampus of wild-type mice at the adult age (3 months old) resulted in similar AD/ADRD phenotypic alterations in the following 3-6 months. The NMDAR antagonist memantine (MEM) is approved by FDA as a symptomatic treatment for moderate-severe AD patients. According to the chronic neurohyperactivity in AD progression and the modified Ca2+ hypothesis that Ca2+ dysregulation is an early and “life-long” pathogenesis, the maintenance of NMDAR normal activity by MEM or other safe NMDAR antagonists could be a disease-modifying early treatment in preclinical/prodromal stages. This prediction is endorsed by clinical trials using MEM and other NMDAR antagonists in mild cognitive impairment (MCI) and early AD patients, showing beneficial effects of maintaining cognitive functions. Consistently, we showed that, in GluN3A KO mice and 5xFAD mice, early and chronic MEM treatment (started at 3-month of age and lasted for 3-6 months) prevented or attenuated AD phenotypes. Meanwhile, the chronic MEM therapy in mice showed preconditioning effect of neuroprotection against ischemic stroke that strikes over 50% AD patients. Large clinical trials of long-term and more systematic examinations on AD/ADRD progression and the comorbidity of stroke are warranted for this innovative therapy. Our results support the modification of Ca2+ hypothesis of AD with the novel amyloid-independent mechanism. Specifically, the deficiency of GluN3A alone causes lifelong Ca2+-related progression of AD pathophysiology and amyloid pathology. The long-term GluN3A modulation of NMDARs signifies new therapeutic targets and possible preventive interventions for late-onset AD/ ADRD.
In humans, positive social interactions and relationships are essential for maintaining good mental and physical health. Insufficiency of these interactions-i.e., social isolation–is associated with negative health outcomes, including anxiety and cognitive decline. To investigate the impacts of long-term, recurrent patterns of social isolation on behavior, we developed the repeated social isolation (RSI) model, where C57BL/6 mice were subjected to social isolation, social interaction, and re-isolation, followed by the administration of 2 mg/kg dihydromyricetin (DHM). DHM is a flavonoid known to ameliorate anxiety and cognitive impairment partly via γ-aminobutyric A receptors (GABAARs) and has the potential to counteract the negative effects of social isolation. In this pilot study, mice exposed to RSI exhibited increased anxiety-like behavior and decreased cognition, while DHM partially ameliorated these changes. In the social interaction test, male RSI mice had shorter latency to attack and less social interaction, while female RSI mice avoided conflict and interaction altogether. Compared to the 4-week social isolation model, DHM showed less significance in therapeutic efficacy, especially in anxious behaviors, potentially due to 1) small sample size and/or 2). Overall, RSI increased anxiety- like behavior, reduced cognition, and led to changes in social behavior, while DHM showed some therapeutic effects. Future studies will incorporate a larger sample size and investigate the cellular or molecular changes that may explain the findings in this study.
Angelman syndrome (AS) is a rare neurogenetic disorder caused by deletion or mutations in the UBE3A gene, which lead to the deficiency of the UBE3A protein in neurons. UBE3A is crucial for normal neuronal communication, as it regulates the turnover of synaptic proteins and synaptic plasticity. Exosomes, small extracellular vesicles released by various cells, including neurons, play important roles in intercellular communication. Exosomes contain a variety of molecules, including proteins and nucleic acids, and can transfer these components between cells. Emerging evidence indicates that exosomes are critical for normal brain functions, and in recent years many studies have investigated the therapeutic potential of exosomes as vehicles for delivering therapeutic cargoes in various neurological disorders. In this study, we investigated the potential role of exosomes in regulating spine morphology in AS mice. Our results showed that activation of the lysosomal calcium channel TRPML1 stimulated exosome release from synaptosomes prepared from adult WT mice, but not from synaptosomes prepared from adult AS mice. Intriguingly, UBE3A was present in exosomes secreted from WT mice. It has been previously shown that hippocampal neurons of AS mice exhibit fewer dendritic spines, as compared to those from WT mice. Incubation of cultured hippocampal neurons from AS mice with conditioned medium from cultured hippocampal neurons from WT mice rescued the number of dendritic spines. Our data suggest that this effect is most likely due to exosomes in the medium, since purified exosomes from conditioned medium of WT neurons produced a similar rescue effect in cultured neurons from AS mice. Moreover, intravenous injection of exosomes prepared from synaptosomes of adult WT mice seemed to enhance contextual memory recall and associated immediate early gene (IEG) expression, and te number of dendritic spines in CA1 pyramidal neurons in adult AS mice. Whether and to what degree UBE3A present in WT exosomes participates in the rescue of AS neuronal morphology remains to be determined. Together, these results reveal both altered exosomal secretion and composition in AS mice. Treatment of AS neurons or adult AS mice with exosomes rescued dendritic spine deficits in vitro and in vivo. These results open new therapeutical approaches for using exosomes as a potential treatment for this disease.
Alzheimer's disease (AD) is a neurodegenerative condition characterized by cognitive decline and memory loss. The current lack of understanding regarding the cause of AD has impeded the development of animal models for drug testing, resulting in a dearth of effective prevention and treatment methods. Despite efforts to target Aβ plaques and tau protein tangles, which have proven ineffective, it is evident that these factors alone do not fully account for the cognitive deficits and memory loss associated with AD. While clinical trials seek effective treatments, success remains uncertain.
Understanding molecular mechanisms of Alzheimer’s disease (AD) has proven challenging as disease effects occur at multiple scales in different brain regions. We apply multiplexed error-robust fluorescence in situ hybridization (MERFISH) to generate spatially resolved single-cell RNA atlases from multiple cortical and subcortical brain regions in 5xFAD and age-matched C57 wild-type mice. We also investigate the effect of the TREM2R47H mutation, a strong risk factor for the development of AD in humans, producing similar atlases for Trem2R47H and Trem2R47H-5xFAD mice. We identify amyloid- beta plaque proximal molecular alterations in microglia and astrocytes, but also in five neuronal cell types. Spatial analysis of microglia and astrocyte concentrations reveals Trem2R47H -dependent regional variations, as well as regional transcriptional variation independent of either 5xFAD or Trem2R47H mutations. Cortical excitatory neurons exhibit a consistent Trem2R47H -induced expression increase in Ntrk2, and other MAPK signaling- associated genes, and thalamic excitatory neurons exhibit both 5xFAD and Trem2R47H induced gene program alterations. Additionally, nearly every neuronal cell type exhibits subclusters with decreased 5xFAD populations. Taken together, our MERFISH analysis of 5xFAD and Trem2R47H Alzheimer’s mouse models reveals spatially localized, cell-type-specific, plaque and Trem2R47H induced transcriptome dysregulations in cortical and subcortical brain regions.
Apolipoprotein E ε4 (APOE ε4) confers the greatest genetic risk for late-onset Alzheimer's disease (AD). The adjacent Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene may increase risk through APOE ε4 independent associations with AD- sensitive brain regions like the hippocampus. ANOVA and multiple linear regression tested TOMM40 rs2075650 ('650) G vs. A genotype on total hippocampal volume using UK Biobank data (n=10,130), across all participants and by APOE haplotype groups. Age and sex interactions with TOMM40 '650 were also tested. Across participants, having both APOE ε4 and TOMM40 '650 G carriage was related to hippocampal atrophy. Among non-APOE ε4 adults, age and sex jointly modulated '650 G carriage effects. Compared to younger middle- aged adults, older women and men respectively showed modest protective and markedly detrimental associations. TOMM40 '650 G carriage may have APOE ε4-independent associations with hippocampal volume based on age and sex.
As part of our participation in the Model-AD consortium, the UCI group has developed at least 12 novel mouse models that are relevant to studying the mechanisms underlying late-onset Alzheimer's disease (LOAD). These new models include variants in Abca7, Clu, Picalm, and Trem2. Modeling LOAD is hampered by the subtle effects imparted by the GWAS variants versus the much stronger phenotypic effects imparted by autosomal dominant AD mutations. We have successfully built a platform mouse in which the Aβ sequence has been humanized, and we found that wildtype-hAβ is sufficient to induce synaptic deficits and loss and accelerate the formation of astrocyte-associated Periodic Acid Schiff granules, normally associated with aging. We are actively introducing human tau alleles into these platform mice. Our strategy is to couple the humanizing of critical AD genes (APP, tau) with GWAS variants (Abca7, Clu, Picalm,) to better assess the impact that these alleles have on the phenotype. Modeling late-onset Alzheimer's disease represents a significant challenge, but success will likely yield substantial insights into disease mechanisms and advance drug discovery and evaluation efforts.
For degenerative diseases, a major causal hypothesis is chronic cell stress, which damages cell proteins. To maintain cellular homeostasis, damaged proteins must be replaced via nuclear protein synthesis, ER folding, and Golgi transport. If protein damage exceeds the cell’s replacement capacity, protein misfolding occurs, which, if unchecked, forms cytotoxic aggregates of misfolded polymorphic structures (CAMPS) that attach to membranes, disrupt their function, and degrade homeostasis.
Neurodegenerative diseases are particularly challenging from both a research and a drug development perspective. A deeper understanding of the genetics of neurogenerative disease may reveal novel therapeutic targets. Alternatively, identification of common mechanisms underlying neural protection, repair, inflammation, and regeneration could provide therapeutic targets broadly applicable to neurodegenerative diseases. Beyond understanding the etiology of neurodegenerative diseases, there is a need for easily measured biomarkers that can be reliable predictors for the rate of progression in individuals and biomarkers that can be leveraged to measure clinical efficacy of new therapeutics. Despite advances, there are no novel disease-modifying therapies that provide significant benefit for patients who suffer from these debilitating disorders. As we look to the future, gene therapy has the potential to transform treatment for a wide range of neurological diseases; creating therapies that could slow, halt or even restore normal function.
Aging is a major risk factor for Alzheimer’s disease (AD) and related dementias. We used viral vectors to initiate tau over-expression in mice of different ages. Delivery of tau containing the FTD-associated mutation P301L produced tauopathy in nontransgenic C57BL/6Nia mice, including increased phosphorylated tau and formation of neurofibrillary tangles. Surprisingly, tauopathy was only modestly increased in aged mice, and these increases seem insufficient to account for the exponential increase in risk of AD in the aged. Using viral constructs over-expressing different tau variants, we observed that 4R2N tau (without mutations) was neurotoxic, while P301L tau aggregated more. Rapamycin was used to slow the rate of biological aging, then tauopathy was induced by viral over-expression of P301L tau. The magnitude of the tauopathy produced was not affected by prior long-term treatment with rapamycin. Finally, we used viral constructs with capsids allowing uptake across the blood brain barrier to deliver P301L tau intravenously, producing modest 2-fold tau over-expression. Nontransgenic mice developed tauopathy (increased phosphorylated and aggregated tau). However, mice with pre-exising amyloid deposits developed greater tauopathy. This model will be useful to explore mechanisms of and treatments for amyloid- induced tauopathy.
During the past century, since the discovery of the neurodegenerative disease that was first described by Dr. Alois Alzheimer, widespread efforts have focused on the etiology, diagnosis, prevention, and effective treatment of Alzheimer’s disease (AD). Although many insights have been generated, no therapeutics have ever been identified that might lead to treating the underlying progression of this devastating, ultimately fatal dementia.
Alzheimer’s disease is a continuum condition characterized by specific pathologies such as amyloid β plaques (Aβ), neurofibrillary tangles, inflammation, and neurodegeneration. There is consensus that the preclinical phase in which there is AD pathology but no symptomatology could be the appropriate phase to target AD pathology with preventive measures. Therefore, an important focus is placed on identifying modifiable risks for AD and other dementia before severe irreversible brain damage occurs. Recent studies show that peripheral inflammation and microbes play a crucial role in AD pathogenesis by inducing neuroinflammation, brain pathology, and cognitive decline. Periodontal disease a localized peripheral chronic inflammatory condition affecting about 50% of people over 55 years of age is characterized by dysbiosis (microbial imbalance) with high Gram-negative pathogenic bacterial load and increased systemic inflammation. We posed that periodontal disease with its significant local and systemic inflammatory and microbial burden contribute to AD pathogenesis. Literature data including results coming from our group will show support for periodontal disease cont ribution to AD brain pathology.
