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Alzheimer's disease (AD) is a distressing neurodegenerative condition characterized by the accumulation of amyloid-beta (Aβ) plaques and tau tangles within the brain. The interconnectedness between membrane transporters (SLCs) and microRNAs (miRNAs) in AD pathogenesis has gained increasing attention. This review explores the localization, substrates, and functions of SLC transporters in the brain, emphasizing the roles of transporters for glutamate, glucose, nucleosides, and other essential compounds. The examination delves into the significance of SLCs in AD, their potential for drug development, and the intricate realm of miRNAs, encompassing their transcription, processing, functions, and regulation. MiRNAs have emerged as significant players in AD, including those associated with mitochondria and synapses. Furthermore, this review discusses the intriguing nexus of miRNAs targeting SLC transporters and their potential as therapeutic targets in AD. Finally, the review underscores the interaction between SLC transporters and miRNA regulation within the context of Alzheimer's disease, underscoring the need for further research in this area. This comprehensive review aims to shed light on the complex mechanisms underlying the causation of AD and provides insights into potential therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: The intricate and complex molecular mechanisms that underlie the progression of Alzheimer's disease (AD) have prompted a concerted and vigorous research endeavor aimed at uncovering potential avenues for therapeutic intervention. Objective: This study aims to elucidate the role of miRNA PC-5P-12969 in the pathogenesis of AD. Methods: We assessed the differential expression of miRNA PC-5P-12969 in postmortem AD brains, AD animal and cell models using real-time reverse-transcriptase RT-PCR, we also checked the gene and protein expression of GSK3α and APP. Results: Our investigation revealed a notable upregulation of miRNA PC-5P-12969 in postmortem brains of AD patients, in transgenic mouse models of AD, and in mutant APP overexpressing-HT22 cells. Additionally, our findings indicate that overexpression of miRNA PC-5P-12969 exerts a protective effect on cell survival, while concurrently mitigating apoptotic cell death. Further-more, we established a robust and specific interaction between miRNA PC-5P-12969 and GSK3α. Our luciferase reporter assays provided confirmation of the binding between miRNA PC-5P-12969 and the 3′-UTR of the GSK3α gene. Manipulation of miRNA PC-5P-12969 levels in cellular models of AD yielded noteworthy alterations in the gene and protein expression levels of both GSK3α and APP. Remarkably, the manipulation of miRNA PC-5P-12969 levels yielded significant enhancements in mitochondrial respiration and ATP production, concurrently with a reduction in mitochondrial fragmentation, thus unveiling a potential regulatory role of miRNA PC-5P-12969 in these vital cellular processes. Conclusions: In summary, this study sheds light on the crucial role of miRNA PC-5P-12969 and its direct interaction with GSK3α in the context of AD. [ABSTRACT FROM AUTHOR]

In the current study, for the first time, we study mitophagy enhancer urolithin A and a combination of urolithin A+green tea extract EGCG against human Aβ peptide-induced mitochondrial and synaptic, dendritic, inflammatory toxicities and behavioral changes in humanized homozygous amyloid beta knockin (hAbKI) mice of late-onset Alzheimer's disease (AD). Our findings reveal significantly increased positive effects of urolithin A and a combination treatment of urolithin A+EGCG in hAbKI mice for phenotypic behavioral changes including motor coordination, locomotion/exploratory activity, spatial learning and working memory. mRNA and protein levels of mitochondrial fusion, synaptic, mitophagy and autophagy genes were upregulated, and mitochondrial fission genes are downregulated in urolithin A and combine treatment in hAbKI mice; however, the effect is stronger in combined treatment. Immunofluorescence analysis of hippocampal brain sections shows similar findings of mRNA and protein levels. Mitochondrial dysfunction is significantly reduced in both treatment groups, but a stronger reduction is observed in combined treatment. Dendritic spines and lengths are significantly increased in both treatment groups, but the effect is stronger in combined treatment. The fragmented number of mitochondria is reduced, and mitochondrial length is increased, and mitophagosomal formations are increased in both the groups, but the effect is stronger in the combined treatment. The levels of amyloid beta (Aβ) 40 and Aβ42 are reduced in both treatments, however, the reduction is higher for combined treatment. These observations suggest that urolithin A is protective against human Aβ peptide-induced toxicities; however, combined treatment of urolithin A+EGCG is effective and stronger, indicating that combined therapy is promising to treat late-onset AD patients. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of mental dementia in the aged population. AD is characterized by the progressive decline of memory and multiple cognitive functions, and changes in behavior and personality. Recent research has revealed age‐dependent increased levels of VDAC1 in postmortem AD brains and cerebral cortices of APP, APPxPS1, and 3xAD.Tg mice. Further, we found abnormal interaction between VDAC1 and P‐Tau in the AD brains, leading to mitochondrial structural and functional defects. Our current study aimed to understand the impact of a partial reduction of voltage‐dependent anion channel 1 (VDAC1) protein on mitophagy/autophagy, mitochondrial and synaptic activities, and behavior changes in transgenic TAU mice in Alzheimer's disease. To determine if a partial reduction of VDAC1 reduces mitochondrial and synaptic toxicities in transgenic Tau (P301L) mice, we crossed heterozygote VDAC1 knockout (VDAC1+/−) mice with TAU mice and generated double mutant (VDAC1+/−/TAU) mice. We assessed phenotypic behavior, protein levels of mitophagy, autophagy, synaptic, other key proteins, mitochondrial morphology, and dendritic spines in TAU mice relative to double mutant mice. Partial reduction of VDAC1 rescued the TAU‐induced behavioral impairments such as motor coordination and exploratory behavioral changes, and learning and spatial memory impairments in VDAC1+/−/TAU mice. Protein levels of mitophagy, autophagy, and synaptic proteins were significantly increased in double mutant mice compared with TAU mice. In addition, dendritic spines were significantly increased; the mitochondrial number was significantly reduced, and mitochondrial length was increased in double mutant mice. Based on these observations, we conclude that reduced VDAC1 is beneficial in symptomatic‐transgenic TAU mice. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common forms of neurodegeneration, defined by reduced cognitive function, which is caused by the gradual death of neurons in the brain. Recent studies have shown an age-dependent rise in the levels of voltage-dependent anion channel 1 (VDAC1) in AD. In addition, we discovered an aberrant interaction between VDAC1 and P-TAU in the brains of AD patients, which led to abnormalities in the structural and functional integrity of the mitochondria. The purpose of our study is to understand the protective effects of reduced VDAC1 against impaired mitochondrial dynamics and defective mitochondrial biogenesis in transgenic TAU mice. Recently, we crossed heterozygote VDAC1 knockout (VDAC1+/−) mice with transgenic TAU mice to obtain double-mutant VDAC1+/−/TAU mice. Our goal was to evaluate whether a partial decrease in VDAC1 lessens the amount of mitochondrial toxicity in transgenic Tau (P301L) mice. We found that mitochondrial fission proteins were significantly reduced, and mitochondrial fusion and biogenesis proteins were increased in double-mutant mice compared to TAU mice. On the basis of these discoveries, the current work may have significance for the development of reduced-VDAC1-based treatments for individuals suffering from AD as well as other tauopathies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in older people. AD is associated with the loss of synapses, oxidative stress, mitochondrial structural and functional abnormalities, microRNA deregulation, inflammatory responses, neuronal loss, accumulation of amyloid-beta (Aβ) and phosphorylated tau (p-tau). AD occurs in two forms: early onset, familial AD and late-onset, sporadic AD. Causal factors are still unknown for a vast majority of AD patients. Genetic polymorphisms are proposed to contribute to late-onset AD via age-dependent increases in oxidative stress and mitochondrial abnormalities. Recent research from our lab revealed that reduced levels of Rlip76 induce oxidative stress, mitochondrial dysfunction and synaptic damage, leading to molecular and behavioral phenotypes resembling late-onset AD. Rlip76 is a multifunctional 76 kDa protein encoded by the RALBP1 gene, located on chromosome 18. Rlip is a stress-protective ATPase of the mercapturic acid pathway that couples clathrin-dependent endocytosis with the efflux of glutathione–electrophile conjugates. Rlip is evolutionarily highly conserved across species and is ubiquitously expressed in all tissues, including AD-affected brain regions, the cerebral cortex and hippocampus, where highly active neuronal metabolisms render the cells highly susceptible to intracellular oxidative damage. In the current article, we summarize molecular and cellular features of Rlip and how depleted Rlip may exacerbate oxidative stress, mitochondrial dysfunction and synaptic damage in AD. We also discuss the possible role of Rlip in aspects of learning and memory via axonal growth, dendritic remodeling, and receptor regulation. We conclude with a discussion of the potential for the contribution of genetic polymorphisms in Rlip to AD progression and the potential for Rlip-based therapies. [ABSTRACT FROM AUTHOR]

Despite successful virologic control with combination antiretroviral therapy (cART), about half of people living with the human immunodeficiency virus-1 (HIV) develop an HIV-associated neurocognitive disorder (HAND). It is estimated that 50% of individuals who are HIV-positive in the United States are aged 50 years or older. Therefore, a new challenge looms as individuals living with HIV increase in age. There is concern that Alzheimer's disease (AD) may become prevalent with an earlier onset of cognitive decline in people living with HIV (PLWH). Clinical data studies reported the presence of AD biomarkers in PLWH. However, the functional significance of the interaction between HIV or HIV viral proteins and AD biomarkers is still not well studied. The main goal of the present study is to address this knowledge gap by determining if the HIV envelope glycoprotein 120 (HIV-gp120) can affect the cognitive functions in the Tau mouse AD model. Male Tau and age-matched, wild-type (WT) control mice were treated intracerebroventricularly (ICV) with HIV-gp120. The animals were evaluated for cognitive function using a Y-maze. We found that HIV-gp120 altered cognitive function in Tau mice. Notably, HIV-gp120 was able to promote a cognitive decline in transgenic Tau (P301L) mice compared to the control (HIV-gp120 and WT). We provide the first in vivo evidence of a cognitive interaction between an HIV viral protein and Tau mice. [ABSTRACT FROM AUTHOR]

Background: DNA damage accumulation and mitochondrial abnormalities are elevated in neurons during aging and may contribute to neurodegenerative pathologic conditions such as Alzheimer's disease. BRCA1 interacting protein 1 or BRIP1 is a 5' to 3' DNA helicase that catalyzes many abnormal DNA structures during DNA replication, gene transcription, and recombination, and contribute to genomic integrity.Objective: BRIP1 functions were reasonably well studied in DNA repair; however, there is limited data on its role and regulation during aging and neurodegenerative diseases.Methods: We used immunohistochemistry, western blot, and qRT-PCR assays to analyze the expression of BRIP1. Immunofluorescence studies were performed to study the formation of R-loops, reactive oxygen species (ROS) generation, and mitochondrial morphology. Flow cytometry and transmission electron microscopy were used to evaluate mitochondrial ROS and mitochondrial structures, respectively. Oxygen consumption rate was measured using Seahorse, and the Presto Blue™ assays were used to evaluate cell viability.Results: Our results demonstrate the expression of BRIP1 in mouse and human brain tissues and in neuronal cell lines. BRIP1 levels were elevated in the hippocampal regions of the brains, specifically in the dentate gyrus. BRIP1 downregulation in neuronal cells caused increased R-loop formation basally and in response to H2O2 treatment. Furthermore, BRIP1 deficient cells exhibited elevated levels of excitotoxicity induced by L-Glutamic acid exposure as evidenced by (mitochondrial) ROS levels, deteriorated mitochondrial health, and cell death compared to BRIP1 proficient neuronal cells.Conclusion: Overall, our results indicate an important role for BRIP1 in maintaining neuronal cell health and homeostasis by suppressing cellular oxidative stress. [ABSTRACT FROM AUTHOR]

This article reviews recent advances in the study of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and their functions in type 2 diabetes mellitus (T2DM), ischemic stroke (IS), and vascular dementia (VaD). miRNAs and lncRNAs are gene regulation markers that both regulate translational aspects of a wide range of proteins and biological processes in healthy and disease states. Recent studies from our laboratory and others have revealed that miRNAs and lncRNAs expressed differently are potential therapeutic targets for neurological diseases, especially T2DM, IS, VaD, and Alzheimer's disease (AD). Currently, the effect of aging in T2DM, IS, and VaD and the cellular and molecular pathways are largely unknown. In this article, we highlight results from the works on the molecular connections between T2DM and IS, and IS and VaD. In each disease, we also summarize the pathophysiology and the differential expressions of miRNAs and lncRNAs. Based on current research findings, we hypothesize that 1) T2DM bi-directionally and age-dependently induces IS and VaD, and 2) these changes are precursors to the onset of dementia in elderly people. Research into these hypotheses is required to examine further whether research efforts on reducing T2DM, IS, and VaD may affect dementia and/or delay the AD disease process in the aged population. [ABSTRACT FROM AUTHOR]

The purpose of the 'First Regional Healthy Aging and Dementia Research Symposium' was to discuss the latest research in healthy aging and dementia research, public health trends related to neurodegenerative diseases of aging, and community-based programs and research studying health, nutrition, and cognition. This symposium was organized by the Garrison Institute on Aging (GIA) of the Texas Tech University Health Sciences Center (TTUHSC), and was held in Lubbock, Texas, October 24-25, 2018. The Symposium joined experts from educational and research institutions across the United States. The two-day Symposium included all GIA staff and researchers. Students, postdoctoral fellows, and faculty members involved in dementia research presented at the Symposium. Healthcare professionals, from geriatricians to social workers working with patients with neurodegenerative diseases, also presented. In addition, experts traveled from across the United States to participate. This event was comprised of multiple sessions, each with several oral presentations, followed by questions and answers, and discussion. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is an autoimmune, inflammatory disease, caused by environmental and genetic factors. Aim: To elucidate the association of human leukocyte antigen (HLA)‐DRB1*/DQB1* alleles/haplotypes and the variations of polymorphic amino acid changes in peptide binding pockets in RA patients from south India. Methods: HLA typing was performed in 176 RA patients and 176 healthy controls by polymerase chain reaction—sequence‐specific primers method. Results: Strong susceptible association for alleles such as DRB1*04:01(odds ratio [OR] = 3.66), 04:06 (OR = 3.81), 03:01 (OR = 2.93), 06:01 (OR = 2.53) and protective association for alleles such as DRB1*13:01 (OR = 0.17), 14:01 (OR = 0.15), 05:02 (OR = 0.17), and 05:03 (OR = 0.338) were observed in RA patients. The 2‐locus haplotypes such as 04‐02:01 (OR = 3.844), 04‐06:01 (OR = 6.57), 07‐03:01 (OR = 6.16), 07‐06:01 (OR = 3.42), 12‐06:01 (OR = 5.24), 15‐03:01 (OR = 4.69) with susceptible and DRB1*14‐DQB1*05:03 (OR = 0.078) with protective associations were observed in RA patients. The acid‐base analysis revealed that the basic group BB allele was positively associated (OR = 2.372) and the acidic group AA allele was negatively associated (OR = 0.086). The analysis on shared epitopes has revealed that the combination QKRAA+, (Q)RRAA+ or (Q)RRAA− was positively associated with RA (OR = 2.78). The amino acid variation at HLA‐DQβ molecule revealed susceptible associations for residues E86 and L87 (P1); E74 (P3); A13, Y26, I/S28, T28, I71 and E74 (P4); L9, T30, D37 and D57 (P9), whereas, the amino acids A86 and T87 (P1); S74 (P3); G13/26, A71 and S74 (P4); H30 and T37, S57 (P9), showed protective associations. Conclusions: Alleles DRB1*04:06 and*04:01 showed strong susceptible and DRB1*13:01 and *14:01 showed protective associations in RA patients. The amino acid variations in DQβ molecules revealed significant molecular markers for susceptibility to and protection from RA in south India. [ABSTRACT FROM AUTHOR]

The present study was undertaken to delineate the association(s) of KIR–HLA combination in South Indian Type 2 diabetes mellitus (T2DM) patients. The T2DM patients (n = 343) and healthy controls (n = 309) were genotyped for KIR/HLA ligands by PCR‐SSP method. The increased frequency of activatory KIR (aKIR) 2DS2 (OR = 1.91; p < 2.91 × 10−4) was observed in patients suggesting a susceptible association. The frequencies of iKIR 2DL2 (OR = 0.38; p < 1.55 × 10−5) and aKIRs 2DS1 (OR = 0.60; p < 0.001) and 3DS1 (OR = 0.52; p < 5.83 × 10−5) were decreased in patients suggesting protective associations. The C1/C2 combinatorial analysis has revealed an increased frequency of C1+/C2− in T2DM patients (OR = 1.62; p < 0.014). The KIR "AB" genotype (OR = 2.41; p < 3.87 × 10−5) was observed to be higher in patients. However, the "BB" genotype (OR = 0.32; p < 4.71 × 10−7) was increased in controls. The KIR motifs, "Tel‐B/B" (OR = 1.84; p < 0.007), were observed higher among patients. However, the frequency of "Tel‐A/B" motif genotype was decreased in patients (OR = 0.56; p < 3.13 × 10−4). The iKIR/HLA combinations such as 2DL2/3 +C1 and 3DL2+A3/A11 were increased in patients (OR = 3.90; p < 7.5 × 10−5) suggesting susceptible associations. On the contrary, the aKIR+HLA combinations such as 2DS2+C1, 2DS1+C2 and 3DS1+Bw4 were less frequent in patients (OR = 0.32; p < 4.2 × 10−4) suggesting protective associations. Thus, the present study clearly establishes the positive and negative associations of different KIR–HLA receptor combinations with T2DM in South India. [ABSTRACT FROM AUTHOR]

The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer's disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on Aβ and curcumin has revealed that curcumin prevents Aβ aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and Aβ in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin's bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD. [ABSTRACT FROM AUTHOR]

Background: Worldwide, South Asians contribute to a high proportion of coronary artery disease (CAD) burden, mainly attributed to a high prevalence of diabetes. Early identification of such high-risk individuals would enable aggressive disease modification and prevention of complications. Definition of susceptible genotypes early in the course of disease may be one such avenue for reduction in morbidity and mortality from CAD. Aim: Our study was aimed to investigate the insertion/deletion polymorphism of angiotensin-converting enzyme (ACE I/D) gene and susceptibility to CAD in patients with type 2 diabetes mellitus (T2DM) in a South Indian population. Subjects and Methods: ACE (I/D) genotyping was performed by polymerase chain reaction specific primer for 187 CAD patients and 185 age- and sex-matched controls. Results: We observed that the ACE"II" genotype was found to be significantly associated with CAD patients (odds ratio [OR] = 1.689; P = 0.028). However, multiple logistic regression analysis revealed that ACE "DD" genotype was found to be most predominant risk factor for CAD patients with T2DM (OR = 6.118; P = 0.001). Conclusion: Our results showed that ACE (I/D) genotypes and alleles presented functional dimorphism in the development of CAD and CAD with T2DM patients in South India. This finding may be extremely useful in identifying subsets of patients where early aggressive treatment of risk factors is warranted. [ABSTRACT FROM AUTHOR]

Stroke is a brain disease that occurs when blood flow stops, resulting in reduced oxygen supply to neurons. Stroke occurs at any time and at any age, but increases after the age of 55. It is the second leading cause of death and the third leading cause of disability-adjusted, life-years. The pathophysiology of ischemic stroke is complex and recent molecular, cellular, and animal models and postmortem brain studies have revealed that multiple cellular changes have been implicated, including oxidative stress/mitochondrial dysfunction, inflammatory responses, micro RNA alterations, and marked changes in brain proteins. These cellular changes provide new information for developing therapeutic strategies for ischemic stroke treatment. Research also revealed that stroke increases with a number of modifiable factors and most strokes can be prevented and/or controlled through pharmacological or surgical interventions and lifestyle changes. Ischemic stroke is the major risk factor for vascular dementia and Alzheimer's disease. This review summarizes the latest research findings on stroke, including causal factors and molecular links between stroke and vascular disease/Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The genes of Human Leukocyte Antigen (HLA) system are implicated in the susceptibility of several diseases including Type 2 diabetes (T2DM). Therefore, we aimed to investigate the association of HLA alleles with T2DM in south India. A total of 344 patients (195 males; 149 females) and 309 controls (186 males; 123 females) were genotyped for HLA-DR/-DQ alleles. Based on predominant DR/DQ haplotypes, 222 patients and 222 age/sex matched controls were HLA-A/-B genotyped. HLA alleles were typed by PCR-SSP methods. Susceptible association was observed for the alleles A*33 (OR = 13.8), A*01 (OR = 3.69), A*02 (OR = 2.91), B*07 (OR = 4.12), DRB1*11 (OR = 2.23), DRB1*04 (OR = 1.51), DRB1*03 (OR = 1.90) and DQB1*02 (OR = 1.49). Protective association was observed for the alleles A*11 (OR = 0.59), A*68 (OR = 0.68), B*40 (OR = 0.50), B*54 (OR = 0.42), B*57 (OR = 0.31), B*51 (OR = 0.29) and DRB1*10 (OR = 0.45). Gender stratified analysis too confirmed many of these associations. Predominant susceptible haplotypes were A*33-B*40 (OR = 10.27), A*01-B*07 (OR = 4.97), A*02-B*07 (OR = 6.50), DRB1*03-DQB1*05 (OR = 1.88), DRB1*03-DQB1*06 (OR = 3.01), DRB1*04-DQB1*05 (2.63), A*01-B*07-DRB1*10 (OR = 8.26) and A*11-B*35-DRB1*07 (OR = 9.338). Haplotypes A*03-B*07 (OR = 0.57; p < 0.034) and DRB1*10-DQB1*05 (OR = 0.57; p < 0.033) were protectively associated. Further, a very strong susceptible association was documented for four-locus haplotypes such as A*11-B*40-DRB1*15-DQB1*06 ( n = 15; OR = 16.01; p < 0.001); A*01-B*07-DRB1*10-DQB1*05 ( n = 8; OR = 8.26; p < 0.043) and A*11-B*07-DRB1*07-DQB1*05 (n = 8; OR = 8.26; p < 0.043). Thus, a number of HLA alleles and haplotypes showed susceptible and protective association(s) in T2DM patients from south India. [ABSTRACT FROM AUTHOR]

The predisposition to ischemic stroke (IS) might involve interactions of several genes and environmental factors. The present study was aimed to evaluate the influence of polymorphisms in methylenetetrahydrofolate reductase (MTHFR-C677T) and apolipoprotein-E (apo-E) as risk factors for IS patients in south Indian population. 200 IS patients and 193 age and sex matched controls were genotyped for MTHFR-C677T and apoE by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Statistically significant association was observed for MTHFR CT genotype (IS-Pooled: OR = 4.29; p = 5.01 × 10 − 5 ; IS-Males: OR = 4.13; p = 0.001; IS-Females: OR = 8.62; p = 0.027; IS-Large Vessel Disease (LVD)- Pooled: OR = 4.14; p = 0.0002) and T allele (IS-Pooled: OR = 4.82; p = 1.49 × 10 − 5 ; IS-Males: OR = 4.33; p = 0.0002; IS-Females: OR = 7.99; p = 0.031; IS-LVD-Pooled: OR = 4.13; p = 0.0001). Further, reduced frequencies of CC genotype (IS-Pooled: OR = 0.20; p = 9.80 × 10 − 6 ; IS-Males: OR = 0.25; p = 0.001; IS-Females: OR = 0.12; p = 0.027; IS-LVD-Pooled: OR = 0.23; p = 0.0001) and C allele (IS-Pooled: OR = 0.21; p = 1.49 × 10 − 5 ; IS-Males: OR = 0.23; p = 0.0002; IS-Females: OR = 0.13; p = 0.031; IS-LVD-Pooled: OR = 0.24; p = 0.0001) were observed in IS patients than the controls. No association was observed for apoE genotypes/alleles in IS/LVD cases. Our study demonstrated the presence of risk for MTHFR CT genotype/T allele and ‘CT-3/3’ (n = 33 vs. 5; OR = 7.42; p = 0.001) genotypic combination in the development of IS in south India. Further, follow-up study of these stroke cases i.e., in later stages of the disease whether they are developing the neurological disorders such as Alzheimer's Disease (AD) and vascular dementia (VaD) is needed to draw a fruitful conclusion in connection between neurological disorders and with these two polymorphisms, before translating it into clinical practice. [ABSTRACT FROM AUTHOR]

Background Nephrotic syndrome (NS) is a debilitating renal problem in children resulting from an interaction between environmental and genetic factors including human leukocyte antigen genes (HLA). The aim of this work was to study the probable link between HLA alleles/haplotypes and NS in south India. Methods HLA DRB1*/DQB1* alleles were genotyped in 183 NS (76 steroid sensitive-SSNS; 107 steroid resistant-SRNS) and paediatric healthy controls (PHCs; n = 91) using polymerase chain reaction-sequence specific primers (PCR-SSP). HLA-A/-B genotyping was performed for patients ( n = 70) positive for DRB1*07-DQB1*02 haplotype to identify four locus extended haplotype. Results The following alleles and haplotypes were strongly associated with NS ( P < 0.05 as significant): DRB1*07 (SSNS, P < 7.98 × 10-6; SRNS, P < 0.008), DQB1*02 (SSNS, P < 3.99 × 10-6; SRNS, P < 0.002), DRB1*07-DQB1*02 (SSNS, P < 1.32 × 10-4; SRNS, P < 0.010), DRB1*07-DQB1*0301,0304 (DQ7) (SSNS, P < 0.001) and DRB1*03-DQB1*02 (SRNS, P < 0.048). Protective associations were observed for alleles DRB1*10 (SRNS, P < 0.013), DQB1*05 (SSNS, P < 4.34 × 10-6; SRNS, P < 0.01), DQB1*06 (SSNS, P < 0.003), and haplotypes DRB1*10-DQB1*06 (SSNS, P < 0.046; SRNS, P < 0.032) and DRB1*15-DQB1*05 (SSNS, P < 0.018). HLA-A/-B typing of 70 NS cases with two locus haplotype DRB1*07-DQB1*02 (70/183; 38.25%) revealed the presence of an extended haplotype 'A*03-B*07-DRB1*07-DQB1*02' ( n = 35; 50%). Conclusion Our study revealed strong susceptible association of DRB1*07 with SRNS and DQB1*02 with SSNS. A gender predominant protective association was observed for DRB1*10 with SRNS females; DQB1*05 with SSNS and SRNS males. Further, the study documented the presence of an extended haplotype and pleiotropic action of DRB1*/DQB1* alleles in immune-mediated aetiology of NS in south India. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes mellitus (T2DM) is related to an elevated risk of mild cognitive impairment (MCI). Plasma clusterin is reported associated with the early pathology of Alzheimer's disease (AD) and longitudinal brain atrophy in subjects with MCI. The rs11136000 single nucleotide polymorphism within the clusterin (CLU) gene is also associated with the risk of AD. We aimed to investigate the associations among plasma clusterin, rs11136000 genotype and T2DM-associated MCI. Methods: A total of 231 T2DM patients, including 126 MCI and 105 cognitively healthy controls were enrolled in this study. Demographic parameters were collected and neuropsychological tests were conducted. Plasma clusterin and CLU rs11136000 genotype were examined. Results: Plasma clusterin was significantly higher in MCI patients than in control group p = 0.007). In subjects with MCI, plasma clusterin level was negatively correlated with Montreal cognitive assessment and auditory verbal learning test_delayed recall scores (p = 0.027 and p = 0.020, respectively). After adjustment for age, educational attainment, and gender, carriers of rs11136000 TT genotype demonstrated reduced risk for MCI compared with the CC genotype carriers (OR = 0.158, χ² = 4.113, p = 0.043). Multivariable regression model showed that educational attainment, duration of diabetes, high-density lipoprotein cholesterol (HDL-c), and plasma clusterin levels are associated with MCI in T2DM patients. Conclusions: Plasma clusterin was associated with MCI and may reflect a protective response in T2DM patients. TT genotype exhibited a reduced risk of MCI compared to CC genotype. Further investigations should be conducted to determine the role of clusterin in cognitive decline. [ABSTRACT FROM AUTHOR]

Seven human-specific Alu markers were studied in 574 unrelated individuals from 10 endogamous groups and 2 hill tribes of Tamil Nadu and Kerala states. DNA was isolated, amplified by PCR-SSP, and subjected to agarose gel electrophoresis, and genotypes were assigned for various Alu loci. Average heterozygosity among caste populations was in the range of 0.292–0.468. Among tribes, the average heterozygosity was higher for Paliyan (0.3759) than for Kani (0.2915). Frequency differences were prominent in all loci studied except Alu CD4. For Alu CD4, the frequency was 0.0363 in Yadavas, a traditional pastoral and herd maintaining population, and 0.2439 in Narikuravars, a nomadic gypsy population. The overall genetic difference (Gst) of 12 populations (castes and tribes) studied was 3.6%, which corresponds to the Gst values of 3.6% recorded earlier for Western Asian populations. Thus, our study confirms the genetic similarities between West Asian populations and South Indian castes and tribes and supported the large scale coastal migrations from Africa into India through West Asia. However, the average genetic difference (Gst) of Kani and Paliyan tribes with other South Indian tribes studied earlier was 8.3%. The average Gst of combined South and North Indian Tribes (CSNIT) was 9.5%. Neighbor joining tree constructed showed close proximity of Kani and Paliyan tribal groups to the other two South Indian tribes, Toda and Irula of Nilgiri hills studied earlier. Further, the analysis revealed the affinities among populations and confirmed the presence of North and South India specific lineages. Our findings have documented the highly diverse (micro differentiated) nature of South Indian tribes, predominantly due to isolation, than the endogamous population groups of South India. Thus, our study firmly established the genetic relationship of South Indian castes and tribes and supported the proposed large scale ancestral migrations from Africa, particularly into South India through West Asian corridor. [ABSTRACT FROM AUTHOR]

The purpose of our study is to investigate early cellular, molecular, morphological and behavioral changes in humanized amyloid-beta-knock-in (hAbKI) mice. Using seven-month-old homozygous hAbKI mice, we studied behavioral phenotype parameters, including spatial learning and memory (Morris Water Maze), locomotor activity (open field), working memory (Y-maze) and motor coordination (rotarod); mRNA abundance, protein levels, soluble amyloid-beta 40 and 42 levels and regional immunoreactivities of key markers of mitochondrial dynamics, mitochondrial biogenesis, synaptic health, mitophagy and autophagy; mitochondrial function and using transmission electron microscopy & Golgi–Cox staining, we assessed mitochondrial morphology and dendritic spines. Our extensive behavioral analysis revealed that seven-month-old hAbKI mice showed impairments in motor coordination, reduced locomotor and exploration activities, impairments in working memory and spatial learning and memory. Our mRNA and protein analyses revealed the increased expression of mitochondrial-fission genes and reduced expression of mitochondrial-fusion, mitochondrial-biogenesis, synaptic, autophagy and mitophagy genes in seven-month-old hAbKI mice. An immunofluorescence analysis revealed altered immunoreactivities and agreed with the immunoblot results. Transmission-electron-microscopy data revealed increased mitochondrial fragmentation and reduced mitochondrial length in both hippocampal and cortical tissues of seven-month-old hAbKI mice and mitochondrial function defective. A Golgi–Cox-staining analysis revealed reduced dendritic spines in both cerebral cortices and hippocampi of hAbKI mice. Soluble amyloid-beta (1–40 and 1–42) were detected in three-month-old hAbKI mice and progressively increased in seven-month-old mice. These observations suggest that the human amyloid-beta peptide is sufficient to cause behavioral, mitochondrial, synaptic and ultrastructural changes in seven-month-old hAbKI mice. Our study findings also suggest that hAbKI mice might serve as a model for preclinical studies of preventive therapies. [ABSTRACT FROM AUTHOR]

The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer's disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. We hypothesized that Rlip may play an important role in maintaining cognitive function. The aim of this study is to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype (WT) and Rlip+/− mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, stress response, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues from these mice. Furthermore, we compared the cognitive function of WT and Rlip+/− mice. Behavioral, basic motor and sensory function tests in Rlip+/− mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function and CREB signaling genes in the Rlip+/− mouse brain. Our results suggest that Rlip deficiency-associated increases in OS and mitochondrial dysfunction could contribute to the development or progression of OS-related AD processes. [ABSTRACT FROM AUTHOR]

Aim To study the HLA/KIR interactions in health (HC) and disease (DC) (T1DM, T2DM, AITD, CAD, IS, PKF and AKF) cohorts with reference to two extended haplotypes (EHs). Methods Individuals with ‘DRB1∗07-DQB1∗02’ (HC = 168/1353; DC = 271/1376) and ‘DRB1∗15-DQB1∗06’ (HC = 542/1737; DC = 427/1617) haplotypes were typed for HLA-A/B/C by PCR-SSP. Individuals with EHs were KIR genotyped by duplex PCR-SSP. Results Among DRB1∗07-DQB1∗02 individuals, 20.23% (HC, 34/168) and 22.14% (DC, 60/271) possessed the EH ‘A∗03-B∗07-Cw∗07-DRB1∗07-DQB1∗02’. Among DRB1∗15-DQB1∗06 individuals, 9.59% (HC, 52/542) and 19.20% (DC, 82/427) possessed ‘A∗03-B∗07-Cw∗07-DRB1∗15-DQB1∗06’ (AEH 7.1). KIR typing in ‘A∗03-B∗07-Cw∗07-DRB1∗07-DQB1∗02’ (DC, 60; HC, 34) revealed an increased frequency of inhibitory-KIR (iKIR) 2DL3 (susceptible; OR = 59.21; p < 1.33 × 10 −5 ) and reduced frequency of 3DL2 (protective; OR = 0.18; p < 2.55× 10 −4 ). Likewise, KIR typing in ‘A∗03-B∗07-Cw∗07-DRB1∗15-DQB1∗06’ (DC, 82; HC, 52), have revealed an increased frequency of iKIR 2DL2 (susceptible; OR = 11.29; p < 0.000) and reduced frequency of 2DL4 (protective; OR = 0.057; p < 0.00). HLA/KIR combinatorial analysis have revealed iKIR combinations 2DL2/3 + C1, 3DL2 + A3 and 3DL1 + Bw4 iso80 were decreased (protective; OR = 0.19; p < 0.007) and 2DL2/3 + C1 and 3DL1 + Bw4 were increased (susceptible; OR = 4.23; p < 0.024) for ‘A∗03-B∗07-Cw∗07-DRB1∗07-DQB1∗02’. However, the iKIR combinations 2DL2/3 + C1, 2DL1 + C2, 3DL2 + A3, 3DL1 + Bw4 iso80 were increased (susceptible; OR = 2.75; p < 0.037) and aKIR combinations 2DS2 + C1, 2DS1 + C2 and 3DS1 + Bw4 Iso80 were decreased (protective; OR = 0.36; p < 0.040) for ‘A∗03-B∗07-Cw∗07-DRB1∗15-DQB1∗06’. Conclusions The predominance of the extended haplotypes revealed a selection advantage for these haplotypes in south India. The evolutionary pressure has propensity to maintain HLA-KIR combinations in health and diseases and raises interesting insights and speculations. [ABSTRACT FROM AUTHOR]

Aim To find out the amino acid variations within the peptide binding pockets of DQB1* in P1 (86 and 87), P4 (13, 26 and 74) and P9 (9, 37 and 57) in AITD patients (n = 235; Hashimotos Thyroiditis, HT, n = 180; Graves types, GD, n = 55) and controls. Methods HLA-DQB1* sub-typing was performed by PCR-SSP method and the amino acid sequences of DQB1* were retrieved from the IMGT/HLA database. Results Significant differences in the presence of amino acids were observed at positions Pocket 1, Pocket 4 and Pocket 9.Of these Phe 86 , Gly 86 (each OR = 11.3; p < 0.008), Leu 87 (OR = 2.10; p < 6.0 × 10 - 5 ) , Ile 26 (OR = 11.3; p < 0.008), Leu 26 (OR = 2.24; p < 3.6 × 10 - 6 ) , His 9 (OR = 2.41; p < 0.0004), Ala 57 (OR = 2.01; p < 0.0002) were increased in HT and Asp 57 (OR = 3.65; p < 1.5 × 10 - 6 ) was increased in GD. However, amino acids Ala 86 (OR = 0.42; p < 1.4 × 10 - 6 ) , Tyr 87 (OR = 0.58; p < 0.001), Gly 26 (OR = 0.50; p < 2.1 × 10 - 4 ) , Ser 74 (OR = 0.50; p < 2.1 × 10 - 4 ) , Phe 9 (OR = 0.10; p < 1.7 × 10 - 4 ) and Ser 57 (OR = 0.35; p < 0.0006) in HT and Ala 57 (OR = 0.33; p < 0.043) in GD were decreased significantly. The high risk DQB1* alleles such as 0202, 0603, 0609, 0302, 0303 and 0503 in HT and GD were observed respectively. However, the lower risk for alleles DQB1*0501, 0502, 0601 and 0602 in HT and DQB1*0501 in GD. Allele/genotype combination analysis revealed that the Leucine (HT: OR = 2.19; p < 7.8 × 10 - 6 ) , Leucine/Non-Leucine (HT: OR = 2.67;p < 5.9 × 10 - 5 ) at position β 26 and Non-Alalanine (OR = 2.40; p < 6.6 × 10 - 7 ) , Alanine/Non-Alanine (OR = 1.90; p < 0.0057), Non-Alalanine/Non-Alanine (OR = 2.10; p < 0.007), at position β 86 were increased risk for HT. Whereas Non-Leucine (OR = 0.45; p < 7.8 × 10 - 6 ) , Non-Leucine/Non-Leucine (OR = 0.34; p < 1.5 × 10 - 6 ) at position β 26 and Alanine (OR = 0.41; p < 6.6 × 10 - 7 ) Alanine/Alanine (OR = 0.41; p < 8.5 × 10 - 5 ) at position β 86 were decreased in HT. Conclusion The presence of amino acid variations in important pockets leads to predisposition to AITD in south India. [ABSTRACT FROM AUTHOR]