Gulf war toxicant-induced effects on the hippocampal dendritic arbor are reversed by treatment with a Withania somnifera extract.

Gulf War Illness (GWI) is a multi-symptom disorder that manifests with fatigue, sleep disturbances, mood-cognition pathologies, and musculoskeletal symptoms. GWI affects at least 25% of the military personnel that served in Operations Desert Shield and Desert Storm from 1990 to 1991. We modeled Gulf War toxicant exposure in C57BL/6J mice by combined exposure to pyridostigmine bromide (an anti-sarin drug), chlorpyrifos (an organophosphate insecticide), and DEET (an insect repellent) for 10 days followed by oral treatment with Withania somnifera root extract for 21 days beginning at 12 weeks post-exposure. W. somnifera, commonly referred to as ashwagandha, has been used in traditional Ayurvedic medicine for centuries to improve memory and reduce inflammation, and its roots contain bioactive molecules which share functional groups with modern pain, cancer, and anti-inflammatory drugs. Previously, we observed that GWI mice displayed chronic reductions in dendritic arbor and loss of spines in granule cells of the dentate gyrus of the hippocampus at 14 weeks post-exposure. Here, we examined the effects of treatment with W. somnifera root extract on chronic dendrite and spine morphology in dentate granule cells of the mouse hippocampus following Gulf War toxicant exposure. GWI mice showed approximately 25% decreases in dendritic length (p < 0.0001) and overall dendritic spine density with significant reductions in thin and mushroom spines. GWI mice treated with the Ayurvedic W. somnifera extract exhibited dendritic lengths and spine densities near normal levels. These findings demonstrate the efficacy of the Ayurvedic treatment for neuroprotection following these toxic exposures. We hope that the extract and the neuronal processes influenced will open new avenues of research regarding treatment of Gulf War Illness and neurodegenerative disorders.

Impact of the COVID-19 pandemic on some modifiable risk factors of dementia in an aging, rural Indian population.

Introduction: The impact of the COVID-19 pandemic and associated lockdowns is likely to have caused adverse changes in lifestyle-related/cardiovascular risk factors and other such modifiable risk factors of dementia. We aimed to examine the pandemic's impact on some modifiable risk factors of dementia among rural Indians belonging to a large, prospective aging cohort-Srinivaspura Aging, NeuoSenescence, and COGnition (SANSCOG). Methods: This was a cross-sectional study among adults aged ≥ 45 years (n = 3,148; 1,492 males and 1,656 females) residing in the villages of Srinivaspura in Karnataka state, India. SANSCOG study data (clinical and biochemical assessments) of these participants were obtained from three distinct periods: (i) the "pre-COVID period"-before India's nationwide lockdown on 24 March 2020, (ii) the "COVID period"-during the first and second waves of the pandemic, wherein the social restrictions were prominent (25 March 2020 to 30 September 2021), and (iii) the "post-COVID period"-after easing of restrictions (from 1 October 2021 onward). Proportions of participants with diabetes, hypertension, obesity, dyslipidemia (diagnosed using standard criteria), and depression (diagnosed using the Geriatric Depression Scale) were compared between the above three periods. Results: The odds of having obesity, abnormal triglycerides, and depression among individuals in the COVID period were 1.42 times, 1.38 times, and 2.65 times more than the odds in the pre-COVID period, respectively. The odds of having hypertension, obesity, abnormal total cholesterol, abnormal triglycerides, abnormal LDL, and depression among individuals in the post-COVID period were 1.27 times, 1.32 times, 1.58 times, 1.95, 1.23, and 3.05 times more than the odds in the pre-COVID period, respectively. The odds of diabetes did not differ between any of the three periods. Discussion: We found significantly higher odds of some of the studied risk factors in the COVID and post-COVID periods compared to the pre-COVID period, suggesting that the pandemic adversely impacted the physical and psychological health of this marginalized, rural Indian population. We call for urgent public health measures, such as multimodal, lifestyle-based, and psychosocial interventions, to mitigate this negative impact and reduce the future risk of dementia.

Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort.

Women carry a higher burden of Alzheimer's disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of familial AD in humans and in APPswe/PS1ΔE9 mice. Activity dependent protein translation and associative learning and memory deficits were examined in APPswe/PS1ΔE9 mice and wild-type mice. As a human comparator group, progression of cognitive dysfunction was assessed in mutation carriers and non-carriers from DIAN (Dominantly Inherited Alzheimer Network) cohort. Female APPswe/PS1ΔE9 mice did not show recall deficits after contextual fear conditioning until 8 months of age. Further, activity dependent protein translation and Akt1-mTOR signaling at the synapse were impaired in male but not in female mice until 8 months of age. Ovariectomized APPswe/PS1ΔE9 mice displayed recall deficits at 4 months of age and these were sustained until 8 months of age. Moreover, activity dependent protein translation was also impaired in 4 months old ovariectomized APPswe/PS1ΔE9 mice compared with sham female APPswe/PS1ΔE9 mice. Progression of memory impairment differed between men and women in the DIAN cohort as analyzed using linear mixed effects model, wherein men showed steeper cognitive decline irrespective of the age of entry in the study, while women showed significantly greater performance and slower decline in immediate recall (LOGIMEM) and delayed recall (MEMUNITS) than men. However, when the performance of men and women in several cognitive tasks (such as Wechsler's logical memory) are compared with the estimated year from expected symptom onset (EYO) we found no significant differences between men and women. We conclude that in familial AD patients and mouse models, females are protected, and the onset of disease is delayed as long as estrogen levels are intact.

Genes critical for development and differentiation of dopaminergic neurons are downregulated in Parkinson's disease.

We performed transcriptome analysis using RNA sequencing on substantia nigra pars compacta (SNpc) from mice after acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment and from Parkinson's disease (PD) patients. Acute and chronic exposure to MPTP resulted in decreased expression of genes involved in sodium channel regulation. However, upregulation of pro-inflammatory pathways was seen after single dose but not after chronic MPTP treatment. Dopamine biosynthesis and synaptic vesicle recycling pathways were downregulated in PD patients and after chronic MPTP treatment in mice. Genes essential for midbrain development and determination of dopaminergic phenotype such as, LMX1B, FOXA1, RSPO2, KLHL1, EBF3, PITX3, RGS4, ALDH1A1, RET, FOXA2, EN1, DLK1, GFRA1, LMX1A, NR4A2, GAP43, SNCA, PBX1, and GRB10 were downregulated in human PD and overexpression of GFP tagged LMX1B rescued MPP+ induced death in SH-SY5Y neurons. Downregulation of gene ensemble involved in development and differentiation of dopaminergic neurons indicate their potential involvement in pathogenesis and progression of human PD.

Prevalence of neuropsychiatric conditions and cognitive impairment in two parallel, aging study cohorts from rural and urban India.

INTRODUCTION: With the rising proportion of the elderly in India, the burden of neuropsychiatric conditions and cognitive impairment is escalating. METHODS: Baseline data of cognitively healthy subjects ≥45 years of age, from two longitudinal, aging cohorts in rural (n = 3262) and urban (n = 693) India, were used to calculate prevalence of depression, early-life stressful events, stroke, head injury, and cognitive impairment. RESULTS: Depression prevalence was significantly higher in rural than urban subjects, with female preponderance in both groups. Early life stressor (parental death) and head injury were significantly more common in rural than in urban India, whereas stroke was more in urban India. There was no significant difference in overall prevalence of cognitive impairment between the rural and urban cohorts; however, women had higher prevalence than men in rural, whereas this was reverse in urban subjects. Depression and stroke were significantly associated with cognitive impairment in the rural cohort. DISCUSSION: Longitudinal assessment of these neuropsychiatric conditions, with parallel cognitive monitoring, will help identify their causal relationship with dementia.

COGNITO (Computerized assessment of adult information processing): Normative scores for a rural Indian population from the SANSCOG study.

INTRODUCTION: Neuropsychological assessments are inexpensive and efficient methods to understand the cognitive abilities of individuals in research studies and clinical settings. Normative scores for such measures are crucial in serving as a reference standard for identifying cognitively healthy and impaired individuals belonging to similar sociodemographic characteristics. METHODS: Study subjects in rural India recruited into the Srinivaspura Aging, Neuro Senescence and Cognition (SANSCOG) study were administered the COGNITO battery of tests, which traverse cognitive domains of attention, memory, language, and visuospatial abilities. Percentile norms based on age and education stratification were derived for the above cohort. RESULTS: Percentile norms are commensurate with literacy levels in this population. The percentile scores for the cognitive tests show a decline for the individuals aged 75 years and above indicating lower cognitive functioning in this age group. DISCUSSION: This is the first-ever study reporting norms for diverse cognitive domains for illiterate, literate, low-literate individuals enrolled in a large-scale community-based cohort study in rural India.

Approaches to engage an aging, rural cohort in southern India during the COVID-19 crisis and the psychological impact of COVID-19 in this cohort.

INTRODUCTION: The COVID-19 pandemic produced an unprecedented crisis across the world. Long-term cohort studies were stalled, including our longitudinal aging cohort study in rural India. METHODS: We describe approaches undertaken to engage with our cohort (n = 1830) through multiple rounds of calls and how we provided useful services to our subjects during the lockdown period. Consenting subjects also underwent telephonic assessments for depression and anxiety using validated, self-report questionnaires. RESULTS: Subjects reported benefitting from our telephonic engagement strategies, including the COVID-related safety awareness and counselling service. The proportion of subjects with depression increased from 7.42% pre-COVID to 28.97% post-COVID. DISCUSSION: We envisage that such engagement strategies would improve subject rapport and cohort retention, and thus, could be adopted by similar cohort studies across the world. This marginalized, rural Indian community had severe, adverse psychological impact in this pandemic. Urgent public health measures are needed to mitigate this impact and develop appropriate preventive strategies.

Comparison of risk factors for dementia among rural and urban elderly adults-data from two cohort studies in India.

INTRODUCTION: Studies on risk factors for dementia in India, especially rural India, are sparse and therefore we aimed to assess risk factors in a rural cohort on aging and compare it with an urban cohort. METHODS: We are presenting baseline data on proportion of hypertension, diabetes, obesity, physical inactivity, and Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) scores in both cohorts. RESULTS: The rural cohort is younger and less educated than the urban cohort. The chi-square test showed that the proportion of participants with hypertension, diabetes, and obesity was lower in the rural cohort, whereas physical inactivity was higher in comparison with the urban cohort; however, the proportion of high-risk CAIDE scores was higher in the rural cohort. DISCUSSION: Despite the rural cohort having a smaller proportion of participants with hypertension, diabetes, and obesity, the overall CAIDE score was higher-the main reason for this is low educational level.

Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) study: Study protocol.

INTRODUCTION: Prospective, population-based, aging, and cognition studies are an important approach to understand normal and pathological aging processes. METHODS: This is a longitudinal, community-based cohort study (n = 10,000) in rural India, with long-term follow-up for comprehensive evaluation of risk and protective factors associated with cognitive changes during aging. All participants will undergo comprehensive clinical, neurocognitive, and biochemical assessments. Genotyping using genome-wide association studies will be done for all participants. Whole genome sequencing and brain imaging (magnetic resonance imaging) will be done in a subset. RESULTS: This study will generate a rich database of clinical, neurocognitive, biochemical, neuroimaging, and genetic data that can help identify risk and protective factors for dementia and other related disorders. DISCUSSION: This longitudinal study is first of its kind, involving comprehensive evaluations, spanning phenotype to genotype, in a rural Indian cohort, and has major public health implications.

Protein Glutathionylation and Glutaredoxin: Role in Neurodegenerative Diseases.

Oxidative stress has been implicated in the pathogenesis and progression of many neurodegenerative disorders including Parkinson's disease and Alzheimer's disease. One of the major enzyme systems involved in the defense against reactive oxygen species are the tripeptide glutathione and oxidoreductase glutaredoxin. Glutathione and glutaredoxin system are very important in the brain because of the oxidative modification of protein thiols to protein glutathione mixed disulfides with the concomitant formation of oxidized glutathione during oxidative stress. Formation of Pr-SSG acts as a sink in the brain and is reduced back to protein thiols during recovery, thus restoring protein functions. This is unlike in the liver, which has a high turnover of glutathione, and formation of Pr-SSG is very minimal as liver is able to quickly quench the prooxidant species. Given the important role glutathione and glutaredoxin play in the brain, both in normal and pathologic states, it is necessary to study ways to augment the system to help maintain the protein thiol status. This review details the importance of glutathione and glutaredoxin systems in several neurodegenerative disorders and emphasizes the potential augmentation of this system as a target to effectively protect the brain during aging.

Depression and anxiety during the first and second waves of the COVID-19 pandemic in two large, prospective, aging cohorts in rural and urban India.

Introduction: The COVID-19 pandemic resulted in a wide variety of adverse consequences, including disruption of long-term, human research studies globally. Two long-term, prospective, aging cohort studies, namely, Srinivaspura Aging, Neurosenescence and COGnition (SANSCOG) study and Tata Longitudinal Study of Aging (TLSA), conducted in rural and urban India, respectively, had to be suspended during first and second waves of COVID-19. Methods: We conducted telephonic assessments to screen for depression and anxiety in the above two cohorts comprising of adults ≥45 years, during the first wave (2020) and second wave (2021) lockdown periods in India. Further, we included depression assessments data from two additional time periods-pre-COVID (2019) and the "inter-wave" period (between the first and second waves) to compare proportions of depression in these cohorts, during four distinct time periods-(i) pre-COVID, (ii) COVID first wave lockdown, (iii) inter-wave period, and (iv) COVID second wave lockdown (rural: 684, 733, 458, 611 and urban: 317, 297, 204, 305 respectively). Results: During COVID first wave, 28.8% and 5.5% had depression and anxiety, respectively in the rural cohort. Corresponding figures in the urban cohort were 6.5% and 1.7%. During second wave, 28.8% of rural subjects had depression and 3.9% had anxiety, whereas corresponding figures in urban subjects were 13.1% and 0.66%. During the above-mentioned four time periods, proportions of depression were: rural-8.3%, 28.8%, 16.6%, 28.8%; urban-12%, 6.1%, 8.8%, 13.1%. Conclusions: Multi-fold increase in depression among aging, rural Indians during first and second waves, with high depression among subjects ≥65 years and those with comorbidities during the first wave, is concerning. Urgent public health measures are needed to address this added mental health burden and thereby, prevent further potential adverse consequences.

Rural-urban and gender differences in metabolic syndrome in the aging population from southern India: Two parallel, prospective cohort studies.

Background: Despite the growing evidence of metabolic syndrome as a major risk factor for cardiovascular and cerebrovascular disease, there are limited studies from India on its prevalence, especially in the aging population. We aimed to estimate the prevalence of metabolic syndrome and associated comorbidities in two prospective, aging cohorts from rural and urban India. Methods: In these two parallel, prospective, aging (≥ 45 years) cohorts, the samples included 2171 people from rural India (Srinivaspura Aging, Neuro Senescence and COGnition, SANSCOG cohort; April 23, 2018 to Sept 25, 2021) and 332 people from urban India (Tata Longitudinal Study on Aging, TLSA cohort; July 8, 2015 to Oct 23, 2021). Using cross-sectional data from baseline clinical and biochemical assessments, we calculated metabolic syndrome prevalence using two well established criteria, namely consensus criteria and National Cholesterol Education Program - Adult Treatment Panel III (NCEP-ATP III) criteria; further, rural-urban, gender, and age-wise differences were compared. Findings: Proportions of metabolic syndrome were 46.2 and 54.8% as per consensus criteria in rural and urban participants, respectively; corresponding numbers using NCEP-ATP III criteria were 40.3 and 45.1%. Rural-dwelling older adults had a significantly lesser prevalence of all individual metabolic syndrome parameters except impaired triglycerides and high-density lipoprotein levels. Rural women had a significantly higher prevalence of metabolic syndrome than rural men, whereas there was no significant difference among urban participants. We did not observe any consistent age-wise trend when comparing both cohorts. There was high burden of comorbidities among both groups, mostly undiagnosed in rural participants. Interpretation: Roughly one in two older adults had metabolic syndrome, urban significantly more than rural, reaching an alarming 63.1% among urban participants aged 65-74 years. The very high prevalence of undiagnosed co-morbidities among rural adults is extremely concerning, calling for urgent public health measures in this marginalised and health-disparate population. Funding: SANSCOG study is funded through the Centre for Brain Research (CBR), Indian Institute of Science (IISc) by Pratiksha Trust, the philanthropic arm of Mr. Kris Gopalakrishnan. TLSA is funded by Tata Trusts.

Normative data for three physical frailty parameters in an aging, rural Indian population.

Introduction: Physical frailty is associated with multiple adverse health outcomes. Since physical characteristics markedly vary with different populations, population-specific norms for physical frailty parameters are necessary. Such norms are lacking for the Indian population, especially for older, rural Indians. We aimed to develop normative values for three quantitative, frailty parameters-handgrip strength, "Timed Up-and-Go" (TUG) test time, and physical activity in an aging, rural Indian population. Methods: The study sample is from an ongoing, prospective, cohort (Srinivaspura NeuoSenescence and COGnition, SANSCOG) comprised of rural, community-dwelling, cognitively healthy, aging Indians. Subjects are recruited through area sampling strategy, from villages of Srinivaspura, Kolar district, Karnataka state, India. Three physical frailty parameters of Fried's phenotype-handgrip strength (n = 1787), TUG time (n = 1863), and physical activity (n = 1640) were assessed using digital hand dynamometry, TUG test, and General Physical Activity Questionnaire (GPAQ), respectively. Results: The 10th, 25th, 50th, 75th, 90th percentiles for the three frailty parameters were: right-hand grip strength (kg): males-13.9, 18.6, 23.8, 28.7, 33.7 and females-7.8, 10.6, 14.2, 17.9, 21.3; left-hand grip strength (kg): males-13.3, 18.3, 23.6, 28.9, 32.9 and females-7.9, 10.5, 14.3, 17.8, 21.2; TUG time (s): males-9.1, 10.1, 11.4, 13.4, 15.5 and females-9.5, 10.7, 12.4, 14.5, 16.6; physical activity (MET-minutes/week): males-1680; 4320; 8880; 15,840; 23,352 and females-1680; 4320; 9240; 15,120; 20,160. Discussion: Our findings show that from 45 years onwards, overall grip strength decreases and TUG time increases, with women performing significantly poorer than men across all age groups, except >75 years, where no differences were seen. Physical activity did not show any consistent trend according to age or gender. Reference values for this aging, rural Indian population were substantially lower for grip strength and higher for TUG time than aging populations in several Western and other Asian countries.

Changing demography and the challenge of dementia in India.

In India, increasing lifespan and decreasing fertility rates have resulted in a growing number of older persons. By 2050, people over 60 years of age are predicted to constitute 19.1% of the total population. This ageing of the population is expected to be accompanied by a dramatic increase in the prevalence of dementia. The aetiopathogenesis of dementia has been the subject of a number of prospective longitudinal studies in North America and Europe; however, the findings from these studies cannot simply be translated to the Indian population. The population of India is extremely diverse in terms of socio-economic, cultural, linguistic, geographical, lifestyle-related and genetic factors. Indeed, preliminary data from recently initiated longitudinal studies in India indicate that the prevalence of vascular and metabolic risk factors, as well as white matter hyperintensities, differs between urban and rural cohorts. More information on the complex role of vascular risk factors, gender and genetic influences on dementia prevalence and progression in Indian populations is urgently needed. Low-cost, culturally appropriate and scalable interventions need to be developed expeditiously and implemented through public health measures to reduce the growing burden of dementia. Here, we review the literature concerning dementia epidemiology and risk factors in the Indian population and discuss the future work that needs to be performed to put in place public health interventions to mitigate the burden of dementia.

Burden of Vitamin D, Vitamin B12 and Folic Acid Deficiencies in an Aging, Rural Indian Community.

Introduction: The important role of micronutrient deficiencies in aging-related disorders including dementia is becoming increasingly evident. However, information on their burden in India is scarce, especially, among aging and rural communities. Methods: Prevalence of vitamin D, B12 and folic acid deficiency was measured in an ongoing, aging cohort, from rural India-Srinivaspura Aging Neurosenescence and COGnition (SANSCOG) study cohort. Serum level estimation of vitamin D, B12 and folic acid, using chemiluminescence immunoassay, was performed on 1648 subjects (872 males, 776 females). Results: Mean vitamin D, B12 and folic acid levels were 23.4 ± 10.6 ng/ml, 277.4 ± 194.4 pg/ml and 6 ± 3.5 ng/ml), respectively. Prevalence of low vitamin D (<30 ng/ml), vitamin D deficiency (<20 ng/ml), B12 deficiency (<200 pg/ml) and folic acid deficiency (<3 ng/ml) were 75.7, 39.1, 42.3, and 11.1%, respectively. Significantly more women had vitamin D deficiency, whereas more men had folic acid deficiency. Women belonging to the oldest age group (≥75 years) had the maximum burden of low vitamin D (94.3%) and folic acid deficiency (21.8%). Discussion: Older, rural-dwelling Indians have high burden of vitamin D and B12 deficiencies, which is concerning given the potentially negative consequences on cognition, immunity and frailty in the aging population. Urgent public health strategies are needed to address this issue and prevent or mitigate adverse consequences.

Endothelin-1 mediated vasoconstriction leads to memory impairment and synaptic dysfunction.

Cerebrovascular lesions seen as white matter hyperintensity in MRI of elderly population caused due to micro-infracts and micro-bleeds contributes to vascular dementia. Such vascular insult caused by impairment in blood flow to specific area in brain involving small vessels can gradually worsen the pathology leading to cognitive deficits. In the present study we developed a transient model of vaso-constriction to study the impact of such pathology by bilateral injection of ET-1 (Endothelin-1; a 21 amino acid vasoconstricting peptide) into lateral ventricles of C57 mice. The impediment in cerebral blood flow decreased CD31 expression in endothelial cells lining the blood vessels around the hippocampal region, leading to memory deficits after 7 days. Activity dependent protein translation, critical for synaptic plasticity was absent in synaptoneurosomes prepared from hippocampal tissue. Further, Akt1- mTOR signaling cascade was downregulated indicating the possible cause for loss of activity dependent protein translation. However, these effects were reversed after 30 days indicating the ephemeral nature of deficits following a single vascular insult. Present study demonstrates that vasoconstriction leading to memory deficit and decline in activity dependent protein translation in hippocampus as a potential molecular mechanism impacting synaptic plasticity.

Glutaredoxin 1 Downregulation in the Substantia Nigra Leads to Dopaminergic Degeneration in Mice.

BACKGROUND: Parkinson's disease (PD) is characterized by a severe loss of the dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Perturbation of protein thiol redox homeostasis has been shown to play a role in the dysregulation of cell death and cell survival signaling pathways in these neurons. Glutaredoxin 1 (Grx1) is a thiol/disulfide oxidoreductase that catalyzes the deglutathionylation of proteins and is important for regulation of cellular protein thiol redox homeostasis. OBJECTIVES: We evaluated if the downregulation of Grx1 could lead to dopaminergic degeneration and PD-relevant motor deficits in mice. METHODS: Grx1 was downregulated unilaterally through viral vector-mediated transduction of short hairpin RNA against Grx1 into the SNpc. Behavioral assessment was performed through rotarod and elevated body swing test. Stereological analysis of tyrosine hydroxylase-positive and Nissl-positive neurons was carried out to evaluate neurodegeneration. RESULTS: Downregulation of Grx1 resulted in contralateral bias of elevated body swing and reduced latency to fall off, accelerating rotarod. This was accompanied by a loss of tyrosine hydroxylase-positive neurons in the SNpc and their DA projections in the striatum. Furthermore, there was a loss Nissl-positive neurons in the SNpc, indicating cell death. This was selective to the SNpc neurons because DA neurons in the ventral tegmental area were unaffected akin to that seen in human PD. Furthermore, Grx1 mRNA expression was substantially decreased in the SNpc from PD patients. CONCLUSIONS: Our study indicates that Grx1 is critical for the survival of SNpc DA neurons and that it is downregulated in human PD. © 2020 International Parkinson and Movement Disorder Society.

Glutaredoxin1 Diminishes Amyloid Beta-Mediated Oxidation of F-Actin and Reverses Cognitive Deficits in an Alzheimer's Disease Mouse Model.

Aims: Reactive oxygen species (ROS) generated during Alzheimer's disease (AD) pathogenesis through multiple sources are implicated in synaptic pathology observed in the disease. We have previously shown F-actin disassembly in dendritic spines in early AD (34). The actin cytoskeleton can be oxidatively modified resulting in altered F-actin dynamics. Therefore, we investigated whether disruption of redox signaling could contribute to actin network disassembly and downstream effects in the amyloid precursor protein/presenilin-1 double transgenic (APP/PS1) mouse model of AD. Results: Synaptosomal preparations from 1-month-old APP/PS1 mice showed an increase in ROS levels, coupled with a decrease in the reduced form of F-actin and increase in glutathionylated synaptosomal actin. Furthermore, synaptic glutaredoxin 1 (Grx1) and thioredoxin levels were found to be lowered. Overexpressing Grx1 in the brains of these mice not only reversed F-actin loss seen in APP/PS1 mice but also restored memory recall after contextual fear conditioning. F-actin levels and F-actin nanoarchitecture in spines were also stabilized by Grx1 overexpression in APP/PS1 primary cortical neurons, indicating that glutathionylation of F-actin is a critical event in early pathogenesis of AD, which leads to spine loss. Innovation: Loss of thiol/disulfide oxidoreductases in the synapse along with increase in ROS can render F-actin nanoarchitecture susceptible to oxidative modifications in AD. Conclusions: Our findings provide novel evidence that altered redox signaling in the form of S-glutathionylation and reduced Grx1 levels can lead to synaptic dysfunction during AD pathogenesis by directly disrupting the F-actin nanoarchitecture in spines. Increasing Grx1 levels is a potential target for novel disease-modifying therapies for AD.

CaV1.3 L-Type Calcium Channels Increase the Vulnerability of Substantia Nigra Dopaminergic Neurons in MPTP Mouse Model of Parkinson's Disease.

Mechanisms underlying the selective vulnerability of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) over those in the ventral tegmental area (VTA) to degeneration in Parkinson's disease (PD) remain poorly understood. DA neurons of SNpc and VTA are autonomous pacemakers but pacemaking in SNpc but not in VTA is accompanied by calcium influx through L-type calcium channel, CaV1.3 contributing to increased intracellular calcium and hence to cell death. CaV1.342A, an alternatively spliced short variant of CaV1.3 has increased calcium influx. We, therefore studied the role of CaV1.342 (full-length channel) and CaV1.342A in mouse SNpc in PD pathogenesis by quantifying mRNA levels of CaV1.342 and CaV1.342A in SNpc and followed the change in their levels in MPTP induced parkinsonism mouse model. Using in situ hybridization and immunohistochemistry we observed the localization of mRNA of CaV1.342 and CaV1.342A in tyrosine hydroxylase (TH) positive DA neurons. Further, mRNA levels of CaV1.342A were higher in SNpc as compared to the cortex. Upon MPTP treatment, mRNA levels of CaV1.342 and CaV1.342A maintained their levels in SNpc in spite of the loss of ~50% of the DA neurons. This indicates that the expression of CaV1.342 and CaV1.342A is maintained at a robust level during the degenerative process in the parkinsonism model.

Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer's disease mice and correlates with memory deficits in human subjects.

Calpain hyperactivation is implicated in late-stages of neurodegenerative diseases including Alzheimer's disease (AD). However, calpains are also critical for synaptic function and plasticity, and hence memory formation and learning. Since synaptic deficits appear early in AD pathogenesis prior to appearance of overt disease symptoms, we examined if localized dysregulation of calpain-1 and/or 2 contributes to early synaptic dysfunction in AD. Increased activity of synaptosomal calpain-2, but not calpain-1 was observed in presymptomatic 1 month old APPswe/PS1ΔE9 mice (a mouse model of AD) which have no evident pathological or behavioural hallmarks of AD and persisted up to 10 months of age. However, total cellular levels of calpain-2 remained unaffected. Moreover, synaptosomal calpain-2 was hyperactivated in frontal neocortical tissue samples of post-mortem brains of AD-dementia subjects and correlated significantly with decline in tests for cognitive and memory functions, and increase in levels of ß-amyloid deposits in brain. We conclude that isoform-specific hyperactivation of calpain-2, but not calpain-1 occurs at the synapse early in the pathogenesis of AD potentially contributing to the deregulation of synaptic signaling in AD. Our findings would be important in paving the way for potential therapeutic strategies for amelioration of cognitive deficits observed in ageing-related dementia disorders like AD.