Hemraj B Dodiya

Neurocrine Biosciences, Inc. · Toxicology Preclinical

It has recently become well-established that there is a connection between Alzheimer’s disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-depe...

Background Microglia, the brain-resident macrophages perform immune surveillance and engage with pathological processes resulting in phenotype changes necessary for maintaining homeostasis. In preceding studies, we showed that antibiotic-induced perturbations of the gut microbiome of APPPS1-21 mice resulted in significant attenuation in Aβ amyloido...

It has recently become well-established that there is a connection between Alzheimer’s disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-depe...

Background Previous studies show that antibiotic-mediated (abx) alteration of the gut microbiome (GMB) results in a reduction of amyloid beta (Aβ) plaques and proinflammatory microglial phenotype in male APPPS1-21 mice. However, the effect of GMB perturbation on astrocyte phenotypes and microglial-astrocyte communication in the context of amyloidos...

Sleep apnea, a clinical condition characterized by repetitive pauses in breathing that cause intermittent hypoxia (IH), affects a billion people worldwide, increases the risk for mild cognitive impairment, and is estimated to occur in up to 50% of individuals with Alzheimer’s Disease (AD). Previous work in wildtype mice has shown that IH impairs sp...

Background: Microglia, the brain-resident macrophages perform immune surveillance and engage with pathological processes resulting in phenotype changes necessary for maintaining homeostasis. In preceding studies, we showed that antibiotic-induced perturbations of the gut microbiome of APPPS1-21 mice resulted in significant attenuation in Ab amyloid...

Tau-mediated neurodegeneration is a hallmark of Alzheimer's disease. Primary tauopathies are characterized by pathological tau accumulation and neuronal and synaptic loss. Apolipoprotein E (ApoE)-mediated neuroinflammation is involved in the progression of tau-mediated neurodegeneration, and emerging evidence suggests that the gut microbiota regula...

Microglia, the brain‐resident macrophages perform immune surveillance and engage in pathological processes by changing their phenotype and maintain homeostasis. Previously, we showed that antibiotic‐mediated changes in the gut microbiome of APPPS1‐21 transgenic mice resulted in significant decrease in amyloidosis and altered microglial phenotype th...

Although mounting evidence supports that an unbalanced gut microbiota (GM) is linked to amyloid‐β deposition, the contribution of the GM to tau‐mediated neurodegeneration (TN) is poorly characterized. Our preliminary data have shown that the GM manipulations, using either treatment with a combination of antibiotics (ABX) or raising animals in germ‐...

Blood–brain barrier (BBB) dysfunction is emerging as a key pathogenic factor in the progression of Alzheimer’s disease (AD), where increased microvascular endothelial permeability has been proposed to play an important role. However, the molecular mechanisms leading to increased brain microvascular permeability in AD are not fully understood. We st...

The gut microbiome consists of the trillions of bacteria and other microbes whose metabolic activities and interactions with the immune system go beyond the gut itself. We are all aware that bacteria and other microorganisms have a significant impact on our health. Also, health of the bacteria directly reflects the health status of the body where t...

We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid β (Aβ) plaque pathology and altered phenotypes of plaque-associated microglia. Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aβ amyl...

Background: Alzheimer's disease (AD) is a fatal progressive neurodegenerative disease. Mounting evidence supports that an unbalanced gut microbiota (GM) is linked to amyloid-β deposition potentially by disrupting neuroinflammation and metabolic homeostasis. However, the contribution of the GM to tau-mediated neurodegeneration is poorly characteriz...

Background Microglia, resident macrophages of CNS constantly screen the brain and engage in pathological processes by changing their morphology, expressing various antigens and become phagocytic. This activation causes the release of a wave of chemical mediators that promote the neuroinflammatory milieu. Thus, microglial homeostasis represents a hi...

Background In prior efforts, we demonstrated reduced amyloidosis and altered microgliosis in long‐term antibiotics (abx)‐treated APPPS1‐21 male mice. Restoration of the gut microbiome into abx‐treated male mice by fecal microbiota transfer (FMT) established a causality between the gut microbiome and amyloidosis. We have used FMT studies using our c...

The opportunities in the fields of probiotics and prebiotics to a great degree stem from what we can learn about how they influence the microbiota and interact with the host. We discuss recent insights, cutting-edge technologies and controversial results from the perspective of early career researchers innovating in these areas. This perspective em...

In preceding efforts, we demonstrated that antibiotic (ABX) cocktail-mediated perturbations of the gut microbiome in two independent transgenic lines, termed APPSWE/PS1ΔE9 and APPPS1-21, leads to a reduction in Aβ deposition in male mice. To determine whether these observed reductions of cerebral Aβ amyloidosis are specific to any individual antibi...

We demonstrated that an antibiotic cocktail (ABX)-perturbed gut microbiome is associated with reduced amyloid-β (Aβ) plaque pathology and astrogliosis in the male amyloid precursor protein ( APP) SWE /presenilin 1 (PS1) ΔE9 transgenic model of Aβ amyloidosis. We now show that in an independent, aggressive APP SWE /PS1 L166P (APPPS1-21) mouse model...

Objective Recent evidence suggesting an important role of gut-derived inflammation in brain disorders has opened up new directions to explore the possible role of the gut-brain axis in neurodegenerative diseases. Given the prominence of dysbiosis and colonic dysfunction in patients with Parkinson’s disease (PD), we propose that toll-like receptor 4...

Recent evidence provides support for involvement of the microbiota-gut-brain axis in Parkinson's disease (PD) pathogenesis. We propose that a pro-inflammatory intestinal milieu, due to intestinal hyper-permeability and/or microbial dysbiosis, initiates or exacerbates PD pathogenesis. One factor that can cause intestinal hyper-permeability and dysbi...

The mechanism of neurodegeneration in Parkinson's disease (PD) remains unknown but it has been hypothesised that the intestinal tract could be an initiating and contributing factor to the neurodegenerative processes. In PD patients as well as in animal models for PD, alpha-synuclein-positive enteric neurons in the colon and evidence of colonic infl...

The integrity and function of the gut is impaired in HIV-infected individuals, and gut pathogenesis may play a role in several HIV-associated disorders. Methamphetamine is a popular illicit drug abused by HIV-infected individuals. However, the effect of methamphetamine on the gut and its potential to exacerbate HIV-associated gut pathology is not k...

Background: Alcohol increases intestinal permeability to pro-inflammatory microbial products that promote liver disease, even after a period of sobriety. We sought to test the hypothesis that alcohol affects intestinal stem cells using an in vivo model and ex vivo organoids generated from jejunum and colon from mice fed chronic alcohol. Methods:...

Parkinson's disease (PD) is usually characterized by cardinal motor impairments. However, a range of non-motor symptoms precede the motor-phase and are major determinants for the quality of life. To date, no disease modifying treatment is available for PD patients. The gold standard therapy of levodopa is based on restoring dopaminergic neurotransm...

Susceptibility to develop hepatic encephalopathy (HE) in the setting of alcoholic liver injury (ALI) is poorly understood. ALI progression to cirrhosis is the leading cause of mortality and morbidity associated with alcohol use and development of HE is a sign of poor prognosis and correlates with mortality(1). ALI and HE are characterized by hepati...

Alcoholic liver disease (ALD) progression to cirrhosis and development of hepatic encephalopathy (HE) are characterized by hepatic and brain inflammation involving innate immune cells. Identifying the risk factors and immune mechanisms involved in susceptibility to liver and brain injury are significant unmet needs. Circadian rhythm disruption prom...

Recent investigations have focused on the potential role of gastrointestinal (GI) abnormalities in the pathogenesis of Parkinson's disease (PD). The ‘dual-hit’ hypothesis of PD speculates that a putative pathogen enters the brain via two routes: the olfactory system and the GI system. Here, we investigated (1) whether local exposures of the neuroto...

Background: Recent evidence suggests that Parkinson’s disease (PD) is associated with intestinal microbiota dysbiosis, abnormal intestinal permeability, and intestinal inflammation. Objective: Our study aimed to determine if these gut abnormalities are present in another synucleinopathy, multiple system atrophy (MSA). Methods: In six MSA and 11 hea...

Introduction Alzheimer's disease (AD) is characterized by appearance of both extracellular senile plaques and intracellular neurofibrillary tangles, comprised of aggregates of misfolded amyloid-β (Aβ) and hyper-phosphorylated tau, respectively. In a previous study, we demonstrated that g3p, a capsid protein from bacteriophage M13, binds to and remo...

Transplanted multipotent human fetal neural stem cells (hfNSCs) significantly improved the function of parkinsonian monkeys in a prior study primarily by neuroprotection, with only 3%-5% of cells expressing a dopamine (DA) phenotype. In this paper, we sought to determine whether further manipulation of the neural microenvironment by overexpression...

Assessing the efficacy of human stem cell transplantation in rodent models is complicated by the significant immune rejection that occurs. Two recent reports have shown conflicting results using neonatal tolerance to xenografts in rats. Here we extend this approach to mice and assess whether neonatal tolerance can prevent the rapid rejection of xen...

The pace of nigrostriatal degeneration, both with regards to striatal denervation and loss of melanin and tyrosine hydroxylase-positive neurons, is poorly understood especially early in the Parkinson's disease process. This study investigated the extent of nigrostriatal degeneration in patients with Parkinson's disease at different disease duration...

HIV-1 proteins, including the transactivator of transcription (Tat), are believed to be involved in HIV-associated neurocognitive disorders by disrupting Ca²⁺ homeostasis, which leads to progressive dysregulation, damage, or death of neurons in the brain. We have found previously that bath-applied Tat abnormally increased Ca²⁺ influx through overac...

Despite clinicopathological evidence that Parkinson's disease (PD) may begin in peripheral tissues, identification of premotor Parkinson's disease is not yet possible. Alpha-synuclein aggregation underlies Parkinson's disease pathology, and its presence in peripheral tissues may be a reliable disease biomarker. We sought evidence of alpha-synuclein...

The diagnosis of Parkinson's disease rests on motor signs of advanced central dopamine deficiency. There is an urgent need for disease biomarkers. Clinicopathological evidence suggests that α-synuclein aggregation, the pathological signature of Parkinson's disease, can be detected in gastrointestinal tract neurons in Parkinson's disease. We studied...

The CONSORT checklist was prepared and references specific text in the study that fulfills the checklist requirements. (DOC)

A flow diagram illustrating the clinical study protocol described in this supporting document is shown as Figure 1 . (DOC)

Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. The pathological hallmark of PD is neuronal inclusions termed Lewy bodies whose main component is alpha-synuclein protein. The finding of these Lewy bodies in the intestinal enteric nerves led to the hypothesis that the intestine might be an early site of PD dis...

Multiple laboratories have recently demonstrated that long-term dopaminergic transplants form Lewy bodies in patients with Parkinson's disease. Debate has arisen as to whether these Lewy bodies form from the transfer of α synuclein from the host to the graft or whether they form from intrinsic responses of the graft from being placed into what was,...

Parkinson's disease is a progressive neurodegenerative disorder affecting, in part, dopaminergic motor neurons of the ventral midbrain and their terminal projections that course to the striatum. Symptomatic strategies focused on dopamine replacement have proven effective at remediating some motor symptoms during the course of disease but ultimately...

We examined the transduction efficiency of different adeno-associated virus (AAV) capsid serotypes encoding for green fluorescent protein (GFP) flanked by AAV2 inverted terminal repeats in the nonhuman primate basal ganglia as a prelude to translational studies, as well as clinical trials in patients with Parkinson's disease (PD). Six intact young...

We explored the relationship between ubiquitin proteasome system (UPS) and lysosomal markers and the formation of alpha-synuclein (alpha-syn) inclusions in nigral neurons in Parkinson disease (PD). Lysosome Associated Membrane Protein 1(LAMP1), Cathepsin D (CatD), and Heat Shock Protein73 (HSP73) immunoreactivity were significantly decreased within...