A5058384553- Neuroscience and Neuropharmacology Research
- Alzheimer's disease research and treatments
- Amino Acid Enzymes and Metabolism
- Renin-Angiotensin System Studies
- Nuclear Receptors and Signaling
- Cellular transport and secretion
- Neuroinflammation and Neurodegeneration Mechanisms
- Neurological Disorders and Treatments
- Nerve injury and regeneration
- Parkinson's Disease Mechanisms and Treatments
- Cholesterol and Lipid Metabolism
- Immune Response and Inflammation
- 14-3-3 protein interactions
- Nitric Oxide and Endothelin Effects
- Gut microbiota and health
- Tryptophan and brain disorders
- Genetic Associations and Epidemiology
- Receptor Mechanisms and Signaling
- Mitochondrial Function and Pathology
- Axon Guidance and Neuronal Signaling
- MicroRNA in disease regulation
- Single-cell and spatial transcriptomics
- Lysosomal Storage Disorders Research
- Medicinal Plants and Bioactive Compounds
- Neurogenesis and neuroplasticity mechanisms
Northwestern University
2017-2024
Western University
2013-2017
Robarts Clinical Trials
2015
Abstract Background Previous studies show that antibiotic-mediated (abx) alteration of the gut microbiome (GMB) results in a reduction amyloid beta (Aβ) plaques and proinflammatory microglial phenotype male APPPS1-21 mice. However, effect GMB perturbation on astrocyte phenotypes microglial-astrocyte communication context amyloidosis has not been examined. Methods To study whether modulates amyloidosis, female mice were treated with broad-spectrum abx leading to perturbation. GFAP +...
Ace1 knockin mice have increased neuronal ACE1 and hippocampal neuron loss that is accelerated by Aβ blocked approved angiotensin pathway drugs.
Abstract Introduction Angiotensin‐converting enzyme (ACE) has been implicated in the metabolism of amyloid beta; however, causal effect ACE inhibition on risk Alzheimer's disease (AD) dementia and other common dementias is largely unknown. Methods We examined association genetically proxied with four types using a two‐sample Mendelian randomization (MR) approach. Results Genetically was associated increased AD (odds ratio per one standard deviation reduction serum [95% confidence interval];...
The sodium-coupled, hemicholinium-3-sensitive, high-affinity choline transporter (CHT) is responsible for transport of into cholinergic nerve terminals from the synaptic cleft following acetylcholine release and hydrolysis. In this study, we address regulation CHT function by plasma membrane cholesterol. We show first time that concentrated in cholesterol-rich lipid rafts both SH-SY5Y cells mouse forebrain. Treatment expressing rat with filipin, methyl-β-cyclodextrin (MβC) or cholesterol...
Sodium-coupled, high-affinity choline transporters (CHTs) are inhibited by 3-morpholinosydnonimine (SIN-1) [peroxynitrite (ONOO − ) donor]; ONOO can be produced from nitric oxide and reactive oxygen species during neurodegeneration. SIN-1 rapidly increases CHT internalization the cell surface, this correlates with decreased uptake. This study addresses mechanisms which inhibits function in human neuronal SH-SY5Y cells. Thus, mutant L531A-CHT, does not constitutively internalize into cells a...
Alzheimer's disease (AD) is a common age-related neurodegenerative disorder that characterized by progressive cognitive decline. The deficits in cognition and attentional processing are observed clinically AD linked to impaired function of cholinergic neurons release the neurotransmitter acetylcholine (ACh). high-affinity choline transporter (CHT) present at presynaptic nerve terminal responsible for reuptake produced hydrolysis ACh following its release. Disruption CHT leads decreased...
Abstract The high‐affinity choline transporter (CHT) is responsible for uptake into cholinergic neurons, with this being the rate‐limiting step acetylcholine production. Altering CHT protein disposition directly impacts activity and neurotransmission. Amyloid precursor (APP) interacts proteins increases their endocytosis from cell surface. goal of study was to examine regulation trafficking by wild‐type APP (APP wt ) determine if differs Swedish mutant Swe in SH‐SY5Y human neuroblastoma...
Abstract Background Amyloid plaque deposition and axonal degeneration are early events in AD pathogenesis. Aβ disrupts microtubules presynaptic dystrophic neurites, resulting the accumulation of impaired endolysosomal autophagic organelles transporting β-site amyloid precursor protein cleaving enzyme (BACE1). Consequently, neurites generate Aβ42 significantly contribute to deposition. Farnesyltransferase inhibitors (FTIs) have recently been investigated for repositioning toward treatment...
Lysosomes are critical for maintaining protein homeostasis and cellular metabolism. Lysosomal dysfunction disrupted trafficking contribute to cell death in neurodegenerative disorders, including Parkinson's disease dementia. We describe three complementary protocols—the use of glycosylation, western blotting, immunofluorescence, hydrolase activity measurement—to analyze the lysosomal proteins patient-derived neurons differentiated from iPSCs. These methods should help identify phenotypes...
Abstract Current scientific research is driven by the ability to manipulate gene expression utilizing Cre/loxP system in transgenic mouse models. However, artifacts Cre-driver lines that introduce undesired effects and confound results are increasingly being reported. Here, we show aberrant neuroinflammation synaptic changes two widely used Neuroinflammation CaMKIIα-iCre mice was characterized activation proliferation of microglia astrocytes layers hippocampus. Increased GFAP Iba1 levels...
Angiotensin I converting enzyme (ACE1) maintains blood pressure homeostasis by angiotensin into II in the renin-angiotensin system (RAS). ACE1 is expressed brain, where an intrinsic RAS regulates complex cognitive functions including learning and memory. has been implicated neurodegenerative disorders Alzheimer's disease Parkinson's disease, but mechanisms remain incompletely understood. Here, we performed single-nucleus RNA sequencing to characterize expression of genes hippocampus...
Abstract Angiotensin I converting enzyme (ACE1) maintains blood pressure homeostasis by angiotensin (angI) into II (angII) in the renin-angiotensin system (RAS). ACE1 is expressed brain, where an intrinsic RAS regulates complex cognitive functions including learning and memory. has been implicated neurodegenerative disorders Alzheimer’s disease (AD) Parkinson’s (PD), but mechanisms remain incompletely understood. Here, we performed single-nucleus RNA sequencing to characterize expression...
Alzheimers disease (AD) is the most common form of dementia, and multiple lines evidence support relevance amyloid beta deposition plaque accumulation in neurotoxicity cognitive decline AD. Rare mutations angiotensin converting enzyme 1 (ACE1) have been highly associated with late onset AD patients; however, mechanism for ACE1 mutation pathogenesis unknown. Given strong association abeta to pathogenesis, we investigated whether degrades abeta; affects burden 5XFAD mice vivo. To investigate...
Abstract Background Angiotensin‐converting enzyme ( ACE ) is a validated risk locus for developing late‐onset Alzheimer’s disease (LOAD). ACE1 controls blood pressure through the renin‐angiotensin system (RAS), but it also present and acts locally in brain. Hypertension associated with an increased AD, people taking select RAS‐targeting therapeutics have reduced incidence of AD. The variant rs4980 (R1284Q murine mutation) was discovered LOAD families WGS. Our group previously showed that...
The high-affinity choline transporter (CHT) is a membrane protein found in cholinergic neurons responsible for the clearance of from synaptic cleft following acetylcholine release. Dysfunction these underlies cognitive decline seen several neurological disorders, including Alzheimer's disease (AD). Several observations suggest that uptake disordered AD, thus further understanding mechanisms regulating CHT activity could provide insight into novel therapeutic strategies. active at plasma but...
Alzheimer's disease (AD) is characterized by amyloid plaques, neurofibrillary tangles, and synaptic neuronal loss. The mechanism of neuron death in AD, however, remains unexplored. Recently, a rare autosomal dominant coding mutation, T835M, was discovered the Un-coordinated 5c (Unc5c) netrin receptor gene that segregated with late-onset AD (LOAD). This mutation leads to cell HEK-293T cells reduces survival presence neurotoxic stimuli cultured primary neurons[1]. Combining this result robust...
Abstract Current scientific research is driven by the ability to manipulate gene expression utilizing Cre/loxP system in transgenic mouse models. However, artifacts Cre-driver lines that introduce undesired effects and confound results are increasingly being reported. Here, we show aberrant neuroinflammation synaptic changes two widely used Neuroinflammation CaMKIIα-iCre mice was characterized activation proliferation of microglia astrocytes layers hippocampus. Increased GFAP Iba1 levels...