A5009847380- Alzheimer's disease research and treatments
- Parkinson's Disease Mechanisms and Treatments
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Neuroinflammation and Neurodegeneration Mechanisms
- Neurological Disorders and Treatments
- Blood properties and coagulation
- Protease and Inhibitor Mechanisms
- Botulinum Toxin and Related Neurological Disorders
- Dementia and Cognitive Impairment Research
- Neurological Disease Mechanisms and Treatments
- Intracerebral and Subarachnoid Hemorrhage Research
- Barrier Structure and Function Studies
- Nerve injury and regeneration
- Cell Adhesion Molecules Research
- Stress Responses and Cortisol
- Blood Coagulation and Thrombosis Mechanisms
- Mast cells and histamine
- Renin-Angiotensin System Studies
- Caveolin-1 and cellular processes
- Advanced Glycation End Products research
- Cholinesterase and Neurodegenerative Diseases
- S100 Proteins and Annexins
- Folate and B Vitamins Research
- Ginkgo biloba and Cashew Applications
- Complement system in diseases
Rockefeller University
2016-2025
St. Michael's Hospital
2019
Laboratory of Molecular Genetics
2009-2010
University of Pennsylvania
2001-2007
Institute for Neurodegenerative Disorders
2006
Institute on Aging
2005
Children's Hospital of Philadelphia
2005
New York Medical College
1979
Brain lesions containing filamentous and aggregated alpha-synuclein are hallmarks of neurodegenerative synucleinopathies. Oxidative stress has been implicated in the formation these lesions. Using HEK 293 cells stably transfected with wild-type mutant alpha-synuclein, we demonstrated that intracellular generation nitrating agents results aggregates. Cells were exposed simultaneously to nitric oxide- superoxide-generating compounds, peroxynitrite was by monitoring oxidation dihydrorhodamine...
Alterations in cerebrovascular regulation related to vascular oxidative stress have been implicated the mechanisms of Alzheimer's disease (AD), but their role amyloid deposition and cognitive impairment associated with AD remains unclear. We used mice overexpressing Swedish mutation precursor protein (Tg2576) as a model examine reactive oxygen species produced by NADPH oxidase alterations, deposition, behavioral deficits observed these mice. found that 12- 15-month-old Tg2576 lacking...
Abstract The thrombolytic protease tissue plasminogen activator (tPA) is expressed in the CNS, where it regulates diverse functions including neuronal plasticity, neuroinflammation, and blood-brain-barrier integrity. However, its role different brain regions such as substantia nigra (SN) largely unexplored. In this study, we characterize tPA expression, activity, localization SN using a combination of retrograde tracing β-galactosidase reporter mice. We further investigate tPA’s potential...
Previous studies have shown the presence of nitrated α-synuclein (α-syn) in human Lewy bodies and other α-syn inclusions. Herein, effects tyrosine nitration on fibril formation, lipid binding, chaperone-like function, proteolytic degradation were systematically examined by employing chromatographically isolated monomeric, dimeric, oligomeric α-syn. Nitrated monomers dimers but not oligomers accelerated rate formation unmodified when present at low concentrations. Immunoelectron microscopy...
Previous studies demonstrated that alpha-synuclein (alpha-syn) fibrillization is inhibited by dopamine, and to understand the molecular basis of this process were conducted (Conway, K. A., Rochet, J. C., Bieganski, R. M., Lansbury, P. T., Jr. (2001) Science 294, 1346-1349). Dopamine inhibition alpha-syn generated exclusively spherical oligomers depended on dopamine autoxidation but not oxidation, because mutagenesis Met, His, Tyr residues in did abrogate inhibition. However, truncation at...
Increasing evidence supports a vascular contribution to Alzheimer's disease (AD), but direct connection between AD and the circulatory system has not been established. Previous work shown that blood clots formed in presence of β-amyloid peptide (Aβ), which implicated AD, have an abnormal structure are resistant degradation vitro vivo. In present study, we show Aβ specifically interacts with fibrinogen K d 26.3 ± 6.7 nM, binding site is located near C terminus β-chain, causes oligomerize....
Filamentous inclusions of α-synuclein protein are hallmarks neurodegenerative diseases collectively known as synucleinopathies. Previous studies have shown that exposure to oxidative and nitrative species stabilizes filaments in vitro, this stabilization may be due dityrosine cross-linking. To test hypothesis, we mutated tyrosine residues phenylalanine generated recombinant wild type mutant proteins. α-Synuclein proteins lacking some or all form fibrils the same extent protein. Tyrosine not...
Evidence indicates a critical role for cerebrovascular dysfunction in Alzheimer's disease (AD) pathophysiology. We have shown that fibrin(ogen), the principal blood-clotting protein, is deposited AD neurovasculature and interacts with beta-amyloid (Aβ), resulting increased formation of blood clots. As apolipoprotein E (ApoE), lipid-transporting protein three human isoforms (E2, E3, E4), also binds to Aβ, we hypothesized ApoE fibrin(ogen) may combined effect on vascular pathophysiology AD....
Astrocytes express laminin and assemble basement membranes (BMs) at their endfeet, which ensheath the cerebrovasculature. The function of astrocytic in cerebrovascular integrity is unknown. We show that ablation by tissue-specific Cre-mediated recombination disrupted endfeet BMs led to hemorrhage deep brain regions adult mice, resembling human hypertensive hemorrhage. lack impaired vascular smooth muscle cells (VSMCs), where astrocytes have a closer association with VSMCs small arterioles,...
Many Alzheimer’s disease (AD) patients suffer from cerebrovascular abnormalities such as altered cerebral blood flow and microinfarcts. Recently, fibrinogen has been identified a strong risk factor in AD, it specifically binds to β-amyloid (Aβ), thereby altering fibrin clot structure delaying degradation. To determine if the Aβ–fibrinogen interaction could be targeted potential new treatment for we designed high-throughput screen RU-505 an effective inhibitor of interaction. restored...
Numerous epidemiological studies link vascular disorders, such as hypertension, diabetes mellitus, and stroke, with Alzheimer's disease (AD). Hypertension, specifically, is an important modifiable risk factor for late-onset AD. To examine the between midlife hypertension onset of AD later in life, we chemically induced chronic TgSwDI mouse model early adulthood. Hypertension accelerated cognitive deficits Barnes maze test (P<0.05 after 3 months treatment; P<0.001 6 months), microvascular...
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with important vascular and hemostatic alterations that should be taken into account during diagnosis treatment. This study evaluates whether anticoagulation dabigatran, clinically approved oral direct thrombin inhibitor low risk of intracerebral hemorrhage, ameliorates AD pathogenesis in transgenic mouse model AD. TgCRND8 mice their wild-type littermates were treated for 1 year dabigatran etexilate or placebo. Cognition...
Chronic stress significantly alters limbic neuroarchitecture and function, potentiates emotionality in rats. restraint (CRS) increases aggression among familiar rats, anxiety, enhances fear conditioning. immobilization (CIS) induces anxiety behavior dendritic hypertrophy the basolateral amygdala, which persist beyond a recovery period. However, little else is known about emotional impact of CIS as model chronic or depression. Therefore, authors present two experiments examining learned...
α-Synuclein (α-syn) is a major protein component of the neuropathological hallmarks Parkinson's disease and related neurodegenerative disorders termed synucleinopathies. Neither mechanism α-syn fibrillization nor degradative process for has been elucidated. Previously, we showed that wild-type, mutated, fibrillar proteins are substrates calpain I in vitro. In this study, demonstrate calpain-mediated cleavage near within middle region soluble with/without tyrosine nitration oxidation...
The increase in blood flow evoked by synaptic activity is essential for normal brain function and underlies functional imaging signals. Nitric oxide, a vasodilator released NMDA receptor activation, critical the increase, but factors linking to nitric oxide-dependent hyperemia are poorly understood. Here, we show that tissue plasminogen activator (tPA), serine protease implicated signaling, required somatosensory stimulation. tPA acts facilitating neuronal oxide release, this effect does not...
Two of the most predominant features Alzheimer's disease (AD) brain are deposition β-amyloid (Aβ) plaques and inflammation. The mechanism behind these pathologies remains unknown, but there is evidence to suggest that inflammation may predate Aβ. Furthermore, immune activation increasingly being recognized as a major contributor pathogenesis disease, disorders involving systemic inflammation, such infection, aging, obesity, atherosclerosis, diabetes, depression risk factors for development...
Alzheimer's disease (AD) is characterized by the presence of proteinaceous brain deposits, atrophy, vascular dysfunction, and chronic inflammation. Along with cerebral inflammation, peripheral inflammation also evident in many AD patients. Bradykinin, a proinflammatory plasma peptide, linked to pathology. For example, bradykinin infusion into hippocampus causes learning memory deficits rats, blockade receptor lessens cognitive impairment mouse models. Even though it has been hypothesized...