506 results match your criteria: "MassGeneral Institute for NeuroDegenerative Disease[Affiliation]"

Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease.

Acta Pharm Sin B

October 2022

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we performed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6.

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In-Depth Characterization of Endo-Lysosomal Aβ in Intact Neurons.

Biosensors (Basel)

August 2022

Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 114, 16th street, Charlestown, MA 02129, USA.

Amyloid-beta (Aβ) peptides are produced within neurons. Some peptides are released into the brain parenchyma, while others are retained inside the neurons. However, the detection of intracellular Aβ remains a challenge since antibodies against Aβ capture Aβ and its precursor proteins (i.

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Who to Enroll in Parkinson Disease Prevention Trials? The Case for Composite Prodromal Cohorts.

Neurology

August 2022

From the Department of Nutrition (S.A.M., A.A.), Harvard T.H. Chan School of Public Health; Epidemiology (K.C.H.), Optum; Department of Neurology (M.A.S.), and MassGeneral Institute for Neurodegenerative Disease (M.A.S.), Massachusetts General Hospital; Department of Epidemiology (A.A.), Harvard T.H. Chan School of Public Health; and Channing Division of Network Medicine (A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Significant progress has been made in expanding our understanding of prodromal Parkinson disease (PD), particularly for recognition of early motor and nonmotor signs and symptoms. Although identification of these prodromal features may improve our understanding of the earliest stages of PD, they are individually insufficient for early disease detection and enrollment of participants in prevention trials in most cases because of low sensitivity, specificity, and positive predictive value. Composite cohorts, composed of individuals with multiple co-occurring prodromal features, are an important resource for conducting prodromal PD research and eventual prevention trials because they are more representative of the population at risk for PD, allow investigators to evaluate the efficacy of an intervention across individuals with varying prodromal feature patterns, are able to produce larger sample sizes, and capture individuals at different stages of prodromal PD.

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Small molecules and antibodies are normally considered separately in drug discovery, except in the case of covalent conjugates. We unexpectedly discovered several small molecules that could inhibit or enhance antibody-epitope interactions which opens new possibilities in drug discovery and therapeutic modulation of auto-antibodies. We first discovered a small molecule, CRANAD-17, that enhanced the binding of an antibody to amyloid beta (Aβ), one of the major hallmarks of Alzheimer's disease, by stable triplex formation.

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Editorial: Progress of Translational Medicine in Alzheimer's Disease.

Front Aging Neurosci

July 2022

Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States.

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Ligand-free mitochondria-localized mutant AR-induced cytotoxicity in spinal bulbar muscular atrophy.

Brain

January 2023

Cell Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Spinal bulbar muscular atrophy (SBMA), the first identified CAG-repeat expansion disorder, is an X-linked neuromuscular disorder involving CAG-repeat-expansion mutations in the androgen receptor (AR) gene. We utilized CRISPR-Cas9 gene editing to engineer novel isogenic human induced pluripotent stem cell (hiPSC) models, consisting of isogenic AR knockout, control and disease lines expressing mutant AR with distinct repeat lengths, as well as control and disease lines expressing FLAG-tagged wild-type and mutant AR, respectively. Adapting a small-molecule cocktail-directed approach, we differentiate the isogenic hiPSC models into motor neuron-like cells with a highly enriched population to uncover cell-type-specific mechanisms underlying SBMA and to distinguish gain- from loss-of-function properties of mutant AR in disease motor neurons.

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Modifiable risk factors for incident dementia and cognitive impairment: An umbrella review of evidence.

J Affect Disord

October 2022

Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address:

Background: Dementia and cognitive impairment can be attributed to genetic and modifiable factors. Considerable evidence emerged in modifiable factors and urgently requires standardized evaluation. We conducted an umbrella review to evaluate the strength and validity of the existing evidence.

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Effects of cerebral amyloid angiopathy on the brain vasculome.

Aging Cell

August 2022

MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.

β-amyloid (Aβ) deposits in brain blood vessel walls underlie the vascular pathology of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). Growing evidence has suggested the involvement of cerebrovascular dysfunction in the initiation and progression of cognitive impairment in AD and CAA patients. Therefore, in this study, we assessed the brain vasculome in a mouse model in order to identify cerebrovascular pathways that may be involved in AD and CAA vascular pathogenesis in the context of aging.

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Editorial: Mechanisms of Action in Neurodegenerative Proteinopathies.

Front Neurosci

June 2022

Genetics and Aging Research Unit, Department of Neurology, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.

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The impact of vascular lesions on cognition is location dependent. Here, we assessed the contribution of small vessel disease lesions in the corpus callosum to vascular cognitive impairment in cerebral amyloid angiopathy, as a model for cerebral small vessel disease. Sixty-five patients with probable cerebral amyloid angiopathy underwent 3T magnetic resonance imaging, including a diffusion tensor imaging scan, and neuropsychological testing.

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HMGB1-NLRP3-P2X7R pathway participates in PM-induced hippocampal neuron impairment by regulating microglia activation.

Ecotoxicol Environ Saf

July 2022

School of Basic Medical Sciences, Experimental Center for Medical Research, Neurologic Disorders and Regeneration Repair Lab of Shandong Higher Education, Weifang Medical University, Weifang, China. Electronic address:

Neuroinflammation is a key mechanism underlying the cognitive impairment induced by PM, and activated microglia plays an important role in this process. However, the mechanisms by which activated microglia induced by PM impair hippocampal neurons have not been fully elucidated. In this study, we focused on the role of HMGB1-NLRP3-P2X7R pathway which mediated the microglia activation in hippocampal neurons impairment induced by PM using a co-culture model of microglia and hippocampal neurons.

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Senescent cells contribute to pathology and dysfunction in animal models. Their sparse distribution and heterogenous phenotype have presented challenges for detecting them in human tissues. We developed a senescence eigengene approach to identify these rare cells within large, diverse populations of postmortem human brain cells.

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Post-Stroke Cognitive Impairment and Dementia.

Circ Res

April 2022

Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Germany (M. Duering, M. Dichgans).

Poststroke cognitive impairment and dementia (PSCID) is a major source of morbidity and mortality after stroke worldwide. PSCID occurs as a consequence of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Cognitive impairment and dementia manifesting after a clinical stroke is categorized as vascular even in people with comorbid neurodegenerative pathology, which is common in elderly individuals and can contribute to the clinical expression of PSCID.

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Neurotechnological Approaches to the Diagnosis and Treatment of Alzheimer's Disease.

Front Neurosci

March 2022

Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, clinically defined by progressive cognitive decline and pathologically, by brain atrophy, neuroinflammation, and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Neurotechnological approaches, including optogenetics and deep brain stimulation, have exploded as new tools for not only the study of the brain but also for application in the treatment of neurological diseases. Here, we review the current state of AD therapeutics and recent advancements in both invasive and non-invasive neurotechnologies that can be used to ameliorate AD pathology, including neurostimulation via optogenetics, photobiomodulation, electrical stimulation, ultrasound stimulation, and magnetic neurostimulation, as well as nanotechnologies employing nanovectors, magnetic nanoparticles, and quantum dots.

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Author Correction: The neuronal-specific isoform of BIN1 regulates β-secretase cleavage of APP and Aβ generation in a RIN3-dependent manner.

Sci Rep

April 2022

Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

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Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.

Hum Mol Genet

August 2022

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

Hereditary spastic paraplegias (HSPs) comprise a large group of inherited neurologic disorders affecting the longest corticospinal axons (SPG1-86 plus others), with shared manifestations of lower extremity spasticity and gait impairment. Common autosomal dominant HSPs are caused by mutations in genes encoding the microtubule-severing ATPase spastin (SPAST; SPG4), the membrane-bound GTPase atlastin-1 (ATL1; SPG3A) and the reticulon-like, microtubule-binding protein REEP1 (REEP1; SPG31). These proteins bind one another and function in shaping the tubular endoplasmic reticulum (ER) network.

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Hereditary spastic paraplegias (HSPs) are a group of inherited, progressive neurodegenerative conditions characterised by prominent lower-limb spasticity and weakness, caused by a length-dependent degeneration of the longest corticospinal upper motor neurons. While more than 80 spastic paraplegia genes (SPGs) have been identified, many cases arise from mutations in genes encoding proteins which generate and maintain tubular endoplasmic reticulum (ER) membrane organisation. The ER-shaping proteins are essential for the health and survival of long motor neurons, however the mechanisms by which mutations in these genes cause the axonopathy observed in HSP have not been elucidated.

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The study of Alzheimer's disease (AD), the most common cause of dementia, faces challenges in terms of understanding the cause, monitoring the pathogenesis, and developing early diagnoses and effective treatments. Rapid and accurate identification of AD biomarkers in the brain is critical to providing key insights into AD and facilitating the development of early diagnosis methods. In this work, we developed a platform that enables a rapid screening of AD biomarkers by employing graphene-assisted Raman spectroscopy and machine learning interpretation in AD transgenic animal brains.

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The neuronal-specific isoform of BIN1 regulates β-secretase cleavage of APP and Aβ generation in a RIN3-dependent manner.

Sci Rep

March 2022

Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Genome-wide association studies have identified BIN1 (Bridging integrator 1) and RIN3 (Ras and Rab interactor 3) as genetic risk factors for late-onset Alzheimer's disease (LOAD). The neuronal isoform of BIN1 (BIN1V1), but not the non-neuronal isoform (BIN1V9), has been shown to regulate tau-pathology and Aβ generation via RAB5-mediated endocytosis in neurons. BIN1 directly interacts with RIN3 to initiate RAB5-mediated endocytosis, which is essential for β-secretase (BACE1)-mediated β-secretase cleavage of β-amyloid precursor protein (APP) to generate Amyloid-β (Aβ), the key component of senile plaques in AD.

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In understanding the role of the neurovascular unit as both a biomarker and target for disease interventions, it is vital to appreciate how the function of different components of this unit change along the vascular tree. The cells of the neurovascular unit together perform an array of vital functions, protecting the brain from circulating toxins and infection, while providing nutrients and clearing away waste products. To do so, the brain's microvasculature dilates to direct energy substrates to active neurons, regulates access to circulating immune cells, and promotes angiogenesis in response to decreased blood supply, as well as pulsating to help clear waste products and maintain the oxygen supply.

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Haemorrhagic amyloid-related imaging abnormalities on MRI are frequently observed adverse events in the context of amyloid β immunotherapy trials in patients with Alzheimer's disease. The underlying histopathology and pathophysiological mechanisms of haemorrhagic amyloid-related imaging abnormalities remain largely unknown, although coexisting cerebral amyloid angiopathy may play a key role. Here, we used MRI in cases that underwent amyloid β immunotherapy during life to screen for haemorrhagic lesions and assess underlying tissue and vascular alterations.

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Melanocortin 1 receptor activation protects against alpha-synuclein pathologies in models of Parkinson's disease.

Mol Neurodegener

February 2022

MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.

Background: Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and risk of Parkinson's disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurotoxicity induced by alpha-synuclein (αSyn), a key player in PD genetics and pathogenesis.

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Background: Astrocytes and microglia react to Aβ plaques, neurofibrillary tangles, and neurodegeneration in the Alzheimer's disease (AD) brain. Single-nuclei and single-cell RNA-seq have revealed multiple states or subpopulations of these glial cells but lack spatial information. We have developed a methodology of cyclic multiplex fluorescent immunohistochemistry on human postmortem brains and image analysis that enables a comprehensive morphological quantitative characterization of astrocytes and microglia in the context of their spatial relationships with plaques and tangles.

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Microfluidic separation of axonal and somal compartments of neural progenitor cells differentiated in a 3D matrix.

STAR Protoc

March 2022

Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.

This protocol describes the differentiation of human neural progenitor cells (hNPCs) in a microfluidic device containing a thin 3D matrix with two separate chambers, enabling a cleaner separation between axons and soma/bulk neurons. We have used this technique to study how mitochondria-associated ER membranes (MAMs) regulate the generation of somal and axonal amyloid β (Aβ) in FAD hNPCs, a cellular model of Alzheimer's disease. This protocol also details the quantification of Aβ molecules and isolation of pure axons via axotomy.

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