Toxic Proteins in Neurodegenerative Disease

Taylor, J. Paul; Hardy, John; Fischbeck, Kenneth H.

doi:10.1126/science.1067122

Cited by 1,137 publications

(862 citation statements)

References 73 publications

(61 reference statements)

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“…Antibodies that recognize conformational epitopes specific of amyloid fibrils have been found in sera of healthy and diseased patients [169], suggesting that autoimmune reactivity can play a role as an amyloid clearance mechanism in both health and disease. Many neurodegenerative diseases have similar symptoms as they result from the aggregation of the same protein(s), making diagnosis challenging at times [2]. Using the antibodies developed against specific conformations of these proteins as diagnostic tools would allow the clinician to make accurate decisions about which therapy to prescribe [170][171][172], greatly benefiting the therapeutic regimen and truly opening the door for personalized medicine.…”

Section: Developing New Technologies For Immunotherapymentioning

confidence: 99%

“…Neurodegenerative disorders of the aging population, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Frontotemporal dementia (FTD), are characterized by the progressive accumulation of misfolded protein aggregates that initially trigger synaptic damage and network dysfunction, and that eventually lead to loss of selected neuronal populations [1,2]. In AD, the proteins amyloid-β (Aβ) and tau accumulate in the neocortex, limbic system, and basal forebrain in the form of plaques and neurofibrillary tangles [3].…”

Section: Introductionmentioning

confidence: 99%

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Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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Section: Developing New Technologies For Immunotherapymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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“…Expanded CAG sequences are translated into elongated polyglutamine (polyQ) stretches. This renders the respective proteins insoluble and leads to the formation of protein aggregates [2][3][4][5][6][7] .…”

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confidence: 99%

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

et al. 2013

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Expansion of CAG repeats is a common feature of various neurodegenerative disorders, including Huntington's disease. Here we show that expanded CAG repeats bind to a translation regulatory protein complex containing MID1, protein phosphatase 2A and 40S ribosomal S6 kinase. Binding of the MID1-protein phosphatase 2A protein complex increases with CAG repeat size and stimulates translation of the CAG repeat expansion containing messenger RNA in a MID1-, protein phosphatase 2A-and mammalian target of rapamycindependent manner. Our data indicate that pathological CAG repeat expansions upregulate protein translation leading to an overproduction of aberrant protein and suggest that the MID1-complex may serve as a therapeutic target for the treatment of CAG repeat expansion disorders.

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“…The AD is characterized by accumulations of amyloid plaques and neurofibrillary tangles (Dickson, 2003;Taylor et al, 2002), which promote oxidative stress and inammation (Pratico et al, 2002) and thus exert direct and indirect neurotoxic effects.…”

Section: Introductionmentioning

confidence: 99%

Optimized Data Preprocessing for Multivariate Analysis Applied to ^99mTc-ECD SPECT Data Sets of Alzheimer's Patients and Asymptomatic Controls

Merhof

Markiewicz

Platsch

et al. 2010

J Cereb Blood Flow Metab

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Multivariate image analysis has shown potential for classification between Alzheimer's disease (AD) patients and healthy controls with a high-diagnostic performance. As image analysis of positron emission tomography (PET) and single photon emission computed tomography (SPECT) data critically depends on appropriate data preprocessing, the focus of this work is to investigate the impact of data preprocessing on the outcome of the analysis, and to identify an optimal data preprocessing method. In this work, technetium-99methylcysteinatedimer ( 99m Tc-ECD) SPECT data sets of 28 AD patients and 28 asymptomatic controls were used for the analysis. For a series of different data preprocessing methods, which includes methods for spatial normalization, smoothing, and intensity normalization, multivariate image analysis based on principal component analysis (PCA) and Fisher discriminant analysis (FDA) was applied. Bootstrap resampling was used to investigate the robustness of the analysis and the classification accuracy, depending on the data preprocessing method. Depending on the combination of preprocessing methods, significant differences regarding the classification accuracy were observed. For 99m Tc-ECD SPECT data, the optimal data preprocessing method in terms of robustness and classification accuracy is based on affine registration, smoothing with a Gaussian of 12 mm full width half maximum, and intensity normalization based on the 25% brightest voxels within the whole-brain region.

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Toxic Proteins in Neurodegenerative Disease

Cited by 1,137 publications

References 73 publications

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

Optimized Data Preprocessing for Multivariate Analysis Applied to ^99mTc-ECD SPECT Data Sets of Alzheimer's Patients and Asymptomatic Controls

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Toxic Proteins in Neurodegenerative Disease

Cited by 1,137 publications

References 73 publications

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

Optimized Data Preprocessing for Multivariate Analysis Applied to 99mTc-ECD SPECT Data Sets of Alzheimer's Patients and Asymptomatic Controls

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Product

Resources

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Optimized Data Preprocessing for Multivariate Analysis Applied to ^99mTc-ECD SPECT Data Sets of Alzheimer's Patients and Asymptomatic Controls