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  1. Article ; Online: Protein transmission in neurodegenerative disease.

    Peng, Chao / Trojanowski, John Q / Lee, Virginia M-Y

    Nature reviews. Neurology

    2020  Volume 16, Issue 4, Page(s) 199–212

    Abstract: Most neurodegenerative diseases are characterized by the intracellular or extracellular aggregation of misfolded proteins such as amyloid-β and tau in Alzheimer disease, α-synuclein in Parkinson disease, and TAR DNA-binding protein 43 in amyotrophic ... ...

    Abstract Most neurodegenerative diseases are characterized by the intracellular or extracellular aggregation of misfolded proteins such as amyloid-β and tau in Alzheimer disease, α-synuclein in Parkinson disease, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis. Accumulating evidence from both human studies and disease models indicates that intercellular transmission and the subsequent templated amplification of these misfolded proteins are involved in the onset and progression of various neurodegenerative diseases. The misfolded proteins that are transferred between cells are referred to as 'pathological seeds'. Recent studies have made exciting progress in identifying the characteristics of different pathological seeds, particularly those isolated from diseased brains. Advances have also been made in our understanding of the molecular mechanisms that regulate the transmission process, and the influence of the host cell on the conformation and properties of pathological seeds. The aim of this Review is to summarize our current knowledge of the cell-to-cell transmission of pathological proteins and to identify key questions for future investigation.
    MeSH term(s) Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Axonal Transport ; Brain/metabolism ; Brain/pathology ; Cell Communication ; DNA-Binding Proteins/metabolism ; Endocytosis ; Exosomes/metabolism ; Genetic Predisposition to Disease ; Humans ; Huntingtin Protein/metabolism ; Huntington Disease/metabolism ; Huntington Disease/pathology ; Membrane Fusion ; Nanotubes ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Neuroglia/metabolism ; Neurons/metabolism ; Parkinson Disease/metabolism ; Parkinson Disease/pathology ; Protein Aggregation, Pathological/metabolism ; Protein Aggregation, Pathological/pathology ; Protein Transport ; alpha-Synuclein/metabolism ; tau Proteins/metabolism
    Chemical Substances Amyloid beta-Peptides ; DNA-Binding Proteins ; Huntingtin Protein ; TARDBP protein, human ; alpha-Synuclein ; tau Proteins
    Language English
    Publishing date 2020-03-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2491514-2
    ISSN 1759-4766 ; 1759-4758
    ISSN (online) 1759-4766
    ISSN 1759-4758
    DOI 10.1038/s41582-020-0333-7
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  2. Article ; Online: LRRK2 Kinase Activity Does Not Alter Cell-Autonomous Tau Pathology Development in Primary Neurons.

    Henderson, Michael X / Changolkar, Lakshmi / Trojanowski, John Q / Lee, Virginia M Y

    Journal of Parkinson's disease

    2021  Volume 11, Issue 3, Page(s) 1187–1196

    Abstract: Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD) and are also associated with genetic risk in idiopathic PD. Mutations in LRRK2, including the most common p.G2019S lead to ... ...

    Abstract Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD) and are also associated with genetic risk in idiopathic PD. Mutations in LRRK2, including the most common p.G2019S lead to elevated kinase activity, making LRRK2 kinase inhibitors prime targets for therapeutic development. However, the role of LRRK2 kinase activity in PD pathogenesis has remained unclear. While essentially all LRRK2-PD patients exhibit dopaminergic neuron loss, many of these patients do not have α-synuclein Lewy bodies in their brains. So, what is the neuropathological substrate of LRRK2-PD? Tau has emerged as a possible candidate due to the presence of tau pathology in the majority of LRRK2 mutation carriers and reports of hyperphosphorylated tau in LRRK2 animal models.
    Objective: In the current study, we aim to address whether a mutation in LRRK2 changes the cell-autonomous seeding of tau pathology in primary neurons. We also aim to assess whether LRRK2 kinase inhibitors are able to modulate tau pathology.
    Methods/results: Treatment of primary neurons with LRRK2 kinase inhibitors leads to prolonged kinase inhibition but does not alter tau pathology induction. The lack of an effect of LRRK2 kinase activity was further confirmed in primary neurons expressing LRRK2G2019S and with two different forms of pathogenic tau. In no case was there more than a minor change in tau pathology induction.
    Conclusion: Together, our results indicate that LRRK2 kinase activity is not playing a major role in the induction of tau pathology in individual neurons. Understanding the impact of LRRK2 kinase inhibitors on pathology generation is important as kinase inhibitors move forward in clinical trials.
    MeSH term(s) Animals ; Brain/metabolism ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Lewy Bodies/metabolism ; Mutation/genetics ; Neurons/metabolism ; Parkinson Disease/genetics
    Chemical Substances LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1)
    Language English
    Publishing date 2021-03-15
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2620609-2
    ISSN 1877-718X ; 1877-7171
    ISSN (online) 1877-718X
    ISSN 1877-7171
    DOI 10.3233/JPD-212562
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  3. Article ; Online: Hippocampal subfield pathologic Burden in Lewy body diseases versus Alzheimer's disease.

    Coughlin, David G / Grossman, Murray / Trojanowski, John Q / Irwin, David J

    Neuropathology and applied neurobiology

    2021  Volume 47, Issue 5, Page(s) 707–708

    MeSH term(s) Alzheimer Disease ; Hippocampus ; Humans ; Lewy Body Disease
    Language English
    Publishing date 2021-02-15
    Publishing country England
    Document type Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 80371-6
    ISSN 1365-2990 ; 0305-1846
    ISSN (online) 1365-2990
    ISSN 0305-1846
    DOI 10.1111/nan.12698
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  4. Article ; Online: Establishing an Autopsy-Based Cerebrospinal Fluid Biomarker Signature in Alzheimer Disease Patients.

    Shaw, Leslie M / Vanderstichele, Hugo / Knapik-Czajka, Malgorzata / Blennow, Kaj / Trojanowski, John Q

    Clinical chemistry

    2022  Volume 68, Issue 10, Page(s) 1336–1337

    MeSH term(s) Alzheimer Disease/cerebrospinal fluid ; Alzheimer Disease/diagnosis ; Amyloid beta-Peptides/cerebrospinal fluid ; Autopsy ; Biomarkers/cerebrospinal fluid ; Humans ; Peptide Fragments/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid
    Chemical Substances Amyloid beta-Peptides ; Biomarkers ; Peptide Fragments ; tau Proteins
    Language English
    Publishing date 2022-09-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80102-1
    ISSN 1530-8561 ; 0009-9147
    ISSN (online) 1530-8561
    ISSN 0009-9147
    DOI 10.1093/clinchem/hvac137
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  5. Article ; Online: Apraxia of Speech in the Spontaneous Speech of Nonfluent/Agrammatic Primary Progressive Aphasia.

    Ash, Sharon / Nevler, Naomi / Irwin, David J / Shellikeri, Sanjana / Rascovsky, Katya / Shaw, Leslie / Lee, Edward B / Trojanowski, John Q / Grossman, Murray

    Journal of Alzheimer's disease reports

    2023  Volume 7, Issue 1, Page(s) 589–604

    Abstract: Background: Apraxia of speech (AOS) is a core feature of nonfluent/agrammatic primary progressive aphasia (naPPA), but its precise characteristics and the prevalence of AOS features in spontaneous speech are debated.: Objective: To assess the ... ...

    Abstract Background: Apraxia of speech (AOS) is a core feature of nonfluent/agrammatic primary progressive aphasia (naPPA), but its precise characteristics and the prevalence of AOS features in spontaneous speech are debated.
    Objective: To assess the frequency of features of AOS in the spontaneous, connected speech of individuals with naPPA and to evaluate whether these features are associated with an underlying motor disorder such as corticobasal syndrome or progressive supranuclear palsy.
    Methods: We examined features of AOS in 30 patients with naPPA using a picture description task. We compared these patients to 22 individuals with behavioral variant frontotemporal dementia and 30 healthy controls. Each speech sample was evaluated perceptually for lengthened speech segments and quantitatively for speech sound distortions, pauses between and within words, and articulatory groping. We compared subgroups of naPPA with and without at least two features of AOS to assess the possible contribution of a motor impairment to speech production deficits.
    Results: naPPA patients produced both speech sound distortions and other speech sound errors. Speech segmentation was found in 27/30 (90%) of individuals. Distortions were identified in 8/30 (27%) of individuals, and other speech sound errors occurred in 18/30 (60%) of individuals. Frequent articulatory groping was observed in 6/30 (20%) of individuals. Lengthened segments were observed rarely. There were no differences in the frequencies of AOS features among naPPA subgroups as a function of extrapyramidal disease.
    Conclusion: Features of AOS occur with varying frequency in the spontaneous speech of individuals with naPPA, independently of an underlying motor disorder.
    Language English
    Publishing date 2023-06-08
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2542-4823
    ISSN (online) 2542-4823
    DOI 10.3233/ADR-220089
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  6. Article ; Online: α-Synuclein pathology in Parkinson's disease and related α-synucleinopathies.

    Henderson, Michael X / Trojanowski, John Q / Lee, Virginia M-Y

    Neuroscience letters

    2019  Volume 709, Page(s) 134316

    Abstract: Over 20 years ago, the synaptic protein α-synuclein was identified as the primary component of the Lewy bodies (LBs) that are a sine qua non of Parkinson's disease (PD). Since that time, extensive research has demonstrated that α-synuclein pathology is ... ...

    Abstract Over 20 years ago, the synaptic protein α-synuclein was identified as the primary component of the Lewy bodies (LBs) that are a sine qua non of Parkinson's disease (PD). Since that time, extensive research has demonstrated that α-synuclein pathology is not only a hallmark of PD, but can also cause neuronal dysfunction and death. Detailed staging of α-synuclein pathology in the brains of patients has revealed a progressive pattern of pathology that correlates with the symptoms of disease. Early in the disease course, PD patients exhibit motor dysfunction, and α-synuclein pathology at this stage is primarily found in regions controlling motor function. At later stages of disease as patients' cognitive function deteriorates, α-synuclein pathology can be found in cortical structures responsible for higher cognitive processing. The stereotypical progression of α-synuclein pathology through the brain over time suggests that there may be a physical transmission of pathological α-synuclein from one area of the brain to another. The transmission hypothesis posits that an initial seed of pathological α-synuclein in one neuron may be released and taken up by another vulnerable neuron and thereby initiate pathological misfolding of α-synuclein in the recipient neuron. In recent years, convergent evidence from various studies has indicated that pathological protein transmission can occur in the human brain. Cell and animal models based on the transmission hypothesis have shown not only that pathological α-synuclein can be transmitted from cell-to-cell, but that this pathology can lead to neuronal dysfunction and degeneration. The α-synuclein transmission hypothesis has profound implications for treatment of what is currently an intractable neurodegenerative disease. In this review, we explore the evidence for cell-to-cell transmission of pathological α-synuclein, the current understanding of how pathological α-synuclein can move to a new cell and template misfolding, and the therapeutic implications of α-synuclein transmission.
    MeSH term(s) Animals ; Brain/metabolism ; Brain/pathology ; Glymphatic System/metabolism ; Glymphatic System/pathology ; Humans ; Lewy Bodies/metabolism ; Lewy Bodies/pathology ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Parkinson Disease/pathology ; Synucleinopathies/genetics ; Synucleinopathies/metabolism ; Synucleinopathies/pathology ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism
    Chemical Substances alpha-Synuclein
    Language English
    Publishing date 2019-06-03
    Publishing country Ireland
    Document type Journal Article ; Review
    ZDB-ID 194929-9
    ISSN 1872-7972 ; 0304-3940
    ISSN (online) 1872-7972
    ISSN 0304-3940
    DOI 10.1016/j.neulet.2019.134316
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  7. Article ; Online: Transmission of α-synuclein seeds in neurodegenerative disease: recent developments.

    Karpowicz, Richard J / Trojanowski, John Q / Lee, Virginia M-Y

    Laboratory investigation; a journal of technical methods and pathology

    2019  Volume 99, Issue 7, Page(s) 971–981

    Abstract: Cell-to-cell transmission of proteopathic alpha-synuclein (α-syn) seeds is increasingly thought to underlie the progression of neurodegenerative diseases including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and related ... ...

    Abstract Cell-to-cell transmission of proteopathic alpha-synuclein (α-syn) seeds is increasingly thought to underlie the progression of neurodegenerative diseases including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and related synucleinopathies. As such, it is important to understand the chemical and biological relationships between cells and pathological aggregates of α-syn. This brief review updates our understanding of the templated spread of α-syn pathology in neurodegenerative disease from the perspective of proteopathic α-syn seeds, including how these seeds are processed by cells as well as their effects on cellular function. Recent advances in understanding the conformations of α-syn seeds are highlighted, and the possible structural basis for the observed heterogeneity of synucleinopathies is discussed. Finally, we propose the possibility that some known risk factors for synucleinopathies may in fact potentiate the cell-to-cell transmission of α-syn pathology via imbalances in interrelated cell biological processes.
    MeSH term(s) Animals ; Disease Progression ; Endocytosis ; Humans ; Synucleinopathies/etiology ; Synucleinopathies/metabolism ; alpha-Synuclein/metabolism
    Chemical Substances alpha-Synuclein
    Language English
    Publishing date 2019-02-13
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 80178-1
    ISSN 1530-0307 ; 0023-6837
    ISSN (online) 1530-0307
    ISSN 0023-6837
    DOI 10.1038/s41374-019-0195-z
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  8. Article ; Online: Neuroimmune interactions in Alzheimer's disease-New frontier with old challenges?

    Prokop, Stefan / Lee, Virginia M Y / Trojanowski, John Q

    Progress in molecular biology and translational science

    2019  Volume 168, Page(s) 183–201

    Abstract: The perceived role of the immune system in neurodegenerative diseases has undergone drastic changes over time. Initially considered as a passive bystander, then condemned as a mediator of neurodegeneration and now established as an important player in ... ...

    Abstract The perceived role of the immune system in neurodegenerative diseases has undergone drastic changes over time. Initially considered as a passive bystander, then condemned as a mediator of neurodegeneration and now established as an important player in the pathogenetic cascade, neuroimmune interactions have come a long way to arrive center stage in Alzheimer's disease research. Despite major breakthroughs in recent years, basic questions remain unanswered as conflicting data describe immune overactivation, inadequate response or exhaustion of the immune system in neurodegenerative diseases. Furthermore, difficulties in translating in vitro and in vivo studies in model systems to the complex human disease condition with multiple overlapping pathologies and the long disease duration in patients suffering from neurodegenerative diseases have hampered progress. Development of novel, advanced model systems, as well as new technologies to interrogate existing disease models and valuable collections of human tissue samples, including brain tissue in parallel with improved imaging and biomarker technologies are guiding the way to better understand the role of the immune system in Alzheimer's disease with hopes for more effective interventions in the future.
    MeSH term(s) Alzheimer Disease/immunology ; Alzheimer Disease/pathology ; Animals ; Humans ; Immune System/immunology ; Immune System/pathology ; Neuroimmunomodulation
    Language English
    Publishing date 2019-10-24
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2471995-X
    ISSN 1878-0814 ; 0079-6603 ; 1877-1173
    ISSN (online) 1878-0814
    ISSN 0079-6603 ; 1877-1173
    DOI 10.1016/bs.pmbts.2019.10.002
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  9. Article ; Online: Polypathologic Associations with Gray Matter Atrophy in Neurodegenerative Disease.

    Phillips, Jeffrey S / Robinson, John L / Cousins, Katheryn A Q / Wolk, David A / Lee, Edward B / McMillan, Corey T / Trojanowski, John Q / Grossman, Murray / Irwin, David J

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2024  Volume 44, Issue 6

    Abstract: Mixed pathologies are common in neurodegenerative disease; however, antemortem imaging rarely captures copathologic effects on brain atrophy due to a lack of validated biomarkers for non-Alzheimer's pathologies. We leveraged a dataset comprising ... ...

    Abstract Mixed pathologies are common in neurodegenerative disease; however, antemortem imaging rarely captures copathologic effects on brain atrophy due to a lack of validated biomarkers for non-Alzheimer's pathologies. We leveraged a dataset comprising antemortem MRI and postmortem histopathology to assess polypathologic associations with atrophy in a clinically heterogeneous sample of 125 human dementia patients (41 female, 84 male) with T1-weighted MRI ≤ 5 years before death and postmortem ordinal ratings of amyloid-[Formula: see text], tau, TDP-43, and [Formula: see text]-synuclein. Regional volumes were related to pathology using linear mixed-effects models; approximately 25% of data were held out for testing. We contrasted a polypathologic model comprising independent factors for each proteinopathy with two alternatives: a model that attributed atrophy entirely to the protein(s) associated with the patient's primary diagnosis and a protein-agnostic model based on the sum of ordinal scores for all pathology types. Model fits were evaluated using log-likelihood and correlations between observed and fitted volume scores. Additionally, we performed exploratory analyses relating atrophy to gliosis, neuronal loss, and angiopathy. The polypathologic model provided superior fits in the training and testing datasets. Tau, TDP-43, and [Formula: see text]-synuclein burden were inversely associated with regional volumes, but amyloid-[Formula: see text] was not. Gliosis and neuronal loss explained residual variance in and mediated the effects of tau, TDP-43, and [Formula: see text]-synuclein on atrophy. Regional brain atrophy reflects not only the primary molecular pathology but also co-occurring proteinopathies; inflammatory immune responses may independently contribute to degeneration. Our findings underscore the importance of antemortem biomarkers for detecting mixed pathology.
    MeSH term(s) Humans ; Male ; Female ; Neurodegenerative Diseases/diagnostic imaging ; Neurodegenerative Diseases/pathology ; Gray Matter/pathology ; tau Proteins/metabolism ; Gliosis/pathology ; Atrophy/pathology ; Amyloid ; Synucleins ; DNA-Binding Proteins/metabolism ; Biomarkers ; Alzheimer Disease/pathology
    Chemical Substances tau Proteins ; Amyloid ; Synucleins ; DNA-Binding Proteins ; Biomarkers
    Language English
    Publishing date 2024-02-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.0808-23.2023
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  10. Article ; Online: Mechanisms of Cell-to-Cell Transmission of Pathological Tau: A Review.

    Gibbons, Garrett S / Lee, Virginia M Y / Trojanowski, John Q

    JAMA neurology

    2018  Volume 76, Issue 1, Page(s) 101–108

    Abstract: Importance: Intracellular tau protein aggregates are a pathological hallmark of neurodegenerative tauopathies, including Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease. Emerging evidence ... ...

    Abstract Importance: Intracellular tau protein aggregates are a pathological hallmark of neurodegenerative tauopathies, including Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease. Emerging evidence supports a model of cell-to-cell transmission of proteinaceous pathological tau seeds, which leads to recruitment and templated fibrillization of endogenous cellular tau followed by the spread of abnormal tau throughout the brain. These findings lead to the strain hypothesis, which predicts that distinct conformational strains or polymorphs of tau may underlie the clinical and neuropathological heterogeneity and cell-type specificity of tauopathies. In this review, we describe the evidence for propagation of distinct tau strains in cell culture and animal models of AD and mechanistic insights into cell-to-cell transmission of pathological tau.
    Observations: Intracranial injections of synthetic tau-preformed fibrils and human brain-derived pathological tau into nontransgenic wild-type mice and transgenic mouse models of AD expressing β-amyloid and tau-amyloid deposits yield widespread pathological tau aggregates observed in neuroanatomically connected brain regions distant from the site of injection. Furthermore, when human brain-derived pathological tau obtained from distinct tauopathies (ie, brains with AD, PSP, and CBD) were injected into the brains of wild-type mice, they seeded tau pathology and faithfully recapitulated cell-type specific tau inclusions characteristic of each tauopathy in a time-dependent, dose-dependent, and injection site-dependent spread reflective of the connectome of the injection site.
    Conclusions and relevance: These findings provide compelling evidence that misfolded or pathological conformers of tau undergo cell-to-cell spread in a tauopathy strain-specific manner. Importantly, evidence to date supports that pathological tau strains do not behave like infectious agents, despite growing evidence that these tau strains undergo templated propagation and spread linked to the neuroanatomical connectome of the injection site.
    MeSH term(s) Animals ; Brain/metabolism ; Cell Communication ; Humans ; Protein Folding ; Tauopathies/metabolism ; tau Proteins/metabolism
    Chemical Substances tau Proteins
    Language English
    Publishing date 2018-11-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2702023-X
    ISSN 2168-6157 ; 2168-6149
    ISSN (online) 2168-6157
    ISSN 2168-6149
    DOI 10.1001/jamaneurol.2018.2505
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