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Charles G. Glabe - One of the best experts on this subject based on the ideXlab platform.

  • early long term administration of the csf1r inhibitor plx3397 ablates microglia and reduces accumulation of intraneuronal amyloid Neuritic plaque deposition and pre fibrillar oligomers in 5xfad mouse model of alzheimer s disease
    Molecular Neurodegeneration, 2018
    Co-Authors: Justyna Sosna, Stephan Philipp, Ricardo Albay, Frank M. Laferla, Charles G. Glabe, Jorge Mauricio Reyesruiz, David Bagliettovargas
    Abstract:

    Besides the two main classical features of amyloid beta aggregation and tau-containing neurofibrillary tangle deposition, neuroinflammation plays an important yet unclear role in the pathophysiology of Alzheimer’s disease (AD). Microglia are believed to be key mediators of neuroinflammation during AD and responsible for the regulation of brain homeostasis by balancing neurotoxicity and neuroprotective events. We have previously reported evidence that Neuritic Plaques are derived from dead neurons that have accumulated intraneuronal amyloid and further recruit Iba1-positive cells, which play a role in either neuronal demise or Neuritic plaque maturation or both. To study the impact of microglia on Neuritic plaque development, we treated two-month-old 5XFAD mice with a selective colony stimulation factor 1 receptor (CSF1R) inhibitor, PLX3397, for a period of 3 months, resulting in a significant ablation of microglia. Directly after this treatment, we analyzed the amount of intraneuronal amyloid and Neuritic Plaques and performed behavioral studies including Y-maze, fear conditioning and elevated plus maze. We found that early long-term PLX3397 administration results in a dramatic reduction of both intraneuronal amyloid as well as Neuritic plaque deposition. PLX3397 treated young 5XFAD mice also displayed a significant decrease of soluble fibrillar amyloid oligomers in brain lysates, a depletion of soluble pre-fibrillar oligomers in plasma and an improvement in cognitive function measured by fear conditioning tests. Our findings demonstrate that CSF1R signaling, either directly on neurons or mediated by microglia, is crucial for the accumulation of intraneuronal amyloid and formation of Neuritic Plaques, suggesting that these two events are serially linked in a causal pathway leading to neurodegeneration and Neuritic plaque formation. CSF1R inhibitors represent potential preventative or therapeutic approach that target the very earliest stages of the formation of intraneuronal amyloid and Neuritic Plaques.

  • Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, Neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease
    BMC, 2018
    Co-Authors: Justyna Sosna, Stephan Philipp, Ricardo Albay, Jorge Mauricio Reyes-ruiz, David Baglietto-vargas, Frank M. Laferla, Charles G. Glabe
    Abstract:

    Abstract Background Besides the two main classical features of amyloid beta aggregation and tau-containing neurofibrillary tangle deposition, neuroinflammation plays an important yet unclear role in the pathophysiology of Alzheimer’s disease (AD). Microglia are believed to be key mediators of neuroinflammation during AD and responsible for the regulation of brain homeostasis by balancing neurotoxicity and neuroprotective events. We have previously reported evidence that Neuritic Plaques are derived from dead neurons that have accumulated intraneuronal amyloid and further recruit Iba1-positive cells, which play a role in either neuronal demise or Neuritic plaque maturation or both. Methods To study the impact of microglia on Neuritic plaque development, we treated two-month-old 5XFAD mice with a selective colony stimulation factor 1 receptor (CSF1R) inhibitor, PLX3397, for a period of 3 months, resulting in a significant ablation of microglia. Directly after this treatment, we analyzed the amount of intraneuronal amyloid and Neuritic Plaques and performed behavioral studies including Y-maze, fear conditioning and elevated plus maze. Results We found that early long-term PLX3397 administration results in a dramatic reduction of both intraneuronal amyloid as well as Neuritic plaque deposition. PLX3397 treated young 5XFAD mice also displayed a significant decrease of soluble fibrillar amyloid oligomers in brain lysates, a depletion of soluble pre-fibrillar oligomers in plasma and an improvement in cognitive function measured by fear conditioning tests. Conclusions Our findings demonstrate that CSF1R signaling, either directly on neurons or mediated by microglia, is crucial for the accumulation of intraneuronal amyloid and formation of Neuritic Plaques, suggesting that these two events are serially linked in a causal pathway leading to neurodegeneration and Neuritic plaque formation. CSF1R inhibitors represent potential preventative or therapeutic approach that target the very earliest stages of the formation of intraneuronal amyloid and Neuritic Plaques

Heiko Braak - One of the best experts on this subject based on the ideXlab platform.

  • sequence of aβ protein deposition in the human medial temporal lobe
    Journal of Neuropathology and Experimental Neurology, 2000
    Co-Authors: Dietmar R Thal, Eva Braak, Udo Rub, Christian Schultz, Irena Sassin, Estifanos Ghebremedhin, Kelly Del Tredici, Heiko Braak
    Abstract:

    Abstract The deposition of Abeta protein (Abeta) and the development of neurofibrillary changes are important histopathological hallmarks of Alzheimer disease (AD). In this study, the medial temporal lobe serves as a model for the changes in the anatomical distribution pattern of different types of Abeta-deposits occurring in the course of AD, as well as for the relationship between the development of Abeta-deposition and that of neurofibrillary pathology. In the first of 4 phases of beta-amyloidosis, diffuse non-Neuritic Plaques are deposited in the basal temporal neocortex. The same plaque type appears in the second phase within the external entorhinal layers pre-beta and pre-gamma, and fleecy amyloid deposits occur in the internal entorhinal layers pri-alpha, pri-beta, pri-gamma, and in CA1. In the third phase, Abeta-deposits emerge in the molecular layer of the fascia dentata, and band-like Abeta-deposits occur in the subpial portion of the molecular layer of both the entorhinal region and the temporal neocortex. In addition, confluent lake-like Abeta-deposits appear in the parvopyramidal layer of the presubicular region. The fourth phase is characterized by diffuse and core-only Plaques in CA4. Diffuse Plaques evolve sporadically in the external entorhinal layer pre-alpha. Parallel to the evolution of beta-amyloidosis as represented by the 4 phases, Neuritic Plaques gradually make their appearance in the temporal neocortex, entorhinal region, CA1, the molecular layer of the fascia dentata, and CA4. A prerequisite for their development is the presence of Abeta and the presence of neurofibrillary tangles in neurons targeting the regions where Neuritic Plaques evolve. Each of the different types of Abeta-deposits, including Neuritic Plaques, plays a specific role in the distinct developmental sequence as represented by the 4 phases so that the medial temporal lobe inexorably becomes involved to an ever greater extent. The step-for-step involvement of connected anatomical subfields highlights the importance of the entorhino-hippocampal pathways for the expansion of beta-amyloidosis. The 4 phases in the evolution of beta-amyloidosis correlate significantly with the stages of the neurofibrillary pathology proposed by Braak and Braak.

  • sequence of abeta protein deposition in the human medial temporal lobe
    Journal of Neuropathology and Experimental Neurology, 2000
    Co-Authors: Dietmar R Thal, Eva Braak, Udo Rub, Christian Schultz, Irena Sassin, Estifanos Ghebremedhin, Del Tredici K, Heiko Braak
    Abstract:

    Abstract The deposition of Abeta protein (Abeta) and the development of neurofibrillary changes are important histopathological hallmarks of Alzheimer disease (AD). In this study, the medial temporal lobe serves as a model for the changes in the anatomical distribution pattern of different types of Abeta-deposits occurring in the course of AD, as well as for the relationship between the development of Abeta-deposition and that of neurofibrillary pathology. In the first of 4 phases of beta-amyloidosis, diffuse non-Neuritic Plaques are deposited in the basal temporal neocortex. The same plaque type appears in the second phase within the external entorhinal layers pre-beta and pre-gamma, and fleecy amyloid deposits occur in the internal entorhinal layers pri-alpha, pri-beta, pri-gamma, and in CA1. In the third phase, Abeta-deposits emerge in the molecular layer of the fascia dentata, and band-like Abeta-deposits occur in the subpial portion of the molecular layer of both the entorhinal region and the temporal neocortex. In addition, confluent lake-like Abeta-deposits appear in the parvopyramidal layer of the presubicular region. The fourth phase is characterized by diffuse and core-only Plaques in CA4. Diffuse Plaques evolve sporadically in the external entorhinal layer pre-alpha. Parallel to the evolution of beta-amyloidosis as represented by the 4 phases, Neuritic Plaques gradually make their appearance in the temporal neocortex, entorhinal region, CA1, the molecular layer of the fascia dentata, and CA4. A prerequisite for their development is the presence of Abeta and the presence of neurofibrillary tangles in neurons targeting the regions where Neuritic Plaques evolve. Each of the different types of Abeta-deposits, including Neuritic Plaques, plays a specific role in the distinct developmental sequence as represented by the 4 phases so that the medial temporal lobe inexorably becomes involved to an ever greater extent. The step-for-step involvement of connected anatomical subfields highlights the importance of the entorhino-hippocampal pathways for the expansion of beta-amyloidosis. The 4 phases in the evolution of beta-amyloidosis correlate significantly with the stages of the neurofibrillary pathology proposed by Braak and Braak.

Christoph K Hitzenberger - One of the best experts on this subject based on the ideXlab platform.

  • visualization of Neuritic Plaques in alzheimer s disease by polarization sensitive optical coherence microscopy
    Scientific Reports, 2017
    Co-Authors: Bernhard Baumann, Adelheid Woehrer, Gerda Ricken, Marco Augustin, Christian Mitter, Michael Pircher, Gabor G Kovacs, Christoph K Hitzenberger
    Abstract:

    One major hallmark of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) is the deposition of extracellular senile Plaques and vessel wall deposits composed of amyloid-beta (Aβ). In AD, degeneration of neurons is preceded by the formation of Aβ Plaques, which show different morphological forms. Most of them are birefringent owing to the parallel arrangement of amyloid fibrils. Here, we present polarization sensitive optical coherence microscopy (PS-OCM) for imaging mature Neuritic Aβ Plaques based on their birefringent properties. Formalin-fixed, post-mortem brain samples of advanced stage AD patients were investigated. In several cortical brain regions, Neuritic Aβ Plaques were successfully visualized in tomographic and three-dimensional (3D) images. Cortical grey matter appeared polarization preserving, whereas Neuritic Plaques caused increased phase retardation. Consistent with the results from PS-OCM imaging, the 3D structure of senile Aβ Plaques was computationally modelled for different illumination settings and plaque sizes. Furthermore, the birefringent properties of cortical and meningeal vessel walls in CAA were investigated in selected samples. Significantly increased birefringence was found in smaller vessels. Overall, these results provide evidence that PS-OCM is able to assess amyloidosis based on intrinsic birefringent properties.

Hitzenberger, Christoph K. - One of the best experts on this subject based on the ideXlab platform.

  • Scientific Reports / Visualization of Neuritic Plaques in Alzheimers disease by polarization-sensitive optical coherence microscopy
    Nature, 2017
    Co-Authors: Baumann Bernhard, Woehrer Adelheid, Ricken Gerda, Augustin Marco, Mitter Christian, Picher Michael, Kovacs, Gabor G., Hitzenberger, Christoph K.
    Abstract:

    One major hallmark of Alzheimers disease (AD) and cerebral amyloid angiopathy (CAA) is the deposition of extracellular senile Plaques and vessel wall deposits composed of amyloid-beta (A). In AD, degeneration of neurons is preceded by the formation of A Plaques, which show different morphological forms. Most of them are birefringent owing to the parallel arrangement of amyloid fibrils. Here, we present polarization sensitive optical coherence microscopy (PS-OCM) for imaging mature Neuritic A Plaques based on their birefringent properties. Formalin-fixed, post-mortem brain samples of advanced stage AD patients were investigated. In several cortical brain regions, Neuritic A Plaques were successfully visualized in tomographic and three-dimensional (3D) images. Cortical grey matter appeared polarization preserving, whereas Neuritic Plaques caused increased phase retardation. Consistent with the results from PS-OCM imaging, the 3D structure of senile A Plaques was computationally modelled for different illumination settings and plaque sizes. Furthermore, the birefringent properties of cortical and meningeal vessel walls in CAA were investigated in selected samples. Significantly increased birefringence was found in smaller vessels. Overall, these results provide evidence that PS-OCM is able to assess amyloidosis based on intrinsic birefringent properties.(VLID)469055

Allen B Reitz - One of the best experts on this subject based on the ideXlab platform.

  • β amyloid1 42 binds to α7 nicotinic acetylcholine receptor with high affinity implications for alzheimer s disease pathology
    Journal of Biological Chemistry, 2000
    Co-Authors: Hoauyan Wang, Daniel H S Lee, Michael R Dandrea, Per A Peterson, Richard P Shank, Allen B Reitz
    Abstract:

    Alzheimer's disease pathology is characterized by the presence of Neuritic Plaques and the loss of cholinergic neurons in the brain. The underlying mechanisms leading to these events are unclear, but the 42-amino acid β-amyloid peptide (Aβ1–42) is involved. Immunohistochemical studies on human sporadic Alzheimer's disease brains demonstrate that Aβ1–42 and a neuronal pentameric cation channel, the α7 nicotinic acetylcholine receptor (α7nAChR), are both present in Neuritic Plaques and co-localize in individual cortical neurons. Using human brain tissues and cells that overexpress either α7nAChR or amyloid precursor protein as the starting material, Aβ1–42 and α7nAChR can be co-immunoprecipitated by the respective specific antibodies, suggesting that they are tightly associated. The formation of the α7nAChR·Aβ1–42complex can be efficiently suppressed by Aβ12–28, implying that this Aβ sequence region contains the binding epitope. Receptor binding experiments show that Aβ1–42 and α7nAChR bind with high affinity, and this interaction can be inhibited by α7nAChR ligands. Human neuroblastoma cells overexpressing α7nAChR are readily killed by Aβ1–42, whereas α7nAChR agonists such as nicotine and epibatidine offered protection. Because Aβ1–42 inhibits α7nAChR-dependent calcium activation and acetylcholine release, two processes critically involved in memory and cognitive functions, and the distribution of α7nAChR correlates with Neuritic Plaques in Alzheimer's disease brains, we propose that interaction of the α7nAChR and Aβ1–42 is a pivotal mechanism involved in the pathophysiology of Alzheimer's disease.

  • beta amyloid 1 42 binds to alpha7 nicotinic acetylcholine receptor with high affinity implications for alzheimer s disease pathology
    Journal of Biological Chemistry, 2000
    Co-Authors: Hoauyan Wang, Michael R Dandrea, Per A Peterson, Richard P Shank, Allen B Reitz
    Abstract:

    Abstract Alzheimer's disease pathology is characterized by the presence of Neuritic Plaques and the loss of cholinergic neurons in the brain. The underlying mechanisms leading to these events are unclear, but the 42-amino acid β-amyloid peptide (Aβ1–42) is involved. Immunohistochemical studies on human sporadic Alzheimer's disease brains demonstrate that Aβ1–42 and a neuronal pentameric cation channel, the α7 nicotinic acetylcholine receptor (α7nAChR), are both present in Neuritic Plaques and co-localize in individual cortical neurons. Using human brain tissues and cells that overexpress either α7nAChR or amyloid precursor protein as the starting material, Aβ1–42 and α7nAChR can be co-immunoprecipitated by the respective specific antibodies, suggesting that they are tightly associated. The formation of the α7nAChR·Aβ1–42complex can be efficiently suppressed by Aβ12–28, implying that this Aβ sequence region contains the binding epitope. Receptor binding experiments show that Aβ1–42 and α7nAChR bind with high affinity, and this interaction can be inhibited by α7nAChR ligands. Human neuroblastoma cells overexpressing α7nAChR are readily killed by Aβ1–42, whereas α7nAChR agonists such as nicotine and epibatidine offered protection. Because Aβ1–42 inhibits α7nAChR-dependent calcium activation and acetylcholine release, two processes critically involved in memory and cognitive functions, and the distribution of α7nAChR correlates with Neuritic Plaques in Alzheimer's disease brains, we propose that interaction of the α7nAChR and Aβ1–42 is a pivotal mechanism involved in the pathophysiology of Alzheimer's disease.