Alzheimer Disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, pr... more Alzheimer Disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammator y gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1β). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aβ antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aβ vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and T yroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.
BackgroundExosomes are small extracellular vesicles (EVs) originated from multivesicular endosome... more BackgroundExosomes are small extracellular vesicles (EVs) originated from multivesicular endosomes which carry biochemical information about their cell‐of‐origin and signals for surrounding cells. EVs may also play a role in spread of proteopathic tau and amyloid beta seeds in Alzheimer’s disease (AD). Thus, brain exosomes may be a valuable therapeutic target for AD treatment. Ability of brain exosomes to cross the blood brain barrier make them a potential diagnostic and monitoring tool. Despite recent progress in development of EV isolation methods, our knowledge of human brain exosomal subpopulations and their roles in disease progression is very limited.MethodCryopreserved parietal cortex from 5 late stage AD (Braak V‐VI) and 3 control (NL) cases were used for the experiment. Brain exosomes/EVs were purified by sucrose density gradient ultracentrifugation after gentle enzymatic and mechanical dissociation of the brain tissue. Microglia‐derived EVs were isolated from the brain EV ...
The Means of Progress in Improving the Results of in vitro Fertilization Based on the Identificat... more The Means of Progress in Improving the Results of in vitro Fertilization Based on the Identification and Correction of the Pathology of Hemostasis 79 schemes of ovulation induction. The cases of women under 41 are treated as relatively promising, to reason the use of donated oocytes in older women (Maheshwari et al., 2008). Paternal age also affects the conception rate: it shrinks with men after 35 due to the quality of sperm to have been deteriorated by this age (Saleh et al., 2002).
Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap ... more Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap in individuals with Alzheimer’s disease (AD). The interaction of white matter ischemic lesions with amyloid pathology seen in AD is poorly characterized. We designed a novel mouse model of subcortical white matter ischemic stroke and AD that can inform our understanding of the cellular and molecular mechanisms of mixed vascular and AD dementia. Subcortical white matter ischemic stroke underlying forelimb motor cortex was induced by local stereotactic injection of an irreversible eNOS inhibitor. Subcortical white matter ischemic stroke or sham procedures were performed on human ApoE4-targeted-replacement (TR):5XFAD mice at 8 weeks of age. Behavioral tests were done at 7, 10, 15, and 20 weeks. A subset of animals underwent 18FDG-PET/CT. At 20 weeks of age, brain tissue was examined for amyloid plaque accumulation and cellular changes. Compared with sham E4-TR:5XFAD mice, those with an early subcortical ischemic stroke showed a significant reduction in amyloid plaque burden in the region of cortex overlying the subcortical stroke. Cognitive performance was improved in E4-TR:5XFAD mice with stroke compared with sham E4-TR:5XFAD animals. Iba-1+ microglial cells in the region of cortex overlying the subcortical stroke were increased in number and morphologic complexity compared with sham E4-TR:5XFAD mice, suggesting that amyloid clearance may be promoted by an interaction between activated microglia and cortical neurons in response to subcortical stroke. This novel approach to modeling mixed vascular and AD dementia provides a valuable tool for dissecting the molecular interactions between these two common pathologies.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
with positive beta-amyloid deposition on PiB PET, defined using a standardized uptake value ratio... more with positive beta-amyloid deposition on PiB PET, defined using a standardized uptake value ratio (SUVR) of 1.5, were included. All voxels in the PiB-PET images were divided by median uptake in cerebellum and transformed into template space. Partial volume correction (PVC) was performed. Voxel-level comparisons were performed across groups both with and without PVC using SPM5.Results were assessed after correction for multiple comparisons using family-wise error at p<0.05. Subjects also completed memory, language, and visuospatial tests that may have been used to augment DATand PCA diagnosis, but was not used in diagnosis of LPA. Results:Cognitively, DAT subjects had poorer memory than lvPPA and PCA subjects, lvPPA subjects had poorer language scores than DAT and PCA subjects, and PCA had poorer visuospatial scores that lvPPA and DAT subjects. The groups did not differ on global SUVR. Regional distribution of PiB-PET was similarly widespread in each of the three groups, although PCA showed greater uptake in bilateral occipital lobe compared to DAT, and greater uptake in right occipital lobe compared to lvPPA. These findings were observed both with and without PVC. No other regional PiB-PET differences were observed across groups. Conclusions:These findings suggest that while beta-amyloid deposition is typically diffuse in Alzheimer’s disease variants, regional differences exist as compared to DAT, although this DAT group may represent those with an earlier onset. The occipital lobe is particularly vulnerable to beta-amyloid deposition, as well as neurodegeneration, in PCA.
The serine threonine kinase Akt is a master regulator of neuronal function controlling survival, ... more The serine threonine kinase Akt is a master regulator of neuronal function controlling survival, growth, metabolism, and polarity, in response to growth factors insulin, cytokines and cell stress. Akt activation is normally transient, and negative control of Akt by the phosphatase PTEN is essential. In vitro studies and some investigations of AD animal models indicate that Akt activity is decreased in AD, and that increasing Akt activity may be a useful therapeutic strategy for the disease. However recent investigations indicate Akt activity may be increased in the AD brain. We thus performed a detailed investigation S55 Oral O3-02: Disease Mechanisms (Signal Transduction
During apoptosis, activation of a family of cysteine proteases related to interleukin-1beta-conve... more During apoptosis, activation of a family of cysteine proteases related to interleukin-1beta-converting enzyme (ICE)-related proteases or "caspases" results in endoproteolytic cleavage of multiple substrates at specific aspartate residues. We have sought to develop new antibody probes for the neoepitopes in protein fragments produced by ICE-related proteolytic cleavage as specific markers of events tightly linked to apoptotic mechanisms. Here, we demonstrate that an antibody probe specific for the C terminus of a 32-kd actin fragment produced by ICE-like activity specifically labels apoptotic but not necrotic, differentiated human neuroblastoma cells in culture. Unlike probes for nonspecific DNA strand breaks confined to the nucleus or cell body, this method allows the detection of cytoskeletal fragments in cell processes as well as the perikaryon long before DNA fragmentation and cell death and therefore serves as a novel marker of apoptosis-related events in distal parts ...
Alzheimer Disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, pr... more Alzheimer Disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammator y gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1β). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aβ antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aβ vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and T yroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.
BackgroundExosomes are small extracellular vesicles (EVs) originated from multivesicular endosome... more BackgroundExosomes are small extracellular vesicles (EVs) originated from multivesicular endosomes which carry biochemical information about their cell‐of‐origin and signals for surrounding cells. EVs may also play a role in spread of proteopathic tau and amyloid beta seeds in Alzheimer’s disease (AD). Thus, brain exosomes may be a valuable therapeutic target for AD treatment. Ability of brain exosomes to cross the blood brain barrier make them a potential diagnostic and monitoring tool. Despite recent progress in development of EV isolation methods, our knowledge of human brain exosomal subpopulations and their roles in disease progression is very limited.MethodCryopreserved parietal cortex from 5 late stage AD (Braak V‐VI) and 3 control (NL) cases were used for the experiment. Brain exosomes/EVs were purified by sucrose density gradient ultracentrifugation after gentle enzymatic and mechanical dissociation of the brain tissue. Microglia‐derived EVs were isolated from the brain EV ...
The Means of Progress in Improving the Results of in vitro Fertilization Based on the Identificat... more The Means of Progress in Improving the Results of in vitro Fertilization Based on the Identification and Correction of the Pathology of Hemostasis 79 schemes of ovulation induction. The cases of women under 41 are treated as relatively promising, to reason the use of donated oocytes in older women (Maheshwari et al., 2008). Paternal age also affects the conception rate: it shrinks with men after 35 due to the quality of sperm to have been deteriorated by this age (Saleh et al., 2002).
Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap ... more Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap in individuals with Alzheimer’s disease (AD). The interaction of white matter ischemic lesions with amyloid pathology seen in AD is poorly characterized. We designed a novel mouse model of subcortical white matter ischemic stroke and AD that can inform our understanding of the cellular and molecular mechanisms of mixed vascular and AD dementia. Subcortical white matter ischemic stroke underlying forelimb motor cortex was induced by local stereotactic injection of an irreversible eNOS inhibitor. Subcortical white matter ischemic stroke or sham procedures were performed on human ApoE4-targeted-replacement (TR):5XFAD mice at 8 weeks of age. Behavioral tests were done at 7, 10, 15, and 20 weeks. A subset of animals underwent 18FDG-PET/CT. At 20 weeks of age, brain tissue was examined for amyloid plaque accumulation and cellular changes. Compared with sham E4-TR:5XFAD mice, those with an early subcortical ischemic stroke showed a significant reduction in amyloid plaque burden in the region of cortex overlying the subcortical stroke. Cognitive performance was improved in E4-TR:5XFAD mice with stroke compared with sham E4-TR:5XFAD animals. Iba-1+ microglial cells in the region of cortex overlying the subcortical stroke were increased in number and morphologic complexity compared with sham E4-TR:5XFAD mice, suggesting that amyloid clearance may be promoted by an interaction between activated microglia and cortical neurons in response to subcortical stroke. This novel approach to modeling mixed vascular and AD dementia provides a valuable tool for dissecting the molecular interactions between these two common pathologies.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
with positive beta-amyloid deposition on PiB PET, defined using a standardized uptake value ratio... more with positive beta-amyloid deposition on PiB PET, defined using a standardized uptake value ratio (SUVR) of 1.5, were included. All voxels in the PiB-PET images were divided by median uptake in cerebellum and transformed into template space. Partial volume correction (PVC) was performed. Voxel-level comparisons were performed across groups both with and without PVC using SPM5.Results were assessed after correction for multiple comparisons using family-wise error at p<0.05. Subjects also completed memory, language, and visuospatial tests that may have been used to augment DATand PCA diagnosis, but was not used in diagnosis of LPA. Results:Cognitively, DAT subjects had poorer memory than lvPPA and PCA subjects, lvPPA subjects had poorer language scores than DAT and PCA subjects, and PCA had poorer visuospatial scores that lvPPA and DAT subjects. The groups did not differ on global SUVR. Regional distribution of PiB-PET was similarly widespread in each of the three groups, although PCA showed greater uptake in bilateral occipital lobe compared to DAT, and greater uptake in right occipital lobe compared to lvPPA. These findings were observed both with and without PVC. No other regional PiB-PET differences were observed across groups. Conclusions:These findings suggest that while beta-amyloid deposition is typically diffuse in Alzheimer’s disease variants, regional differences exist as compared to DAT, although this DAT group may represent those with an earlier onset. The occipital lobe is particularly vulnerable to beta-amyloid deposition, as well as neurodegeneration, in PCA.
The serine threonine kinase Akt is a master regulator of neuronal function controlling survival, ... more The serine threonine kinase Akt is a master regulator of neuronal function controlling survival, growth, metabolism, and polarity, in response to growth factors insulin, cytokines and cell stress. Akt activation is normally transient, and negative control of Akt by the phosphatase PTEN is essential. In vitro studies and some investigations of AD animal models indicate that Akt activity is decreased in AD, and that increasing Akt activity may be a useful therapeutic strategy for the disease. However recent investigations indicate Akt activity may be increased in the AD brain. We thus performed a detailed investigation S55 Oral O3-02: Disease Mechanisms (Signal Transduction
During apoptosis, activation of a family of cysteine proteases related to interleukin-1beta-conve... more During apoptosis, activation of a family of cysteine proteases related to interleukin-1beta-converting enzyme (ICE)-related proteases or "caspases" results in endoproteolytic cleavage of multiple substrates at specific aspartate residues. We have sought to develop new antibody probes for the neoepitopes in protein fragments produced by ICE-related proteolytic cleavage as specific markers of events tightly linked to apoptotic mechanisms. Here, we demonstrate that an antibody probe specific for the C terminus of a 32-kd actin fragment produced by ICE-like activity specifically labels apoptotic but not necrotic, differentiated human neuroblastoma cells in culture. Unlike probes for nonspecific DNA strand breaks confined to the nucleus or cell body, this method allows the detection of cytoskeletal fragments in cell processes as well as the perikaryon long before DNA fragmentation and cell death and therefore serves as a novel marker of apoptosis-related events in distal parts ...
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