Sophia Schedin Weiss - Academia.edu (original) (raw)
Papers by Sophia Schedin Weiss
US neurology, 2019
have no conflicts of interest to declare in relation to the article. Review process: This is an e... more have no conflicts of interest to declare in relation to the article. Review process: This is an expert interview and, as such, has not undergone the journal's standard peer review process. Acknowledgments: Medical writing assistance was provided by Katrina Mountfort of Touch Medical Media.
Alzheimers & Dementia, Jul 1, 2017
Background: The role of vascular disease in Alzheimer’s disease (AD) is still debated. White matt... more Background: The role of vascular disease in Alzheimer’s disease (AD) is still debated. White matter hypointensity (WMH) volume is an imaging measure of vascular burden. Using MRI and Positron Emission Tomography (PET) we examined the voxel-level relationships betweenWMHand 3 key processes inAD: amyloid deposition, tau aggregation and microglial activation. Methods: 15 participants with a clinical diagnosis of AD had T1-weighted MRI, F-flutemetamol, F-AV1451 and C-PBR28 PET scans. 18 healthy controls also had F-flutemetamol and C-PBR28 scans, and 8 of these also had F-AV1451 PET. Z-score maps for each tracer (80-100 minute ratio image for F-AV1451, 90-120 minute ratio image for F-flutemetamol and logan Vd parametric map for C-PBR28 ) were calculated for the AD subjects compared to the controls for each tracer.WMHvolumes from theMRIwere calculated from Freesurfer software. Multiple regression in SPM8 was used to calculate voxel wise correlations between WMH volume and tracer uptake. A pvalue of p<0.05 was considered significant. Results:Amyloid deposition: there were correlations between WMH volume and amyloid deposition in the 1) frontal lobe (right medial and anterior orbital gyri, left posterior orbital gyrus, and right superior frontal gyri) 2) parietal lobe (left superior parietal gyrus) and 3) corpus callosum. Tau aggregation: there were correlations between WMH burden and tau aggregation in the left and right posterior temporal lobe Microglial activation :there were correlations between WMH volume and microglial activation in the 1) frontal lobe (right superior/middle frontal gyrus, right subgenual frontal cortex, right medial orbital gyrus) 2) parietal lobe (postcentral / precentral gyrus, left inferolateral part of parietal lobe and 3) occipital lobe (left lateral part of occipital lobe). Conclusions:White matter hypointensity volume correlates at voxel-level with amyloid deposition, tau aggregation and microglial activation. These findings emphasise the complex disease pathogenesis occurring in AD, and the need for a multi-targeted treatment.
Alzheimers & Dementia, Jul 1, 2014
Alzheimers & Dementia, Jul 1, 2012
European Medical Journal Neurology, Aug 9, 2022
Alzheimer's Research & Therapy
Background In Alzheimer’s disease (AD), amyloid-β 1–42 (Aβ42) neurotoxicity stems mostly from its... more Background In Alzheimer’s disease (AD), amyloid-β 1–42 (Aβ42) neurotoxicity stems mostly from its soluble oligomeric aggregates. Studies of such aggregates have been hampered by the lack of oligomer-specific research tools and their intrinsic instability and heterogeneity. Here, we developed a monoclonal antibody with a unique oligomer-specific binding profile (ALZ-201) using oligomer-stabilising technology. Subsequently, we assessed the etiological relevance of the Aβ targeted by ALZ-201 on physiologically derived, toxic Aβ using extracts from post-mortem brains of AD patients and controls in primary mouse neuron cultures. Methods Mice were immunised with stable oligomers derived from the Aβ42 peptide with A21C/A30C mutations (AβCC), and ALZ-201 was developed using hybridoma technology. Specificity for the oligomeric form of the Aβ42CC antigen and Aβ42 was confirmed using ELISA, and non-reactivity against plaques by immunohistochemistry (IHC). The antibody’s potential for cross-pro...
Supplemental material, sj-jpg-5-sjp-10.1177_14034948211064656 for Changes in mortality trends amo... more Supplemental material, sj-jpg-5-sjp-10.1177_14034948211064656 for Changes in mortality trends amongst common diseases during the COVID-19 pandemic in Sweden by Michael Axenhus, Sophia Schedin-Weiss, Bengt Winblad and Anders Wimo in Scandinavian Journal of Public Health
Supplemental material, sj-jpg-4-sjp-10.1177_14034948211064656 for Changes in mortality trends amo... more Supplemental material, sj-jpg-4-sjp-10.1177_14034948211064656 for Changes in mortality trends amongst common diseases during the COVID-19 pandemic in Sweden by Michael Axenhus, Sophia Schedin-Weiss, Bengt Winblad and Anders Wimo in Scandinavian Journal of Public Health
Supplemental material, sj-jpg-1-sjp-10.1177_14034948211064656 for Changes in mortality trends amo... more Supplemental material, sj-jpg-1-sjp-10.1177_14034948211064656 for Changes in mortality trends amongst common diseases during the COVID-19 pandemic in Sweden by Michael Axenhus, Sophia Schedin-Weiss, Bengt Winblad and Anders Wimo in Scandinavian Journal of Public Health
Supplemental material, sj-jpg-2-sjp-10.1177_14034948211064656 for Changes in mortality trends amo... more Supplemental material, sj-jpg-2-sjp-10.1177_14034948211064656 for Changes in mortality trends amongst common diseases during the COVID-19 pandemic in Sweden by Michael Axenhus, Sophia Schedin-Weiss, Bengt Winblad and Anders Wimo in Scandinavian Journal of Public Health
Scandinavian Journal of Public Health, 2021
Objective: It has been found that COVID-19 increases deaths within common diseases in countries t... more Objective: It has been found that COVID-19 increases deaths within common diseases in countries that have implemented strict lockdowns. In order to elucidate the proper national response to a pandemic, the mortality rates within COVID-19 and various diseases need to be studied in countries whose pandemic response differ. Sweden represents a country with lax pandemic restrictions, and we aimed to study the effects of COVID-19 on historical mortality rates within common diseases during 2020. Methods: Regression models and moving averages were used to predict expected premature mortality per the ICD-10 during 2020 using historical data sets. Predicted values were then compared to recorded premature mortality to identify changes in mortality trends. Results: Seasonal increased mortality was found within neurological diseases. Infectious diseases, tumours and cardiac disease mortality rates decreased compared to expected outcome. Conclusions: Changes in mortality trends were observed for...
Journal of Neurochemistry, 2020
Protein glycosylation is crucial for the central nervous system and brain functions, including pr... more Protein glycosylation is crucial for the central nervous system and brain functions, including processes that are defective in Alzheimer disease (AD) such as neurogenesis, synaptic function, and memory formation. Still, the roles of glycans in the development of AD are relatively unexplored. Glycomics studies of cerebrospinal fluid (CSF) have previously shown altered glycosylation pattern in patients with different stages of cognitive impairment, including AD, compared to healthy controls. As a consequence, we hypothesized that the glycan profile is altered in the brain of patients with AD and analyzed the asparagine‐linked (N‐linked) glycan profile in hippocampus and cortex in AD and control brain. Glycans were enzymatically liberated from brain glycoproteins and analyzed by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Eleven glycans showed significantly different levels in hippocampus compared to cortex in both control and AD brain. Two glycans in cortex and four in ...
Alzheimer's & Dementia, 2017
Background: The role of vascular disease in Alzheimer’s disease (AD) is still debated. White matt... more Background: The role of vascular disease in Alzheimer’s disease (AD) is still debated. White matter hypointensity (WMH) volume is an imaging measure of vascular burden. Using MRI and Positron Emission Tomography (PET) we examined the voxel-level relationships betweenWMHand 3 key processes inAD: amyloid deposition, tau aggregation and microglial activation. Methods: 15 participants with a clinical diagnosis of AD had T1-weighted MRI, F-flutemetamol, F-AV1451 and C-PBR28 PET scans. 18 healthy controls also had F-flutemetamol and C-PBR28 scans, and 8 of these also had F-AV1451 PET. Z-score maps for each tracer (80-100 minute ratio image for F-AV1451, 90-120 minute ratio image for F-flutemetamol and logan Vd parametric map for C-PBR28 ) were calculated for the AD subjects compared to the controls for each tracer.WMHvolumes from theMRIwere calculated from Freesurfer software. Multiple regression in SPM8 was used to calculate voxel wise correlations between WMH volume and tracer uptake. A pvalue of p<0.05 was considered significant. Results:Amyloid deposition: there were correlations between WMH volume and amyloid deposition in the 1) frontal lobe (right medial and anterior orbital gyri, left posterior orbital gyrus, and right superior frontal gyri) 2) parietal lobe (left superior parietal gyrus) and 3) corpus callosum. Tau aggregation: there were correlations between WMH burden and tau aggregation in the left and right posterior temporal lobe Microglial activation :there were correlations between WMH volume and microglial activation in the 1) frontal lobe (right superior/middle frontal gyrus, right subgenual frontal cortex, right medial orbital gyrus) 2) parietal lobe (postcentral / precentral gyrus, left inferolateral part of parietal lobe and 3) occipital lobe (left lateral part of occipital lobe). Conclusions:White matter hypointensity volume correlates at voxel-level with amyloid deposition, tau aggregation and microglial activation. These findings emphasise the complex disease pathogenesis occurring in AD, and the need for a multi-targeted treatment.
Biochemical and biophysical research communications, Jan 23, 2016
The toxic amyloid β-peptide (Aβ) is a key player in Alzheimer Disease (AD) pathogenesis and selec... more The toxic amyloid β-peptide (Aβ) is a key player in Alzheimer Disease (AD) pathogenesis and selective inhibition of the production of this peptide is sought for. Aβ is produced by the sequential cleavage of the Aβ precursor protein (APP) by β-secretase (to yield APP-C-terminal fragment β (APP-CTFβ) and soluble APPβ (sAPPβ)) and γ-secretase (to yield Aβ). We reasoned that proteins that associate with γ-secretase are likely to regulate Aβ production and to be targets of pharmaceutical interventions and therefore performed a pull-down assay to screen for such proteins in rat brain. Interestingly, one of the purified proteins was potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (HCN2), which has been shown to be involved in epilepsy. We found that silencing of HCN2 resulted in decreased secreted Aβ levels. To further investigate the mechanism behind this reduction, we also determined the levels of full-length APP, sAPP and APP-CTF species after silencin...
Alzheimer's & Dementia, 2014
Thrombosis and haemostasis, 2010
Zn2+ ions were found to efficiently inhibit activated protein C (APC), suggesting a potential reg... more Zn2+ ions were found to efficiently inhibit activated protein C (APC), suggesting a potential regulatory function for such inhibition. APC activity assays employing a chromogenic peptide substrate demonstrated that the inhibition was reversible and the apparent K I was 13 +/- 2 microM. k cat was seven fold decreased whereas K M was unaffected in the presence of 10 microM Zn2+. The inhibitory effect of Zn2+ on APC activity was also observed when factor Va was used as a substrate in an assay coupled to a prothrombinase assay. The interaction of Zn2+ with APC was accompanied by a reversible approximately 40% decrease in tryptophan fluorescence, consistent with the ion inducing a conformational change in the protein. The apparent K D was 7.4 +/- 1.5 microM and thus correlated well with the apparent K I. In the presence of physiological Ca2+ concentration the K I and K D values were three to four fold enhanced, presumably due to the Ca2+-induced conformational change affecting the confor...
Alzheimer's & Dementia, 2014
Background: AD is characterized by deleterious deposits of Ab and t proteins, which are central t... more Background: AD is characterized by deleterious deposits of Ab and t proteins, which are central to AD pathogenesis. In addition to these pathophysiological changes, AD is also characterized by abnormal glucose metabolism that precedes neuropathological changes. Despite these data, the underlying molecular mechanism behind the potential cause and effect relationship between decreased glucosemetabolism and increased Ab deposition is unknown. In this context, we hypothesized that decreased glucose metabolism may result in decreased Ab clearance and hence its increased deposition in AD brain. Here, it is noteworthy that Liver X receptor (LXR)-mediated Apolipoprotein E (APOE) lipidation and secretion plays a major role in cerebral Ab clearance. Therefore, we aimed to investigate glycolytic control of LXR-APOE pathway and identify its positive modulators for therapeutic purpose. Methods: The astrocytes expressing human APOE2/E3/E4 isoforms (from Dr. David Holtzman, Washington University) were used. The astrocytes were treated for 24 hrs with known LXR and RXR agonists (GW3965 and Bexarotene, respectively), either in presence or absence of inhibitors of glucose uptake and glycolysis (cytochalasin B and 2-deoxy-D-glucose, respectively). Furthermore, astrocytes were also treated with various FDA-approved drugs with potential to enhance glycolysis and in turn activating the LXR-APOE pathway. The uptake of glucose and the production of lactate were measured as markers of glycolysis. The level of secreted APOE was measured using human APOE ELISA, while lipidation status of APOE was measured using non-denaturing gel electrophoresis followed bywestern blotting.Results:The treatment of APOE3 astrocytes with Bexarotene increased APOE lipidation and secretion, which was inhibited by co-treatment with Cytochalasin B and 2-deoxy-D-glucose (Fig.1A). Furthermore, astrocytes were also treated with three drugs from three different categories viz., a b-blocker (Drug 1, 5mM), an anti-cancer agent (Drug 2, 5mM) and an anti-inflammatory agent (Drug 3, 2mM). The Drug 1 and 2 significantly enhanced glucose uptake and lactate production by astrocytes (Fig.1B). Interestingly, these two drugs also significantly enhanced APOE secretion (Fig.1B). The experiments with other drug molecules in APOE3 as well as APOE2 and E4 astrocytes are ongoing. Conclusions: Our data so far suggests potential role of glucose metabolism in APOE lipidation and secretion by astrocytes, further emphasizing our hypothesis.
The FEBS Journal, 2013
Glycosylation is one of the most common, and the most complex, forms of post‐translational modifi... more Glycosylation is one of the most common, and the most complex, forms of post‐translational modification of proteins. This review serves to highlight the role of protein glycosylation in Alzheimer disease (AD), a topic that has not been thoroughly investigated, although glycosylation defects have been observed in AD patients. The major pathological hallmarks in AD are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are composed of phosphorylated tau, and the plaques are composed of amyloid β‐peptide (Aβ), which is generated from amyloid precursor protein (APP). Defects in glycosylation of APP, tau and other proteins have been reported in AD. Another interesting observation is that the two proteases required for the generation of amyloid β‐peptide (Aβ), i.e. γ‐secretase and β‐secretase, also have roles in protein glycosylation. For instance, γ‐secretase and β‐secretase affect the extent of complex N‐glycosylation and sialylation of APP, respectively. These process...
US neurology, 2019
have no conflicts of interest to declare in relation to the article. Review process: This is an e... more have no conflicts of interest to declare in relation to the article. Review process: This is an expert interview and, as such, has not undergone the journal's standard peer review process. Acknowledgments: Medical writing assistance was provided by Katrina Mountfort of Touch Medical Media.
Alzheimers & Dementia, Jul 1, 2017
Background: The role of vascular disease in Alzheimer’s disease (AD) is still debated. White matt... more Background: The role of vascular disease in Alzheimer’s disease (AD) is still debated. White matter hypointensity (WMH) volume is an imaging measure of vascular burden. Using MRI and Positron Emission Tomography (PET) we examined the voxel-level relationships betweenWMHand 3 key processes inAD: amyloid deposition, tau aggregation and microglial activation. Methods: 15 participants with a clinical diagnosis of AD had T1-weighted MRI, F-flutemetamol, F-AV1451 and C-PBR28 PET scans. 18 healthy controls also had F-flutemetamol and C-PBR28 scans, and 8 of these also had F-AV1451 PET. Z-score maps for each tracer (80-100 minute ratio image for F-AV1451, 90-120 minute ratio image for F-flutemetamol and logan Vd parametric map for C-PBR28 ) were calculated for the AD subjects compared to the controls for each tracer.WMHvolumes from theMRIwere calculated from Freesurfer software. Multiple regression in SPM8 was used to calculate voxel wise correlations between WMH volume and tracer uptake. A pvalue of p<0.05 was considered significant. Results:Amyloid deposition: there were correlations between WMH volume and amyloid deposition in the 1) frontal lobe (right medial and anterior orbital gyri, left posterior orbital gyrus, and right superior frontal gyri) 2) parietal lobe (left superior parietal gyrus) and 3) corpus callosum. Tau aggregation: there were correlations between WMH burden and tau aggregation in the left and right posterior temporal lobe Microglial activation :there were correlations between WMH volume and microglial activation in the 1) frontal lobe (right superior/middle frontal gyrus, right subgenual frontal cortex, right medial orbital gyrus) 2) parietal lobe (postcentral / precentral gyrus, left inferolateral part of parietal lobe and 3) occipital lobe (left lateral part of occipital lobe). Conclusions:White matter hypointensity volume correlates at voxel-level with amyloid deposition, tau aggregation and microglial activation. These findings emphasise the complex disease pathogenesis occurring in AD, and the need for a multi-targeted treatment.
Alzheimers & Dementia, Jul 1, 2014
Alzheimers & Dementia, Jul 1, 2012
European Medical Journal Neurology, Aug 9, 2022
Alzheimer's Research & Therapy
Background In Alzheimer’s disease (AD), amyloid-β 1–42 (Aβ42) neurotoxicity stems mostly from its... more Background In Alzheimer’s disease (AD), amyloid-β 1–42 (Aβ42) neurotoxicity stems mostly from its soluble oligomeric aggregates. Studies of such aggregates have been hampered by the lack of oligomer-specific research tools and their intrinsic instability and heterogeneity. Here, we developed a monoclonal antibody with a unique oligomer-specific binding profile (ALZ-201) using oligomer-stabilising technology. Subsequently, we assessed the etiological relevance of the Aβ targeted by ALZ-201 on physiologically derived, toxic Aβ using extracts from post-mortem brains of AD patients and controls in primary mouse neuron cultures. Methods Mice were immunised with stable oligomers derived from the Aβ42 peptide with A21C/A30C mutations (AβCC), and ALZ-201 was developed using hybridoma technology. Specificity for the oligomeric form of the Aβ42CC antigen and Aβ42 was confirmed using ELISA, and non-reactivity against plaques by immunohistochemistry (IHC). The antibody’s potential for cross-pro...
Supplemental material, sj-jpg-5-sjp-10.1177_14034948211064656 for Changes in mortality trends amo... more Supplemental material, sj-jpg-5-sjp-10.1177_14034948211064656 for Changes in mortality trends amongst common diseases during the COVID-19 pandemic in Sweden by Michael Axenhus, Sophia Schedin-Weiss, Bengt Winblad and Anders Wimo in Scandinavian Journal of Public Health
Supplemental material, sj-jpg-4-sjp-10.1177_14034948211064656 for Changes in mortality trends amo... more Supplemental material, sj-jpg-4-sjp-10.1177_14034948211064656 for Changes in mortality trends amongst common diseases during the COVID-19 pandemic in Sweden by Michael Axenhus, Sophia Schedin-Weiss, Bengt Winblad and Anders Wimo in Scandinavian Journal of Public Health
Supplemental material, sj-jpg-1-sjp-10.1177_14034948211064656 for Changes in mortality trends amo... more Supplemental material, sj-jpg-1-sjp-10.1177_14034948211064656 for Changes in mortality trends amongst common diseases during the COVID-19 pandemic in Sweden by Michael Axenhus, Sophia Schedin-Weiss, Bengt Winblad and Anders Wimo in Scandinavian Journal of Public Health
Supplemental material, sj-jpg-2-sjp-10.1177_14034948211064656 for Changes in mortality trends amo... more Supplemental material, sj-jpg-2-sjp-10.1177_14034948211064656 for Changes in mortality trends amongst common diseases during the COVID-19 pandemic in Sweden by Michael Axenhus, Sophia Schedin-Weiss, Bengt Winblad and Anders Wimo in Scandinavian Journal of Public Health
Scandinavian Journal of Public Health, 2021
Objective: It has been found that COVID-19 increases deaths within common diseases in countries t... more Objective: It has been found that COVID-19 increases deaths within common diseases in countries that have implemented strict lockdowns. In order to elucidate the proper national response to a pandemic, the mortality rates within COVID-19 and various diseases need to be studied in countries whose pandemic response differ. Sweden represents a country with lax pandemic restrictions, and we aimed to study the effects of COVID-19 on historical mortality rates within common diseases during 2020. Methods: Regression models and moving averages were used to predict expected premature mortality per the ICD-10 during 2020 using historical data sets. Predicted values were then compared to recorded premature mortality to identify changes in mortality trends. Results: Seasonal increased mortality was found within neurological diseases. Infectious diseases, tumours and cardiac disease mortality rates decreased compared to expected outcome. Conclusions: Changes in mortality trends were observed for...
Journal of Neurochemistry, 2020
Protein glycosylation is crucial for the central nervous system and brain functions, including pr... more Protein glycosylation is crucial for the central nervous system and brain functions, including processes that are defective in Alzheimer disease (AD) such as neurogenesis, synaptic function, and memory formation. Still, the roles of glycans in the development of AD are relatively unexplored. Glycomics studies of cerebrospinal fluid (CSF) have previously shown altered glycosylation pattern in patients with different stages of cognitive impairment, including AD, compared to healthy controls. As a consequence, we hypothesized that the glycan profile is altered in the brain of patients with AD and analyzed the asparagine‐linked (N‐linked) glycan profile in hippocampus and cortex in AD and control brain. Glycans were enzymatically liberated from brain glycoproteins and analyzed by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Eleven glycans showed significantly different levels in hippocampus compared to cortex in both control and AD brain. Two glycans in cortex and four in ...
Alzheimer's & Dementia, 2017
Background: The role of vascular disease in Alzheimer’s disease (AD) is still debated. White matt... more Background: The role of vascular disease in Alzheimer’s disease (AD) is still debated. White matter hypointensity (WMH) volume is an imaging measure of vascular burden. Using MRI and Positron Emission Tomography (PET) we examined the voxel-level relationships betweenWMHand 3 key processes inAD: amyloid deposition, tau aggregation and microglial activation. Methods: 15 participants with a clinical diagnosis of AD had T1-weighted MRI, F-flutemetamol, F-AV1451 and C-PBR28 PET scans. 18 healthy controls also had F-flutemetamol and C-PBR28 scans, and 8 of these also had F-AV1451 PET. Z-score maps for each tracer (80-100 minute ratio image for F-AV1451, 90-120 minute ratio image for F-flutemetamol and logan Vd parametric map for C-PBR28 ) were calculated for the AD subjects compared to the controls for each tracer.WMHvolumes from theMRIwere calculated from Freesurfer software. Multiple regression in SPM8 was used to calculate voxel wise correlations between WMH volume and tracer uptake. A pvalue of p<0.05 was considered significant. Results:Amyloid deposition: there were correlations between WMH volume and amyloid deposition in the 1) frontal lobe (right medial and anterior orbital gyri, left posterior orbital gyrus, and right superior frontal gyri) 2) parietal lobe (left superior parietal gyrus) and 3) corpus callosum. Tau aggregation: there were correlations between WMH burden and tau aggregation in the left and right posterior temporal lobe Microglial activation :there were correlations between WMH volume and microglial activation in the 1) frontal lobe (right superior/middle frontal gyrus, right subgenual frontal cortex, right medial orbital gyrus) 2) parietal lobe (postcentral / precentral gyrus, left inferolateral part of parietal lobe and 3) occipital lobe (left lateral part of occipital lobe). Conclusions:White matter hypointensity volume correlates at voxel-level with amyloid deposition, tau aggregation and microglial activation. These findings emphasise the complex disease pathogenesis occurring in AD, and the need for a multi-targeted treatment.
Biochemical and biophysical research communications, Jan 23, 2016
The toxic amyloid β-peptide (Aβ) is a key player in Alzheimer Disease (AD) pathogenesis and selec... more The toxic amyloid β-peptide (Aβ) is a key player in Alzheimer Disease (AD) pathogenesis and selective inhibition of the production of this peptide is sought for. Aβ is produced by the sequential cleavage of the Aβ precursor protein (APP) by β-secretase (to yield APP-C-terminal fragment β (APP-CTFβ) and soluble APPβ (sAPPβ)) and γ-secretase (to yield Aβ). We reasoned that proteins that associate with γ-secretase are likely to regulate Aβ production and to be targets of pharmaceutical interventions and therefore performed a pull-down assay to screen for such proteins in rat brain. Interestingly, one of the purified proteins was potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (HCN2), which has been shown to be involved in epilepsy. We found that silencing of HCN2 resulted in decreased secreted Aβ levels. To further investigate the mechanism behind this reduction, we also determined the levels of full-length APP, sAPP and APP-CTF species after silencin...
Alzheimer's & Dementia, 2014
Thrombosis and haemostasis, 2010
Zn2+ ions were found to efficiently inhibit activated protein C (APC), suggesting a potential reg... more Zn2+ ions were found to efficiently inhibit activated protein C (APC), suggesting a potential regulatory function for such inhibition. APC activity assays employing a chromogenic peptide substrate demonstrated that the inhibition was reversible and the apparent K I was 13 +/- 2 microM. k cat was seven fold decreased whereas K M was unaffected in the presence of 10 microM Zn2+. The inhibitory effect of Zn2+ on APC activity was also observed when factor Va was used as a substrate in an assay coupled to a prothrombinase assay. The interaction of Zn2+ with APC was accompanied by a reversible approximately 40% decrease in tryptophan fluorescence, consistent with the ion inducing a conformational change in the protein. The apparent K D was 7.4 +/- 1.5 microM and thus correlated well with the apparent K I. In the presence of physiological Ca2+ concentration the K I and K D values were three to four fold enhanced, presumably due to the Ca2+-induced conformational change affecting the confor...
Alzheimer's & Dementia, 2014
Background: AD is characterized by deleterious deposits of Ab and t proteins, which are central t... more Background: AD is characterized by deleterious deposits of Ab and t proteins, which are central to AD pathogenesis. In addition to these pathophysiological changes, AD is also characterized by abnormal glucose metabolism that precedes neuropathological changes. Despite these data, the underlying molecular mechanism behind the potential cause and effect relationship between decreased glucosemetabolism and increased Ab deposition is unknown. In this context, we hypothesized that decreased glucose metabolism may result in decreased Ab clearance and hence its increased deposition in AD brain. Here, it is noteworthy that Liver X receptor (LXR)-mediated Apolipoprotein E (APOE) lipidation and secretion plays a major role in cerebral Ab clearance. Therefore, we aimed to investigate glycolytic control of LXR-APOE pathway and identify its positive modulators for therapeutic purpose. Methods: The astrocytes expressing human APOE2/E3/E4 isoforms (from Dr. David Holtzman, Washington University) were used. The astrocytes were treated for 24 hrs with known LXR and RXR agonists (GW3965 and Bexarotene, respectively), either in presence or absence of inhibitors of glucose uptake and glycolysis (cytochalasin B and 2-deoxy-D-glucose, respectively). Furthermore, astrocytes were also treated with various FDA-approved drugs with potential to enhance glycolysis and in turn activating the LXR-APOE pathway. The uptake of glucose and the production of lactate were measured as markers of glycolysis. The level of secreted APOE was measured using human APOE ELISA, while lipidation status of APOE was measured using non-denaturing gel electrophoresis followed bywestern blotting.Results:The treatment of APOE3 astrocytes with Bexarotene increased APOE lipidation and secretion, which was inhibited by co-treatment with Cytochalasin B and 2-deoxy-D-glucose (Fig.1A). Furthermore, astrocytes were also treated with three drugs from three different categories viz., a b-blocker (Drug 1, 5mM), an anti-cancer agent (Drug 2, 5mM) and an anti-inflammatory agent (Drug 3, 2mM). The Drug 1 and 2 significantly enhanced glucose uptake and lactate production by astrocytes (Fig.1B). Interestingly, these two drugs also significantly enhanced APOE secretion (Fig.1B). The experiments with other drug molecules in APOE3 as well as APOE2 and E4 astrocytes are ongoing. Conclusions: Our data so far suggests potential role of glucose metabolism in APOE lipidation and secretion by astrocytes, further emphasizing our hypothesis.
The FEBS Journal, 2013
Glycosylation is one of the most common, and the most complex, forms of post‐translational modifi... more Glycosylation is one of the most common, and the most complex, forms of post‐translational modification of proteins. This review serves to highlight the role of protein glycosylation in Alzheimer disease (AD), a topic that has not been thoroughly investigated, although glycosylation defects have been observed in AD patients. The major pathological hallmarks in AD are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are composed of phosphorylated tau, and the plaques are composed of amyloid β‐peptide (Aβ), which is generated from amyloid precursor protein (APP). Defects in glycosylation of APP, tau and other proteins have been reported in AD. Another interesting observation is that the two proteases required for the generation of amyloid β‐peptide (Aβ), i.e. γ‐secretase and β‐secretase, also have roles in protein glycosylation. For instance, γ‐secretase and β‐secretase affect the extent of complex N‐glycosylation and sialylation of APP, respectively. These process...