Impaired glymphatic function and clearance of tau in an Alzheimer's disease model methods
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Materials and methods
For pharmacological inhibition of AQP4, TGN-020 ( N -1,3,4-thiadiazol-2-yl-3-pyridinecarboxamide) (Tocris Bioscience) was used ( ). To increase solubility, TGN-020 was dissolved in a cyclodextrin derivative, 20% w/v Captisol ® (CyDex Pharmaceuticals) in water for injection. For TGN-020 experiments, mice were treated intraperitoneally with either TGN-020 (250 mg/kg in 20 ml/kg body weight) or vehicle (empty 20% Captisol ®, 20 ml/kg).
Tau immunohistochemistry
Immunohistochemistry was performed in order to quantify cortical deposition of tau in young rTg4510 mice. Female rTg4510 mice from 3.2 to 4.7 months of age were examined. Mice were perfused with PBS before removing and hemisecting the brain. The right hemisphere was drop fixed in 10% buffered formalin before being processed using the Tissue TEK VIP processor (GMI Inc) and embedded in paraffin wax. Sections (6 µm) of the brain in the sagittal plane were collected using a rotary microtome and mounted on glass slides. Following deparaffinization and rehydration of the tissue sections, antigen retrieval was carried out using the Lab Vision PT module system (Thermo Scientific), where sections were heated to 100°C for 20 min in citrate buffer (TA-250-PM1X; Thermo Scientific). Slides were transferred to a Lab Vision Autostainer (Thermo Scientific) where the following incubations we...
Dynamic contrast-enhanced MRI
Mice were anaesthetized with 2% isoflurane delivered in O 2 at a delivery rate of 1 l/min, and positioned in a stereotaxic frame with the head flexed to 50°. A midline incision was made at a midpoint between the skull base and the occipital margin to the first vertebrae. The underlying muscles were parted to expose the atlanto-occipital membrane and dura mater overlaying the cisterna magna, and a durotomy was performed using a 23-gauge needle. An intrathecal catheter (35-40 mm port length, 80-90 mm intravascular tippet length, Sandown Scientific) extended with polyethylene tubing (0.4 mm × 0.8 mm, Portex) and attached to a 50 µl glass Hamilton syringe driven by a microinfusion pump (sp210iw syringe pump, World Precision Instruments) was filled with low molecular weight paramagnetic contrast agent Magnevist ® (21 mM Gd-DTPA, molecular weight 938 Da; Sche...
MRI acquisition
Following surgery, animals were transferred to an MRI-compatible cradle with head held prone and a snout mask positioned to deliver 1.5% isoflurane in O 2 at a delivery rate of 1 l/min. Core temperature and respiratory rate were monitored using a rectal probe and pressure pad, respectively (SA Instruments). Mice were maintained at 37°C (±2°C) using heated water tubing and a feedback loop controlled warm air blower (SA Instruments). Respiration rate was maintained between 80 and 120 breaths per minute by incrementally adjusting isoflurane dose. All imaging was performed with a 9.4 T VNMRS horizontal bore MRI scanner (Agilent Inc). A 72-mm inner diameter volume coil (Rapid Biomedical) was used for RF transmission and signal was received using a two-channel array head coil (Rapid Biomedical). A 3D T 1 -weighted gradient echo sequence was used to detect the motion of the Gd...
Image processing and analysis
First, the acquired T 1 -weighted MRI images were converted to the 3D NIfTI image format. Second, scan-to-scan misregistration caused by head movement was corrected by rigid-body alignment of each scan to the baseline averaged volume. Third, image intensity was normalized over the time series by estimating the intensity non-uniformity in the baseline volume and correcting all the volumes in the time series using the baseline intensity non-uniformity map, followed by 0.1 mm full-width at half-maximum isotropic Gaussian voxel-wise image intensity smoothing. For presentation of images, a difference image was calculated for each time point using the following expression: (1) D ( i, j, k ) = [ I ( i, j, k ) - B ( i, j, k ) ] where D is the difference image, I is the time series image post Gd-DTPA infusion, B is the average baseline image, and ( i, j,...
Intracerebral infusion of tau and quantification of parenchyma-CSF tau clearance
Tau for intracortical injection was prepared by euthanizing an aged rTg4510 mouse (12 months of age) by overdose with sodium pentobarbital (10 ml/kg, i.p.) and dissecting out the cortex and hippocampus. Tissue was quickly frozen in isopentane on dry ice for storage at -80°C. Frozen tissue was weighed, thawed, and gently mixed in a mortar with a few strokes of a pestle in 10% w/v volumes of cold Tris-buffered saline (TBS) containing protease inhibitor cocktail, phosphatase inhibitor cocktails I and II (Sigma), at a final dilution of 1:100, and 1 mM phenylmethylsulphonyl fluoride. The resultant homogenate was centrifuged at 3000 rpm at 4°C for 5 min, and the pellet discarded. The supernatant was stored at -80°C until characterization and subsequent intracerebral infusion. Total and phosphorylated tau content was quantified by using ELISAs [Human Tau (total) (#...
Intracerebral infusion
Mice were anaesthetized with 2% isoflurane delivered in O 2 at a delivery rate of 1 l/min, and positioned in a stereotaxic frame in the horizontal skull position. A midline incision was made on the top of the head to expose the underlying skull. A small burr hole was made, using a microdrill, above the location of the intracerebral injection. Tau (50 ng) containing brain homogenate (see above for preparation) was infused into either the rostral (anteroposterior, +2 mm, and mediolateral, +2 mm relative to bregma, and ventrodorsal, -0.75 mm, relative to the brain surface) ( ) or caudal (anteroposterior, -2 mm, and mediolateral, +2 mm relative to bregma, and ventrodorsal, -0.75 mm, relative to the brain surface) ( ) cortex, or the striatum (anteroposterior, -0.2 mm, and mediolateral, +2 mm relative to bregma, and ventrodorsal, -1.75 mm, relative to the brain...
Tau ELISAs
Concentration of human tau in CSF samples was quantified using ELISAs. CSF total tau was quantified using Human Tau (total) ELISA Kit (#KHB0041, Invitrogen), and CSF phosphorylated tau was quantified using Human Tau (Phospho) (pS 199 ) ELISA Kit (#KHB7041, Invitrogen), as per the manufacturer's instructions. Briefly, CSF samples were diluted in diluent buffer prior to being incubated in capture antibody-coated wells for 2 h at room temperature. Wells were washed several times before being incubated in detection antibody for 1 h at room temperature. Wells were washed again before being incubated with horseradish peroxidase conjugated secondary antibody for 30 min at room temperature. Wells were then washed again before being incubated with stabilized chromogen for 30 min at room temperature. After this incubation, stop solution was added to each well and the plate was read at 450...
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Evidence quotes (8)
For pharmacological inhibition of AQP4, TGN-020 ( N -1,3,4-thiadiazol-2-yl-3-pyridinecarboxamide) (Tocris Bioscience) was used ( ). To increase solubility, TGN-020 was dissolved in a cyclodextrin derivative, 20% w/v Captisol ® (CyDex Pharmaceuticals) in water for injection. For TGN-020 experiments, mice were treated intraperitoneally with either TGN-020 (250 mg/kg in 20 ml/kg body weight) or vehicle (empty 20% Captisol ®, 20 ml/kg).
Immunohistochemistry was performed in order to quantify cortical deposition of tau in young rTg4510 mice. Female rTg4510 mice from 3.2 to 4.7 months of age were examined. Mice were perfused with PBS before removing and hemisecting the brain. The right hemisphere was drop fixed in 10% buffered formalin before being processed using the Tissue TEK VIP processor (GMI Inc) and embedded in paraffin wax. Sections (6 µm) of the brain in the sagittal plane were collected using a rotary microtome and mounted on glass slides. Following deparaffinization and rehydration of the tissue sections, antigen retrieval was carried out using the Lab Vision PT module system (Thermo Scientific), where sections were heated to 100°C for 20 min in citrate buffer (TA-250-PM1X; Thermo Scientific). Slides were transferred to a Lab Vision Autostainer (Thermo Scientific) where the following incubations were performed: 10 min in H 2 O 2 (0.3%); 30 min in normal goat serum (1:20; Vector Laboratories); 60 min in primary antibody for tau phosphorylated at serine 409 (PG-5; 1:8000 from Peter Davies, Albert Einstein College of Medicine, NY, USA); 30 min in biotinylated goat anti-mouse IgG (1:200, BA9200;...
Mice were anaesthetized with 2% isoflurane delivered in O 2 at a delivery rate of 1 l/min, and positioned in a stereotaxic frame with the head flexed to 50°. A midline incision was made at a midpoint between the skull base and the occipital margin to the first vertebrae. The underlying muscles were parted to expose the atlanto-occipital membrane and dura mater overlaying the cisterna magna, and a durotomy was performed using a 23-gauge needle. An intrathecal catheter (35-40 mm port length, 80-90 mm intravascular tippet length, Sandown Scientific) extended with polyethylene tubing (0.4 mm × 0.8 mm, Portex) and attached to a 50 µl glass Hamilton syringe driven by a microinfusion pump (sp210iw syringe pump, World Precision Instruments) was filled with low molecular weight paramagnetic contrast agent Magnevist ® (21 mM Gd-DTPA, molecular weight 938 Da; Schering Health Care Ltd, in filtered 0.9% NaCl). The catheter was advanced 1 mm into the cisternal space, sealed and anchored in place using superglue and fast setting resin (Araldite ® ).
Following surgery, animals were transferred to an MRI-compatible cradle with head held prone and a snout mask positioned to deliver 1.5% isoflurane in O 2 at a delivery rate of 1 l/min. Core temperature and respiratory rate were monitored using a rectal probe and pressure pad, respectively (SA Instruments). Mice were maintained at 37°C (±2°C) using heated water tubing and a feedback loop controlled warm air blower (SA Instruments). Respiration rate was maintained between 80 and 120 breaths per minute by incrementally adjusting isoflurane dose. All imaging was performed with a 9.4 T VNMRS horizontal bore MRI scanner (Agilent Inc). A 72-mm inner diameter volume coil (Rapid Biomedical) was used for RF transmission and signal was received using a two-channel array head coil (Rapid Biomedical). A 3D T 1 -weighted gradient echo sequence was used to detect the motion of the Gd-DTPA with parameters: repetition time = 15 ms, echo time = 3.4 ms, flip angle = 15°, number of acquisitions = 3, field of view = 1.28 × 1.28 × 1.92 cm, scanning time = 12 min, acquisition matrix size of 128 × 128 × 128, yieldi...
First, the acquired T 1 -weighted MRI images were converted to the 3D NIfTI image format. Second, scan-to-scan misregistration caused by head movement was corrected by rigid-body alignment of each scan to the baseline averaged volume. Third, image intensity was normalized over the time series by estimating the intensity non-uniformity in the baseline volume and correcting all the volumes in the time series using the baseline intensity non-uniformity map, followed by 0.1 mm full-width at half-maximum isotropic Gaussian voxel-wise image intensity smoothing. For presentation of images, a difference image was calculated for each time point using the following expression: (1) D ( i, j, k ) = [ I ( i, j, k ) - B ( i, j, k ) ] where D is the difference image, I is the time series image post Gd-DTPA infusion, B is the average baseline image, and ( i, j, k ) represents the voxel position. Signal intensity measured on the T 1 -weighted magnetic resonance images over time in preselected anatomical areas were used to obtain intensity measurements. Both the T 1 -weighted averaged baseline images and the contrast-enhanced T 1 -weighted magnetic resonanc...
Tau for intracortical injection was prepared by euthanizing an aged rTg4510 mouse (12 months of age) by overdose with sodium pentobarbital (10 ml/kg, i.p.) and dissecting out the cortex and hippocampus. Tissue was quickly frozen in isopentane on dry ice for storage at -80°C. Frozen tissue was weighed, thawed, and gently mixed in a mortar with a few strokes of a pestle in 10% w/v volumes of cold Tris-buffered saline (TBS) containing protease inhibitor cocktail, phosphatase inhibitor cocktails I and II (Sigma), at a final dilution of 1:100, and 1 mM phenylmethylsulphonyl fluoride. The resultant homogenate was centrifuged at 3000 rpm at 4°C for 5 min, and the pellet discarded. The supernatant was stored at -80°C until characterization and subsequent intracerebral infusion. Total and phosphorylated tau content was quantified by using ELISAs [Human Tau (total) (#KHB0041, Invitrogen) and Human Tau (Phospho) [pS 199 ] ELISA Kits, as per the manufacturer's instructions]. The ratio of phosphorylated (pS 199 ) to total tau in the homogenate was 0.32 (±0.03). The ratio of insoluble to soluble tau in the homogenate was assessed by separating proteins by...
Mice were anaesthetized with 2% isoflurane delivered in O 2 at a delivery rate of 1 l/min, and positioned in a stereotaxic frame in the horizontal skull position. A midline incision was made on the top of the head to expose the underlying skull. A small burr hole was made, using a microdrill, above the location of the intracerebral injection. Tau (50 ng) containing brain homogenate (see above for preparation) was infused into either the rostral (anteroposterior, +2 mm, and mediolateral, +2 mm relative to bregma, and ventrodorsal, -0.75 mm, relative to the brain surface) ( ) or caudal (anteroposterior, -2 mm, and mediolateral, +2 mm relative to bregma, and ventrodorsal, -0.75 mm, relative to the brain surface) ( ) cortex, or the striatum (anteroposterior, -0.2 mm, and mediolateral, +2 mm relative to bregma, and ventrodorsal, -1.75 mm, relative to the brain surface) ( ) using a 10 µl glass Hamilton syringe (2.5 µl at 0.5 µl/min, total time 5 min). Either 15, 30, or 60 min after the start of the intracerebral infusion, with the needle left in situ, a midline incision was made at a midpoint between the skull base and the occipital margin...
Concentration of human tau in CSF samples was quantified using ELISAs. CSF total tau was quantified using Human Tau (total) ELISA Kit (#KHB0041, Invitrogen), and CSF phosphorylated tau was quantified using Human Tau (Phospho) (pS 199 ) ELISA Kit (#KHB7041, Invitrogen), as per the manufacturer's instructions. Briefly, CSF samples were diluted in diluent buffer prior to being incubated in capture antibody-coated wells for 2 h at room temperature. Wells were washed several times before being incubated in detection antibody for 1 h at room temperature. Wells were washed again before being incubated with horseradish peroxidase conjugated secondary antibody for 30 min at room temperature. Wells were then washed again before being incubated with stabilized chromogen for 30 min at room temperature. After this incubation, stop solution was added to each well and the plate was read at 450 nm. A set of standards of known (p)Tau concentration [0, 31.25, 62.5, 125, 250, 500, 1000, 2000 pg/ml for total tau, and 0, 15.625, 31.25, 62.5, 125, 250, 500, 1000 pg/ml for phospho (pS 199 ) tau], were run in parallel for each experiment for quantification of CSF sample tau content from the stand...
Machine-readable layer
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