A Randomized, Controlled, Prospective Study of the Effectiveness and Safety of an Intracanalicular Dexamethasone Ophthalmic Insert (0.4 Mg) for the Treatment of Post-Operative Inflammation in Patients Undergoing Refractive Lens Exchange (RLE).

PURPOSE: To determine patient preference and treatment outcomes with an intracanalicular dexamethasone (0.4 mg) insert compared to standard steroid drop regimen in the contralateral eye following bilateral RLE surgery. METHODS: This is a prospective, open-label, interventional, randomized, controlled study in 20 subjects who underwent bilateral RLE. Each patient served as their own control with one eye randomized to the intracanalicular insert (Group A) placed at the time of surgery and the contralateral randomized to topical corticosteroid drops (Group B). All eyes received intracameral moxifloxacin at the time of surgery, and post-operatively, topical moxifloxacin QID for one week and topical NSAID daily for four weeks. Post-operative evaluations were performed on Day 1, Week 1, and Week 4-8. RESULTS: Twenty patients participated. At 4-8 weeks post-operation, 90% of patients evaluated with the COMTOL questionnaire preferred the intracanalicular insert while 10% preferred the topical steroid. Comparative analysis using the visual analog scale showed no difference in pain between the study and control group. No statistical difference was shown in post-operative corneal staining, anterior chamber cell count, anterior chamber flare or intraocular pressure. Mean LogMAR UCVA at 4-8 weeks post-operation was 0.06 (± 0.230) in the study group and 0.065 (± 0.241) in the control group, which was not statistically or clinically different (p > 0.05). CONCLUSION: Patients undergoing bilateral RLE expressed a strong preference towards the use of an intracanalicular insert over a topical steroid for post-operative steroid treatment. There was no clinically or statistically significant difference in outcomes, including rate of cystoid macular edema, visual acuity and elevation of intraocular pressure. NATIONAL CLINICAL TRIAL NUMBER: 04549935.

Evaluation of the IOP-Lowering Effect of a Multi-Pressure Dial at Different Negative Pressure Settings.

Purpose: To evaluate the intraocular pressure (IOP)-lowering effect of a multi-pressure dial (MPD) at targeted negative pressure settings. Methods: Prospective, intrasubject controlled study of 65 healthy subjects randomized to receive no negative pressure for 60 minutes or negative pressure application at designated levels of 25%, 50%, and 75% of baseline IOP for 20 minutes each. The main outcome measure was mean IOP with application of negative pressure. Results: In the study eye group, from a baseline IOP of 15.8 ± 3.6 mm Hg, the mean IOP was 13.5 ± 3.4, 11.5 ± 3.1, and 10.2 ± 2.7 mm Hg with negative pressure settings of 25%, 50% and 75%, respectively. In the control eye group, from a baseline IOP of 15.5 ± 3.0 mm Hg, the mean IOP values at the same time points, without negative pressure, were 15.6 ± 3.0, 15.5 ± 2.5 and 15.3 ± 2.4 mm Hg. The difference between the mean IOPs of the two groups was significantly different at all negative pressure settings (P < 0.001) in comparison with baseline. There was one minor adverse event, a corneal abrasion, that was unrelated to device wear. Conclusions: Negative pressure application to the periocular space with a multi-pressure dial can produce titratable IOP reduction while the device is worn with active negative pressure. To our knowledge, this technology represents the first nonpharmacologic, nonlaser, nonsurgical method for IOP reduction. Translational Relevance: This represents the first study demonstrating the IOP-lowering ability of the multi-pressure dial, a device that uses a novel IOP-lowering strategy by delivering negative pressure to the periocular region.

Short-Term Steady-State Pattern Electroretinography Changes Using a Multi-Pressure Dial in Ocular Hypertensive, Glaucoma Suspect, and Mild Open-Angle Glaucoma Patients: A Randomized, Controlled, Prospective, Pilot Study.

INTRODUCTION: This study evaluates the effects of the multi-pressure dial (MPD) on steady-state pattern electroretinography (ss-pERG) parameters. The study is a randomized, controlled, prospective, pilot trial in a private practice setting with ocular hypertensive (OHT), glaucoma suspect, and open-angle glaucoma (OAG) subjects. METHODS: This study included nine patients (64 ± 9.0 years, nine female) with OHT, glaucoma suspect, or mild OAG. One eye of each subject was randomized to receive negative periocular pressure, while the contralateral eye served as the intrasubject control through the goggle without negative pressure. The Diopsys High Contrast Sensitivity ss-pERG protocol was conducted on both eyes of each subject while wearing the MPD device. Application of negative periocular pressure was set at 50% of baseline intraocular pressure for each study eye. RESULTS: Following 2 h of negative periocular pressure application, the difference in MagnitudeD (MagD) from baseline for eyes randomized to receive negative periocular pressure (+ 0.17 versus - 0.26) was statistically significant (p = 0.023). Over the same period, the change in MagD/Magnitude (MagD/Mag ratio) from baseline for eyes randomized to receive negative periocular pressure was also higher (+ 0.14 versus - 0.16), compared to the control eyes, approached significance (p = 0.059). CONCLUSIONS: Following 2 h of MPD wear, the measured MagD and MagD/Mag ratio improved compared to control, suggesting that negative periocular pressure application to the anterior globe can lead to short-term improvement in one measure of retinal ganglion cell function.

Trabecular microbypass stent implantation in pseudoexfoliative glaucoma: long-term results.

PURPOSE: To evaluate the long-term safety and efficacy of an iStent trabecular microbypass stent in combination with cataract surgery in pseudoexfoliative glaucoma (PXG). SETTING: Private practice, Sioux Falls, South Dakota, USA. DESIGN: Retrospective, consecutive case series. METHODS: Eyes with a preoperative diagnosis of PXG implanted with a single iStent trabecular microbypass stent with concomitant cataract surgery were included. Performance outcome measures included intraocular pressure (IOP) and number of glaucoma medications. Safety outcomes included intraoperative or postoperative complications and the need for secondary procedures. RESULTS: The series included 117 eyes. IOP was reduced by 25% to 15.3 ± 3.7 mm Hg at 5 years postoperatively from 20.5 ± 6.6 mm Hg at baseline. The statistically significant (P < .01) 36% reduction in medication use through 36 months was not sustained, and medication use was unchanged from baseline (1.4 ± 1.0) at 5 years postoperatively (1.3 ± 1.1) (P > .05). At 5 years, 52% of eyes had an IOP of 15 mm Hg or lesser, increased from 22% at baseline. There were no severe postoperative complications; 5 eyes (4%) underwent an additional glaucoma procedure. CONCLUSIONS: Implantation of a trabecular microbypass stent with concomitant cataract surgery provided a sustained reduction in IOP up to 5 years postoperatively. The long-term safety profile of the device in this population was excellent with a low rate of postoperative IOP spikes and low percentage of eyes undergoing a secondary procedure.

Intraocular Pressure Measurement with Pneumatonometry and a Tonometer Tip Cover.

PURPOSE: To investigate the precision and accuracy of IOP measurements using a pneumatonometer and a tonometer tip cover (Tono-Pen® tip cover) acting as a membrane between a cadaver eye model and pneumatonometer probe. METHODS: A total of 480 paired IOP measurements, with and without a Tono-Pen cover, were collected across 4 pressure levels of 7, 10, 20 and 30 mmHg. IOP measurements were obtained by three different pneumatonometer units paired with three different masked operators (three configurations). Four eyes were sampled for each eye pressure level. The sequence of eye pressure, configuration, and measurements with vs. without the Tono-Pen cover was randomized. RESULTS: With the Tono-Pen cover in place, there was a negative bias with a mean IOP difference of - 1.18 mmHg for all 480 paired samples compared with the measurements absent the cover. Compared with the test pressure settings (i.e., 7, 10, 20, 30 mmHg), the overall mean bias was + 0.35 mmHg with the Tono-Pen cover present. With the Tono-Pen cover present, the overall repeatability %CV (percent coefficient of variation) was 3.4% and the reproducibility %CV was 3.8% compared with a repeatability %CV of 3.2% and reproducibility %CV of 5.7% without the Tono-Pen cover. CONCLUSION: Measurement of IOP via pneumatonometry with a Tono-Pen cover in place, also known as the excursion test method, yields precise, accurate and reproducible results. This developed method of pressure measurement is an acceptable and reliable form of IOP measurement.

8 hrs Safety Evaluation Of A Multi-Pressure Dial In Eyes With Glaucoma: Prospective, Open-Label, Randomized Study.

PURPOSE: To investigate the safety and tolerability of the multi-pressure dial with a continuous 8-hr duration in subjects with open-angle glaucoma. DESIGN: Prospective, controlled open-label, randomized, single site study. SUBJECTS: Twenty eyes of 10 subjects with open-angle glaucoma were fitted with a multi-pressure dial and randomized to negative pressure application of -10 mmHg in one eye for 8 (continuous) hours and ambient atmospheric pressure in the contralateral eye. METHODS: Main safety outcome measures include best-corrected visual acuity (BCVA), intraocular pressure (IOP) changes from baseline after negative pressure application, slit lamp and dilated fundus exam findings, and rate of adverse events. Subjective assessments were administered both hourly during the 8-hr study period and immediately following the study period. RESULTS: There were no statistically significant changes in IOP, BCVA or TBUT immediately following the 8-hr study period or at the 1-week follow-up visit. Patient-reported tolerability was favorable with a mean response of 1.8 ± 0.4 (scale → 1=best, 10 = worst). Subjects also reported positive interest in the MPD as a glaucoma therapy with a mean response of 1.8 ± 0.5 (scale → 1=best, 10 = worst). One adverse event was reported (headache) and resolved at conclusion of the Day 0 visit. CONCLUSION: The MPD demonstrated favorable safety with key parameters remaining stable after an 8-hr wear with negative pressure. Negative pressure application through the MPD was well tolerated by subjects enrolled in the study. The favorable findings demonstrate the safety of sustained delivery of negative pressure over a continuous, uninterrupted 8-hr duration.

Short-Term Safety Evaluation of a Multi-Pressure Dial: A Prospective, Open-label, Non-randomized Study.

INTRODUCTION: Prospective, open-label, non-randomized, single site study to assess the safety and tolerability of a multi-pressure dial. METHODS: 30 healthy subjects received application of negative pressure (-15 mmHg) in one eye for 30 minutes and ambient atmospheric pressure in the contralateral eye. To evaluate safety, the primary outcome measures included best corrected visual acuity (BCVA), intraocular pressure (IOP) changes from baseline, slit-lamp and dilated fundus examination findings, and rate of adverse events. Exploratory analyses included in this study also evaluated changes from baseline measurement in tear break-up time (TBUT) and RNFL thickness measured by OCT. In addition to baseline screening, subjects underwent testing and negative pressure application on day 0 and returned 1 week after the initial visit for clinical testing. The follow-up visit did not include use of the multi-pressure dial (MPD) but repeated baseline testing and evaluated for adverse events. RESULTS: No adverse events were reported in the study. After short-term wear of the MPD on day 0, there was a minimal but statistically significant increase of half a line (LogMAR) in BCDVA for study eyes; this increase was not present at 1 week. There were no observed changes in cup-disk ratio and TBUT 1 week after the initial testing. There was a statistically significant pressure reduction in both study and fellow eyes at 1 week following the study, but clinical significance has yet to be determined. CONCLUSION: The MPD, which consists of a pair of goggles connected to a handheld, programmable pump, was well tolerated by subjects enrolled in the study. Key safety parameters remained stable after short-term exposure. The favorable safety results of this study support the safety profile of the MPD and promote further investigation of the device as a potential treatment of glaucoma. FUNDING: Equinox Ophthalmic, Inc. (Newport Beach, CA).

Safety and efficacy of intravitreal injection of steroid and antibiotics in the setting of cataract surgery and trabecular microbypass stent.

PURPOSE: To evaluate the safety and efficacy of intravitreal administration of a steroid and antibiotics during cataract surgery compared with the typical postoperative topical regimen in preventing postoperative inflammation, pain, cystoid macular edema (CME), and endophthalmitis. SETTING: Private practice, Sioux Falls, South Dakota, USA. DESIGN: Retrospective case series. METHODS: The study group included eyes that had an intravitreal injection of triamcinolone-moxifloxacin-vancomycin at the time of cataract surgery with concomitant trabecular microbypass stent insertion. The control eyes had the same procedure but were prescribed topical antibiotics, steroids, and nonsteroidal antiinflammatory drugs postoperatively. Data were recorded preoperatively and 1 day, 1 week, 1 month, and 3 months postoperatively. Primary outcomes included the number of glaucoma medications, intraocular pressure (IOP), and IOP spikes of at least 15 mm Hg from baseline. RESULTS: There were 234 eyes in the study group and 249 eyes in the control group. The mean reduction in glaucoma medications was 0.24 drops in the study group and 0.80 drops in the control group 3 months postoperatively, whereas the mean IOP reduction was 2.59 mm Hg in the study group and 3.63 mm Hg in the control group. Pressure spikes were detected at 54 (5.7%) of 936 postoperative visits in the study group and at 37 (3.7%) of 996 visits in the control group. There were no cases of severe inflammation, CME, infection, or retinal detachments. CONCLUSIONS: Both groups had similar postoperative pressure reductions and incidence of IOP spikes. The results indicate that intravitreal injections of a steroid and antibiotics might be a safe option for glaucomatous eyes having cataract surgery with trabecular microbypass stent insertion.

Retinal Manifestations of Juvenile Dermatomyositis: Case Report of Bilateral Diffuse Chorioretinopathy with Paracentral Acute Middle Maculopathy and Review of the Literature.

PURPOSE: To review a case of bilateral diffuse chorioretinopathy as a presenting sign of juvenile dermatomyositis (JDM) and review the literature regarding retinal manifestations associated with this disease. METHODS: Review of case record and literature regarding retinal manifestations related to juvenile dermatomyositis. RESULTS: A 13-year-old girl presented with bilateral diffuse chorioretinopathy as the presenting sign of juvenile dermatomyositis. A review of the literature suggests that retinopathy associated with JDM is a rare finding that is symptomatic to patients and often responds to systemic treatment of juvenile dermatomyositis. This is also the first documented case of paracentral acute middle maculopathy in the setting of juvenile dermatomyositis. CONCLUSION: Chorioretinopathy is a rare finding in juvenile dermatomyositis. While all patients with JDM likely do not warrant screening ophthalmologic examinations, any patient who has visual symptoms should have a careful dilated examination to evaluate for retinopathy or steroid-induced cataracts.

Evaluation of a Trabecular Microbypass Stent With Cataract Extraction in Severe Primary Open-angle Glaucoma.

PURPOSE: To evaluate the safety and efficacy of a trabecular microbypass stent combined with cataract surgery in patients with severe open-angle glaucoma. PATIENTS: The series included 59 eyes with severe primary open-angle glaucoma and severe visual field loss as defined by American Academy of Ophthalmology preferred practice pattern criteria. MATERIALS AND METHODS: Retrospective case series. Patients were implanted with 1 trabecular microbypass stent with concomitant cataract surgery. Primary outcome measures were intraocular pressure (IOP) and number of glaucoma medications. Safety measures included postoperative IOP pressure spikes ≥15 mm Hg or IOP<6 mm Hg at any time point, and the need for additional surgery. RESULTS: The mean preoperative IOP was 19.25±6.97 mm Hg. Postoperatively, the mean IOP was 14.38±3.63 mm Hg (P<0.01) at 12 months and 14.92±3.86 mm Hg (P<0.01) at 24 months. The mean number of glaucoma medications was 2.27±1.06 preoperatively and 1.63±1.17 (P<0.01) at 24 months postoperative, indicating a 28% reduction in medication use. In total, 4 (7%) eyes required additional surgery. In total, 5 eyes (8%) experienced IOP spikes ≥15 mm Hg, 14 (24%) eyes had IOP spikes ≥10 mm Hg. Overall 55% of eyes had a 20% IOP reduction after 24 months of surgery. Eyes with baseline IOP≤19 had a mean reduction of 2.24 mm Hg 36 months after surgery. CONCLUSIONS: Trabecular microbypass stent implantation during cataract surgery safely and effectively lowers IOP and medication use in patients with severe primary open-angle glaucoma.

Corneal biomechanical properties after laser-assisted in situ keratomileusis and photorefractive keratectomy.

BACKGROUND: The purpose of this study was to evaluate the effects of laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) on corneal biomechanical properties. METHODS: We used the ocular response analyzer to measure corneal hysteresis (CH) and corneal resistance factor (CRF) before and after refractive surgery. RESULTS: In all, 230 eyes underwent LASIK and 115 eyes underwent PRK without mitomycin C (MMC). Both procedures decreased CH and CRF from baseline. When MMC was used after PRK in 20 eyes, it resulted in lower corneal biomechanical properties at 3 months when compared to the other procedures, but all three procedures had similar values at 12 months. CONCLUSION: Significant but similar decreases in corneal biomechanical properties after LASIK, PRK without MMC, and PRK with MMC were noted.

Trabecular microbypass stent implantation with cataract extraction in pseudoexfoliation glaucoma.

PURPOSE: To evaluate the safety and efficacy of a trabecular microbypass stent (iStent) combined with cataract surgery in patients with pseudoexfoliation glaucoma (PXG). SETTING: Vance Thompson Vision, Sioux Falls, South Dakota, USA. DESIGN: Retrospective case series. METHODS: Eyes with PXG had implantation of 1 stent. Data were collected preoperatively and postoperatively through 24 months. Data included intraocular pressure (IOP), number of glaucoma medications, the incidence of postoperative IOP pressure spikes of 15 mm Hg or higher at any timepoint, and the need for additional surgery. RESULTS: The series included 115 eyes. The mean preoperative IOP was 20.00 mm Hg ± 6.95 (SD). One year postoperatively, the mean IOP was 15.54 ± 3.83 mm Hg (P < .01). At 2 years, the mean IOP was 14.51 ± 2.79 (P < .01). The mean number of glaucoma medications was 1.41 ± 1.04 preoperatively and 0.71 ± 0.94 2 years postoperatively (P < .01), indicating a 50% reduction in medication use. Postoperatively, 7 eyes (6%) had an IOP spike of 15 mm Hg or higher above the baseline IOP; the spikes responded to topical therapy. Ninety-eight percent of patients with an IOP of 20 mm Hg or higher achieved a reduction in IOP at the last follow-up. CONCLUSION: Trabecular microbypass stent implantation during cataract surgery safely and effectively lowered IOP and medication use in patients with mild to severe PXG.

Microbypass stent implantation with cataract extraction and endocyclophotocoagulation versus microbypass stent with cataract extraction for glaucoma.

PURPOSE: To compare the outcomes of combined microbypass stent implantation, cataract extraction, and endocyclophotocoagulation (ECP) with those of implantation of the same microbypass stent with concomitant cataract surgery in patients with open-angle glaucoma (OAG). SETTING: Private Practice, Sioux Falls, South Dakota, USA. DESIGN: Retrospective consecutive case series. METHODS: Patients from January 2015 to August 2016 were included. The study group comprised eyes that had implantation of a microbypass stent in combination with cataract extraction and ECP. To compare outcomes, a control group of eyes with similar baseline characteristics that had implantation of a stent in combination with cataract surgery was established. Data were collected preoperatively and postoperatively at 1 day, 1 week, and 1, 3, 6, and 12 months. Data included intraocular pressure (IOP) and number of glaucoma medications. RESULTS: The mean preoperative IOP was 21.49 mm Hg ± 9.56 (SD) in the study group (51 eyes) and 20.66 ± 3.23 mm Hg in the control group (50 eyes). Twelve months postoperatively, the mean IOP reduction was 7.14 mm Hg in the study group and 4.48 mm Hg in the control group and the medication reduction was 38% (0.68) and 63% (1.06), respectively. CONCLUSIONS: Patients who had implantation of the microbypass stent in combination with cataract surgery and ECP had significantly better IOP reduction than those who did not have ECP. The combination procedure was also effective in patients with severe OAG.

Intravitreal Versus Subretinal Tissue Plasminogen Activator Injection for Submacular Hemorrhage.

BACKGROUND AND OBJECTIVE: The objective of this study was to compare visual acuity outcomes between the following procedures used to treat submacular hemorrhages: pneumatic displacement followed by intravitreal tissue plasminogen activator (tPA) if needed (pneumatic ± tPA) and pars plana vitrectomy (PPV) with subretinal tPA (PPV + tPA). PATIENTS AND METHODS: This is a retrospective chart review of submacular hemorrhages treated with either pneumatic ± tPA or PPV + tPA. RESULTS: Eighteen patients had pneumatic ± tPA, and 14 patients had PPV + tPA. The percentage of patients achieving three lines or greater of vision improvement 1 year postoperatively was 46% and 18% in these groups, respectively (P = .194). CONCLUSION: The difference in visual acuity was not statistically significant; however, the lack of a statistical difference is important as pneumatic ± tPA is a less-invasive, less costly procedure that can be done in a clinical setting. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:26-32.].

Comparing consistency of clear corneal incisions using a traditional diamond keratome and a newly designed diamond keratome.

PURPOSE: To compare the consistency of incision architecture utilizing a traditional diamond keratome and a newly designed diamond keratome. METHODS: We used a traditional diamond keratome and newly designed diamond keratome to create clear corneal incisions in human cadaveric donor eyes. Three surgeons with varying levels of experience made 30 incisions with each keratome; and the wound architecture was measured including incision lengths, epithelial and endothelial widths, and the central epithelial incision's deviation from a straight line entrance. RESULTS: The mean absolute difference in right and left incision lengths (traditional: 0.182 ± 0.158 mm and new 0.088±0.077 mm [P<0.003]), mean absolute difference in epithelial and endothelial incision width (traditional: 0.181±0.144 mm and new 0.080±0.092 mm [P<0.002]), endothelial incision central deviation from a straight line (traditional: 0.128±0.242 mm and new -0.046±0.124 mm [P<0.001]) were all significantly more consistent with the newly designed diamond keratome than with the traditional diamond keratome. CONCLUSION: The newly designed diamond keratome creates a more consistent clear corneal incision than a traditional diamond keratome across a variety of surgical skill levels and does not require advanced levels of training to achieve this consistency.

Tau-tubulin kinase 1 enhances prefibrillar tau aggregation and motor neuron degeneration in P301L FTDP-17 tau-mutant mice.

Tau-tubulin kinase-1 (TTBK1) phosphorylates microtubule-associated protein tau at specific serine/threonine residues found in paired helical filaments (PHFs), and its expression is up-regulated in the brain in Alzheimer disease, suggesting its role in tauopathy pathogenesis. To understand the effects of TTBK1 on tauopathy in vivo, we have developed bigenic mice overexpressing full-length TTBK1 and the P301L tau mutant. The bigenic mice show enhanced tau phosphorylation at multiple sites (AT8, 12E8, PHF-1, and pS422), tauC3-immunoreactive tau fragmentation, and accumulation of tau aggregates in cortical and hippocampal neurons at 12-13 mo of age. However, the phosphorylated tau aggregates were predominantly sarkosyl soluble and migrated in the light sucrose density fraction after discontinuous sucrose gradient ultracentrifugation, which suggests that they form small oligomers. The bigenic mice show significant locomotor dysfunction as determined by both rotorod and grip strength tests, as well as enhanced loss of motor neurons in the L4-L5 spinal cord. This neuronal dysfunction and degeneration was associated with increased levels of tau oligomers, cyclin-dependent protein kinase 5 activators p35 and p25, and pY216 phosphorylated glycogen synthase kinase 3-beta. These data suggest that TTBK1 up-regulation enhances tau phosphorylation and oligomerization, whose toxicity results in enhanced neurodegeneration and locomotor dysfunction in a tauopathy animal model.

CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice.

Cytokines play an emerging role as neurotransmitters, neuromodulators, and neurohormones in the brain. This paradigm shift in cytokine function offers a new framework to understand their roles in ameliorating neurodegenerative disorders, such as Alzheimer's disease (AD). Molecular adjuvant therapy of AD animal models with glatiramer acetate induces anti-inflammatory responses and therapeutic effects. Although these effects are potentially mediated through anti-inflammatory cytokine signaling, the exact molecular identities and pathways are poorly understood. Here, we show that virus-mediated expression of the mouse interleukin (IL)-4 gene in beta-amyloid precursor protein + presenilin-1 (APP+PS1) bigenic mice attenuates AD pathogenesis. Introduction of an adeno-associated viral (AAV) vector encoding IL-4 into the hippocampus resulted in sustained expression of IL-4, reduced astro/microgliosis, amyloid-beta peptide (Abeta) oligomerization and deposition, and enhanced neurogenesis. Moreover, increased levels of IL-4 improved spatial learning, promoted phosphorylation of N-methyl-D-aspartate receptor subunit 2B at Tyr 1472, and enhanced its cell surface retention both in vivo and in vitro. Our data suggest that neuronal anti-inflammatory cytokine signaling may be a potential alternative target for non-Abeta-mediated treatment of AD.

AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice.

Accumulation of aggregated amyloid-beta (Abeta) peptide was studied as an initial step for Alzheimer's disease (AD) pathogenesis. Following amyloid plaque formation, reactive microglia and astrocytes accumulate around plaques and cause neuroinflammation. Here brain chemokines play a major role for the glial accumulation. We have previously shown that transgenic overexpression of chemokine CCL2 in the brain results in increased microglial accumulation and diffuse amyloid plaque deposition in a transgenic mouse model of AD expressing Swedish amyloid precursor protein (APP) mutant. Here, we report that adeno-associated virus (AAV) serotype 1 and 2 hybrid efficiently deliver 7ND gene, a dominant-negative CCL2 mutant, in a dose-response manner and express >1,000-fold higher recombinant CCL2 than basal levels after a single administration. AAV1/2 hybrid virus principally infected neurons without neuroinflammation with sustained expression for 6-months. 7ND expressed in APP/presenilin-1 (APP/PS1) bigenic mice reduced astro/microgliosis, beta-amyloidosis, including suppression of both fibrillar and oligomer Abeta accumulation, and improved spatial learning. Our data support the idea that the AAV1/2 system is a useful tool for CNS gene delivery, and suppression of CCL2 may be a therapeutic target for the amelioration of AD-related neuroinflammation.

Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.

Tau-tubulin kinase-1 (TTBK1) is involved in phosphorylation of tau protein at specific Serine/Threonine residues found in paired helical filaments, suggesting its role in tauopathy pathogenesis. We found that TTBK1 levels were upregulated in brains of human Alzheimer' disease (AD) patients compared with age-matched non-AD controls. To understand the effects of TTBK1 activation in vivo, we developed transgenic mice harboring human full-length TTBK1 genomic DNA (TTBK1-Tg). Transgenic TTBK1 is highly expressed in subiculum and cortical pyramidal layers, and induces phosphorylated neurofilament aggregation. TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin. Expression of recombinant TTBK1 in primary mouse cortical neurons significantly downregulated NR2B in a CDK5- and calpain-dependent manner. These data suggest that TTBK1 in AD brain may be one of the underlying mechanisms inducing CDK5 and calpain activation, NR2B downregulation, and subsequent memory dysfunction.