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.
PurposeWe developed a new portable head-mounted perimeter, “imo”, which performs visual field (VF) testing under flexible conditions without a dark room. Besides the monocular eye test, imo can present a test target randomly to either eye without occlusion (a binocular random single eye test). The performance of imo was evaluated.MethodsUsing full HD transmissive LCD and high intensity LED backlights, imo can display a test target under the same test conditions as the Humphrey Field Analyzer (HFA). The monocular and binocular random single eye tests by imo and the HFA test were performed on 40 eyes of 20 subjects with glaucoma. VF sensitivity results by the monocular and binocular random single eye tests were compared, and these test results were further compared to those by the HFA. The subjects were asked whether they noticed which eye was being tested during the test.ResultsThe mean sensitivity (MS) obtained with the HFA highly correlated with the MS by the imo monocular test (R: r = 0.96, L: r = 0.94, P < 0.001) and the binocular random single eye test (R: r = 0.97, L: r = 0.98, P < 0.001). The MS values by the monocular and binocular random single eye tests also highly correlated (R: r = 0.96, L: r = 0.95, P < 0.001). No subject could detect which eye was being tested during the examination.ConclusionsThe perimeter imo can obtain VF sensitivity highly compatible to that by the standard automated perimeter. The binocular random single eye test provides a non-occlusion test condition without the examinee being aware of the tested eye.
Metamorphopsia scores correlate well with measurements of retinal contraction due to idiopathic ERM. Using M-CHARTS is a simple and useful method for quantitatively monitoring metamorphopsia in patients with ERM.
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 calpaindependent 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.
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