Background: The vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex system, an ubiquitous multiprotein assembly responsible for sorting and trafficking protein cargos out of the endosomes. VPS35 can regulate APP metabolism and Aβ formation, and its levels are reduced in Alzheimer's disease (AD) brains. We and others demonstrated that VPS35 genetic manipulation modulates the phenotype of mouse models of AD. However, the translational value of this observation remains to be investigated. Methods: Triple transgenic mice were randomized to receive a pharmacological chaperone, which stabilizes the retromer complex, and the effect on their AD-like phenotype assessed. Results: Compared with controls, treated mice had a significant improvement in learning and memory, an elevation of VPS35 levels, and improved synaptic integrity. Additionally, the same animals had a significant decrease in Aβ levels and deposition, reduced tau phosphorylation and less astrocytes activation. Conclusions: Our study demonstrates that the enhancement of retromer function by pharmacological chaperones is a potentially novel and viable therapy against AD.
The vacuolar protein sorting 35 (VPS35) is a major component of the retromer recognition core complex which regulates intracellular protein sorting and trafficking. Deficiency in VPS35 by altering APP/Aβ metabolism has been linked to late-onset Alzheimer's disease. Here we report that VPS35 is significantly reduced in Progressive Supra-nuclear Palsy and Picks' disease, two distinct primary tauopathies. In vitro studies show that overexpression of VPS35 leads to a reduction of pathological tau in neuronal cells, whereas genetic silencing of VPS35 results in its accumulation. Mechanistically the availability of active cathepsin D mediates the effect of VPS35 on pathological tau accumulation. Moreover, in a relevant transgenic mouse model of tauopathy, down-regulation of VPS35 results in an exacerbation of motor and learning impairments as well as accumulation of pathological tau and loss of synaptic integrity. Taken together, our data identify VPS35 as a novel critical player in tau metabolism and neuropathology, and a new therapeutic target for human tauopathies.
Deficit in retromer complex function secondary to lower levels of one of its major components, the vacuolar protein sorting 35 (VPS35), has been reported in Alzheimer’s disease (AD) brains. VPS35 genetic reduction results in increased Aβ levels and synaptic pathology in mouse models of the disease. However, whether restoration of its levels has an effect on the AD-like phenotype which includes Aβ plaques, tau tangles and memory impairments remains unknown. In this paper, we investigated the effect of VPS35 gene delivery into the central nervous system on the development of the neuropathology and behavioral deficits of the triple transgenic (3xTg) mice. Compared with controls, animals over-expressing VPS35 had an amelioration of spatial learning and working memory, which associated with a significant reduction in Aβ levels and deposition and tau phosphorylation. Additionally, the same animals had a significant improvement of synaptic pathology and neuroinflammation. In vitro study confirmed that VPS35 up-regulation by reducing total levels of APP and tau results in a significant decrease in their metabolic products and phosphorylated isoforms, respectively. Our results demonstrate for the first time that VPS35 is directly involved in the development of AD-like phenotype, and for this reason should be considered as a novel therapeutic target for AD.
To evaluate real-world outcomes of astigmatism management with femtosecond laser arcuate incisions in patients with low corneal astigmatism (<1.0 D) using a novel formula for arcuate incision calculation compared to outcomes after conventional cataract surgery without surgical management of astigmatism. Patients and Methods: The Wörtz-Gupta™ Formula (available at www.lricalc.com) was used to calculate femtosecond laser arcuate parameters for 224 patients with <1 D of corneal astigmatism who underwent cataract surgery; lens power was determined with the Barrett Universal II formula. Uncorrected distance visual acuity (UCDVA) and refractive astigmatism measurements were obtained, with an average follow-up of 4 weeks. Results: The average preoperative cylinder was similar (0.61 D in the femtosecond group [n=124] and 0.57 D in the conventional group [n=100] (P>0.05)). More patients had ≤0.5 D of postoperative corneal astigmatism in the femtosecond group (n=110/124, 89%) than in the conventional group (n=71/100, 71%), respectively (P=0.001). The mean absolute postoperative refractive astigmatism was higher in the conventional surgery group than in the femtosecond group (0.43 ± 0.4 D vs 0.26 ± 0.28 D); these differences were statistically significant (P<0.001). The percentage of patients with UCDVA of 20/20 or better vision was higher in the femtosecond group (62%) than the conventional group (48%) (P=0.025). Conclusion: Using the femtosecond laser for arcuate incisions in combination with a novel nomogram can provide excellent anatomic and refractive outcomes in patients with lower levels of preoperative astigmatism at the time of cataract surgery.
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