Identification of human presequence protease (hPreP) agonists for the treatment of Alzheimer's disease

Vangavaragu, Jhansi Rani; Valasani, Koteswara Rao; Gan, Xueqi; Yan, Shirley ShiDu

doi:10.1016/j.ejmech.2014.02.046

Cited by 28 publications

(19 citation statements)

References 51 publications

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“…Using confocal and immunogold electron microscopy, we confirmed that PreP protein in PreP-overexpressed Tg mice is exclusively localized in mitochondria. Thus, enhancing PreP proteolytic activity may hold a potential therapeutic strategy for treatment of AD at early stage by accelerating clearance of mitochondrial Aβ and improving mitochondrial and synaptic function (41).…”

Section: Discussionmentioning

confidence: 99%

Increased neuronal PreP activity reduces Aβ accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model

et al. 2015

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Accumulation of amyloid-β (Aβ) in synaptic mitochondria is associated with mitochondrial and synaptic injury. The underlying mechanisms and strategies to eliminate Aβ and rescue mitochondrial and synaptic defects remain elusive. Presequence protease (PreP), a mitochondrial peptidasome, is a novel mitochondrial Aβ degrading enzyme. Here, we demonstrate for the first time that increased expression of active human PreP in cortical neurons attenuates Alzheimer disease's (AD)-like mitochondrial amyloid pathology and synaptic mitochondrial dysfunction, and suppresses mitochondrial oxidative stress. Notably, PreP-overexpressed AD mice show significant reduction in the production of proinflammatory mediators. Accordingly, increased neuronal PreP expression improves learning and memory and synaptic function in vivo AD mice, and alleviates Aβ-mediated reduction of long-term potentiation (LTP). Our results provide in vivo evidence that PreP may play an important role in maintaining mitochondrial integrity and function by clearance and degradation of mitochondrial Aβ along with the improvement in synaptic and behavioral function in AD mouse model. Thus, enhancing PreP activity/expression may be a new therapeutic avenue for treatment of AD.

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Section: Discussionmentioning

confidence: 99%

Increased neuronal PreP activity reduces Aβ accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model

et al. 2015

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“…A, respectively. The docking conformations were generated using a triangle matching docking placement methodology [22] and the poses were rescored using the London dG scoring function [23]. Multiple conformations were generated in each docking method and the pose with the lowest score was chosen for the analysis.…”

Section: Generation Of Gk-glucose Complexesmentioning

confidence: 99%

Conformational transition pathway of R308K mutant glucokinase in the presence of the glucokinase activator YNKGKA4

et al. 2018

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Glucokinase ( GK ) plays a vital role in the control of blood glucose levels and its altered activity can lead to the development of forms of diabetes. We have previously identified a mutant GK (R308K) in patients with type 2 diabetes with reduced enzyme activity. In the present study, the activation mechanism of GK from super‐open to the closed state under wild‐type and mutant conditions in the presence of the novel aminophosphonate derivative YNKGKA 4 (an allosteric activator of GK ) was characterized via a series of molecular dynamics simulations. A reliable conformational transition pathway of GK was observed from super‐open to closed state during trajectory analysis. Glucose was also observed to modulate its binding orientation in the active site but with stable moments in the cavity. These observations provide insights into the complicated conformational transitions in the presence of YNKGKA 4 and the molecular mechanism of GK activators for the allosteric regulation of mutant forms of GK .

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“…Small benzimidazole derivatives (Compound 3c is shown in Fig. 17) may provide a promising avenue for AD treatment [689].…”

Section: Drugs Interacting With Human Presequence Proteasementioning

confidence: 99%

Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes. Update 2014

Froestl

Muhs

Pfeifer

2014

JAD

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Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers are very productive. The review on Drugs interacting with Enzymes was accepted in August 2012. However, this field is very dynamic. New potential targets for the treatment of Alzheimer's disease were identified. This update describes drugs interacting with 60 enzymes versus 43 enzymes in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through April 2014.

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Identification of human presequence protease (hPreP) agonists for the treatment of Alzheimer's disease

Cited by 28 publications

References 51 publications

Increased neuronal PreP activity reduces Aβ accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model

Increased neuronal PreP activity reduces Aβ accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model

Conformational transition pathway of R308K mutant glucokinase in the presence of the glucokinase activator YNKGKA4

Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes. Update 2014

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