scholarly journals Therapeutic Targeting of Casein Kinase 1δ/ε in an Alzheimer’s Disease Mouse Model

2019 ◽  
Author(s):  
Paula Adler ◽  
Janice Mayne ◽  
Krystal Walker ◽  
Zhibin Ning ◽  
Daniel Figeys
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Impairment ◽  
Sleep Disturbances ◽  
Casein Kinase ◽  
Amyloid Precursor Protein Processing ◽  
Proof Of Concept ◽  
Hippocampal Function ◽  
Sleep And Cognition

SUMMARYSleep disturbances and memory impairment are common symptoms of Alzheimer’s disease (AD). Given that the circadian clock regulates sleep, hippocampal function, and neurodegeneration, it represents a therapeutic target against AD. Casein kinase 1δ/ε (CK1δ/ε) are clock regulators and overexpressed in AD brains, making them viable targets to improve sleep and cognition. We assessed the effects of a small molecule CK1δ/ε inhibitor (PF-670462) in a cellular model of circadian clocks and in 3xTg-AD mice. Mass spectrometry–based proteomic analyses revealed that PF-670462 treatmentin vitroupregulated multiple proteins that are downregulated in AD, while administration in 3xTg-AD mice reversed hippocampal proteomic alterations in diverse AD-associated and clock-regulated pathways, including synaptic plasticity and amyloid precursor protein processing. Furthermore, PF-670462 rescued working memory and normalized behavioural circadian rhythms in 3xTg-AD mice. Our study provides proof of concept for CK1δ/ε inhibition and direct clock modulation against AD-related proteomic changes, memory impairment, and circadian disturbances.

scholarly journals Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease

2021 ◽  
Author(s):  
Wen-Dai Bao ◽  
Pei Pang ◽  
Xiao-Ting Zhou ◽  
Fan Hu ◽  
Wan Xiong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Impairment ◽  
Iron Homeostasis ◽  
Critical Role ◽  
Gene Set Enrichment Analysis ◽  
Molecular Characteristics ◽  
Intracellular Iron

AbstractIron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

scholarly journals Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signaling

2019 ◽  
Author(s):  
Claire S. Durrant ◽  
Karsten Ruscher ◽  
Olivia Sheppard ◽  
Michael P. Coleman ◽  
Ilknur Özen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Precursor Protein ◽  
Vascular Pathology ◽  
Amyloid Precursor Protein Processing ◽  
App Processing ◽  
Bace1 Inhibition

AbstractAmyloid beta peptides (Aβ) proteins play a key role in vascular pathology in Alzheimer’s Disease (AD) including impairment of the blood brain barrier and aberrant angiogenesis. Although previous work has demonstrated a pro-angiogenic role of Aβ, the exact mechanisms by which amyloid precursor protein (APP) processing and endothelial angiogenic signalling cascades interact in AD remain a largely unsolved problem. Here, we report that increased endothelial sprouting in human-APP transgenic mouse (TgCRND8) tissue is dependent on β-secretase (BACE1) processing of APP. Higher levels of Aβ processing in TgCRND8 tissue coincides with decreased NOTCH3/JAG1 signalling, over-production of endothelial filopodia and increased numbers of vascular pericytes. Using a novel in vitro approach to study sprouting angiogenesis in TgCRND8 organotypic brain slice cultures (OBSCs), we find that BACE1 inhibition normalises excessive endothelial filopodia formation and restores NOTCH3 signalling. These data present the first evidence for the potential of BACE1 inhibition as an effective therapeutic target for aberrant angiogenesis in AD.SignificanceIn this study, we show that targeting amyloid beta processing provides an opportunity to selectively target tip cell filopodia-driven angiogenesis and develop therapeutic targets for vascular dysfunction related to aberrant angiogenesis in AD. Our data provide the first evidence for a safe level of BACE1 inhibition that can normalize excess angiogenesis in AD, without inducing vascular deficits in healthy tissue. Our findings may pave the way for the development of new angiogenesis dependent therapeutic strategies in Alzheimer’s Disease.

scholarly journals The Ameliorating Effect of Phenylsulfonamide Derivatives on Scopolamine-Induced Memory Impairment in Mice via Inhibition of mPGES-1

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 36
Author(s):  
Ryu ◽  
Moon ◽  
Ko ◽  
Lee ◽  
Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inhibitory Activity ◽  
Memory Impairment ◽  
Close Correlation ◽  
Positive Control ◽  
Raw 264.7 Macrophage Cells ◽  
Continuous Work ◽  
Cox 1

Our previous research showed that a novel series of phenylsulfonyl hydrazide derivatives reduced LPS-induced PGE2 levels in RAW 264.7 macrophage cells via an inhibition of mPGES-1 enzyme. As a continuous work, new phenylsulfonamide derivatives (5a-5k) as methylene analogues of phenylsulfonyl hydrazide derivatives, including MPO-0063, were synthesized and biologically evaluated in vitro. Among synthetic compounds, 5a (MPO-0112) showed decreased inhibitory activity against PGE2 production (IC50: 0.34 µM) compared to MPO-0063 (IC50: 0.04 µM) but inhibited the mPGES-1 enzyme (IC50: 7.37 µM) similar to MPO-0063 (IC50: 0.10 µM) together with excellent selectivity over COX-enzymes (COX-1 and 2). According to recent studies on the close correlation between up-regulation of mPGES-1 and Alzheimer's disease, we investigated whether 5a could ameliorate scopolamine-induced memory impairment using the passive avoidance test. The memory impairment-ameliorating effect of 5a (1.0 mg/kg, p.o.) was found to be effective, comparable to that of donepezil (5 mg/kg, p.o.) as a positive control. On the other hand, 5a exhibited little or weak AChE and BuChE inhibitory activity, which implies that 5a could ameliorate scopolamine-induced memory impairment by inhibiting mPGES-1 enzyme instead of cholinesterase enzymes. In addition, MPO-0112 exhibited a favorable in vitro CYP profile, which is suggestive of no potential drug–drug interactions. Therefore, these overall results suggest that 5a as a selective mPGES-1 inhibitor may be a novel therapeutic agent for diseases associated with cognitive deficits, such as Alzheimer’s disease.

scholarly journals BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

Brain ◽  
2016 ◽  
Vol 139 (10) ◽  
pp. 2766-2777 ◽  
Author(s):  
Yen Ying Lim ◽  
Jason Hassenstab ◽  
Carlos Cruchaga ◽  
Alison Goate ◽  
Anne M. Fagan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Impairment ◽  
Autosomal Dominant ◽  
Hippocampal Function ◽  
Autosomal Dominant Alzheimer’S Disease

Acetylcholinesterase Inhibitory Potential and Antioxidant Activities of Five Cultivars of Rosa Damascena Mill. From Isparta, Turkey

2020 ◽  
Vol 18 (4) ◽  
pp. 354-359
Author(s):  
Shirin Tarbiat ◽  
Azize Simay Türütoğlu ◽  
Merve Ekingen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radical ◽  
Neurodegenerative Disorder ◽  
Antioxidant Activities ◽  
Radical Scavenging ◽  
Acetylcholinesterase Activity ◽  
Rosa Damascena ◽  
Free Radical Damage

Alzheimer's disease is a neurodegenerative disorder characterized by memory loss and impairment of language. Alzheimer's disease is strongly associated with oxidative stress and impairment in the cholinergic pathway, which results in decreased levels of acetylcholine in certain areas of the brain. Hence, inhibition of acetylcholinesterase activity has been recognized as an acceptable treatment against Alzheimer's disease. Nature provides an array of bioactive compounds, which may protect against free radical damage and inhibit acetylcholinesterase activity. This study compares the in vitro antioxidant and anticholinesterase activities of hydroalcoholic extracts of five cultivars of Rosa Damascena Mill. petals (R. damascena 'Bulgarica', R. damascena 'Faik', R. damascena 'Iranica', R. damascena 'Complex-635' and R. damascena 'Complex-637') from Isparta, Turkey. The antioxidant activities of the hydroalcoholic extracts were tested for ferric ion reduction and DPPH radical scavenging activities. The anti-acetylcholinesterase activity was also evaluated. All rose cultivars showed a high potency for scavenging free radical and inhibiting acetylcholinesterase activity. There was a significant correlation between antioxidant and acetylcholinesterase inhibitory activity. Among cultivars, Complex-635 showed the highest inhibitory effect with an IC50 value of 3.92 µg/mL. Our results suggest that all these extracts may have the potential to treat Alzheimer's disease with Complex-635 showing more promise.

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

In vivo Evaluation and Alzheimer’s Disease Treatment Outcome of siRNA Loaded Dual Targeting Drug Delivery System

2019 ◽  
Vol 20 (1) ◽  
pp. 56-62 ◽  
Author(s):  
Chi Zhang ◽  
Zhichun Gu ◽  
Long Shen ◽  
Xianyan Liu ◽  
Houwen Lin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Outcome ◽  
Neuroprotective Effect ◽  
Sirna Delivery ◽  
Repeated Administration ◽  
Spatial Learning And Memory ◽  
In Vivo Evaluation

Background: To deliver drugs to treat Alzheimer’s Disease (AD), nanoparticles should firstly penetrate through blood brain barrier, and then target neurons. Methods: Recently, we developed an Apo A-I and NL4 dual modified nanoparticle (ANNP) to deliver beta-amyloid converting enzyme 1 (BACE1) siRNA. Although promising in vitro results were obtained, the in vivo performance was not clear. Therefore, in this study, we further evaluated the in vivo neuroprotective effect and toxicity of the ANNP/siRNA. The ANNP/siRNA was 80.6 nm with good stability when incubated with serum. In vivo, the treatment with ANNP/siRNA significantly improves the spatial learning and memory of APP/PS1 double transgenic mice, as determined by mean escape latency, times of crossing the platform area during the 60 s swimming and the percentage of the distance in the target quadrant. Results and Conclusion: After the treatment, BACE1 RNA level of ANNP/siRNA group was greatly reduced, which contributed a good AD treatment outcome. Finally, after repeated administration, the ANNP/siRNA did not lead to significant change as observed by HE staining of main organs, suggesting the good biocompatibility of ANNP/siRNA. These results demonstrated that the ANNP was a good candidate for AD targeting siRNA delivery.

Sign in / Sign up

Export Citation Format

Share Document