- Cerebrospinal Fluid BACE1 Activity and sAβPPβ as Biomarker Candidates of Alzheimer's Disease. [Journal Article]
- DGDement Geriatr Cogn Disord 2018 May 22; 45(3-4):152-161
- CONCLUSIONS: Further studies using biomarker-underpinned diagnoses are warranted to shed more light on the potential diagnostic utility of BACE1 activity as AD biomarker candidate in MCI.
- O-GlcNAcylation and neuronal energy status: implications for Alzheimer's disease. [Review]
- ARAgeing Res Rev 2018 May 19
- Since the first clinical case reported more than 100 years ago, it has been a long and winding road to demystify the initial pathological events underling the onset of Alzheimer's disease (AD). Fortu...
Since the first clinical case reported more than 100 years ago, it has been a long and winding road to demystify the initial pathological events underling the onset of Alzheimer's disease (AD). Fortunately, advanced imaging techniques extended the knowledge regarding AD origin, being well accepted that a decline in brain glucose metabolism occurs during the prodromal phases of AD and is aggravated with the progression of the disease. In this sense, in the last decades, the post-translational modification O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) has emerged as a potential causative link between hampered brain glucose metabolism and AD pathology. This is not surprising taking into account that this dynamic post-translational modification acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. Within this scenario, the present review aims to summarize the current understanding on the role of O-GlcNAcylation in neuronal physiology and AD pathology, emphasizing the close association of this post-translational modification with the emergence of AD-related hallmarks and its potential as a therapeutic target.
- Elevating Integrin-linked Kinase Expression has Rescued Hippocampal Neurogenesis and Memory Deficits in an AD animal Model. [Journal Article]
- BRBrain Res 2018 May 19
- Alterations in adult neurogenesis have been regarded as a major cause of cognitive impairment in Alzheimer's disease (AD). The underlying mechanism of neurogenesis deficiency in AD remains unclear. I...
Alterations in adult neurogenesis have been regarded as a major cause of cognitive impairment in Alzheimer's disease (AD). The underlying mechanism of neurogenesis deficiency in AD remains unclear. In this study, we reported that Integrin-linked Kinase (ILK) protein levels and phosphorylation were significantly decreased in the hippocampus of APP/PS1 mice. Increased ILK expression of dentate gyrus (DG) rescued the hippocampus-dependent neurogenesis and memory deficits in APP/PS1 mice. Moreover, we demonstrated that the effect of ILK overexpression in the hippocampus was exerted via AKT-GSK3β pathway. Finally, we found that Fluoxetine, a selective serotonin reuptake inhibitor, could improve the impaired hippocampal neurogenesis and memory by enhancing ILK-AKT-GSK3β pathway activity in APP/PS1 mice. Thus, these findings demonstrated the effects of ILK on neurogenesis and memory recovery, suggesting that ILK is an important therapeutic target for AD prevention and treatment.
- Glycosylation status of nicastrin influences catalytic activity and substrate preference of γ-secretase. [Journal Article]
- BBBiochem Biophys Res Commun 2018 May 19
- γ-Secretase complex, the assembly of nicastrin (NCT), Presenilin (PS), Presenilin Enhancer-2 (PEN-2) and Anterior pharynx defective 1 (Aph-1), catalyzes the cleavage of amyloid precursor protein to g...
γ-Secretase complex, the assembly of nicastrin (NCT), Presenilin (PS), Presenilin Enhancer-2 (PEN-2) and Anterior pharynx defective 1 (Aph-1), catalyzes the cleavage of amyloid precursor protein to generate amyloid-β protein (Aβ), the main culprit of Alzheimer's disease. NCT becomes matured through complex glycosylation and play important role in γ-secretase activity by interacting with catalytic subunit PS. However, the role of NCT glycosylation on γ-secretase activity and substrate specificity is still unknown. The purpose of this study is to investigate the effect of NCT glycosylation on γ-secretase activity and substrate specificity in a group of glycosylation mutant lectin resistant CHO (Lec) cells. CHO Lec-1 cells lack glycosyltransferase-I, GnT-I, thus N-glycan on NCT are all oligomannose type, whereas CHO Lec-2 cells synthesize NCT containing sialic acid deficient oligosaccharides due to the impairment of cytidine 5'-monophosphate-sialic acid transporter. Here, we reported that mutant CHO Lec-1 and Lec-2 reduced γ-secretase activity in both cell-based and biochemical assays, and that CHO Lec-1 preferentially reduced Aβ generation. Endogenous level of γ-secretase complex, subcellular distribution of γ-secretase subunits and the level of functional γ-secretase complex remained unchanged in mutants. Interestingly, Coimmunoprecipitation study revealed that mutant γ-secretase could recognize substrate as well as parental γ-secretase. Our data suggests that thorough glycosylation of NCT is critical for enzymatic activity and substrate preference of γ-secretase.
- [Brain microbleeds - definition, pathophysiology and the consequences]. [Journal Article]
- WLWiad Lek 2018; 71(2 pt 2):408-412
- Brain microbleeds are defined as small, circular hypointense changes in T2-sequensec of brain MRI, well demarcated from the surrounding tissue. They represent the phagocytized products of blood distr...
Brain microbleeds are defined as small, circular hypointense changes in T2-sequensec of brain MRI, well demarcated from the surrounding tissue. They represent the phagocytized products of blood distribution extravasated from pathologically altered vessels. The echo-T2-dependent gradient (GRE) and magnetic susceptibility testing (SWI) sequences are usually used to visualize them. The pathogenesis of microbleeds very complex but angiopathy associated with arterial hypertension and cerebral amyloid angiopathy play a special role. Atherosclerotic lesions and inflammatory processes are also important. Microbleeds can be found in healthy people as well as in many disorders such as hypertension, Alzheimer's disease or other types of dementia. Their prevalence increases with age. Microbleeds may have a multidimensional effect on the surrounding brain tissue. It is suggested that they disrupt both the brain structure and the electrical function of neurons. In this review article we present current knowledge on the cerebral microbleeds.
- Electrochemical impedance spectroscopy for real-time detection of lipid membrane damage based on a porous self-assembly monolayer support. [Journal Article]
- ACAnal Chem 2018 May 22
- Layer-by-layer dissolution and permeable pore formation are two typical membrane damage pathways, which induce membrane function disorder and result in serious disease, such as Alzheimer's disease, K...
Layer-by-layer dissolution and permeable pore formation are two typical membrane damage pathways, which induce membrane function disorder and result in serious disease, such as Alzheimer's disease, Keshan disease, Sickle-cell disease and so on. To effectively distinguish and sensitively monitor these two typical membrane damage pathways, a facile electrochemical impedance strategy was developed on a porous self-assembly monolayer (pSAM) supported bilayer lipid membrane (BLM). The pSAM was prepared by selectively electrochemical reductive desorption of the mercaptopropionic acid in a mixed mercaptopropionic acid/11-mercaptoundecanoic acid self-assembled monolayer, which created plenty of nanopores with tens of nanometers in diameter and several nanometers in height (defined as inner-pores). The ultra-low aspect ratio of the inner-pores was advantageous to the mass transfer of electrochemical probe [Fe(CN)6]3-/4-, simplifying the equivalent electric circuit for electrochemical impedance spectroscopy analysis at the electrode/membrane interface. [Fe(CN)6]3-/4- transferring from the bulk solution into the inner-pore induce significant changes of the interfacial impedance properties, improving the detection sensitivity. Based on these, the different membrane damage pathways were effectively distinguished and sensitively monitored with the normalized resistance-capacitance changes of inner-pore-related parameters including the electrolyte resistance within the pore length (Rpore), and the metal/inner-pore interfacial capacitance (Cpore) and the charge-transfer resistance (Rct-in) at the metal/inner-pore interface.
- Path analysis of caregiver characteristics and neuropsychiatric symptoms in Alzheimer's disease patients. [Journal Article]
- GGGeriatr Gerontol Int 2018 May 22
- CONCLUSIONS: Overburdened caregivers and the use of dysfunctional management strategies are associated with a greater presence of neuropsychiatric symptoms in Alzheimer's disease patients. These aspects should be considered when developing interventions for caregivers to manage neuropsychiatric symptoms and overall treatment of patients with dementia. Geriatr Gerontol Int 2018; ••: ••-••.
- Longitudinal Neuroimaging Hippocampal Markers for Diagnosing Alzheimer's Disease. [Journal Article]
- NNeuroinformatics 2018 May 21
- Hippocampal atrophy measures from magnetic resonance imaging (MRI) are powerful tools for monitoring Alzheimer's disease (AD) progression. In this paper, we introduce a longitudinal image analysis fr...
Hippocampal atrophy measures from magnetic resonance imaging (MRI) are powerful tools for monitoring Alzheimer's disease (AD) progression. In this paper, we introduce a longitudinal image analysis framework based on robust registration and simultaneous hippocampal segmentation and longitudinal marker classification of brain MRI of an arbitrary number of time points. The framework comprises two innovative parts: a longitudinal segmentation and a longitudinal classification step. The results show that both steps of the longitudinal pipeline improved the reliability and the accuracy of the discrimination between clinical groups. We introduce a novel approach to the joint segmentation of the hippocampus across multiple time points; this approach is based on graph cuts of longitudinal MRI scans with constraints on hippocampal atrophy and supported by atlases. Furthermore, we use linear mixed effect (LME) modeling for differential diagnosis between clinical groups. The classifiers are trained from the average residue between the longitudinal marker of the subjects and the LME model. In our experiments, we analyzed MRI-derived longitudinal hippocampal markers from two publicly available datasets (Alzheimer's Disease Neuroimaging Initiative, ADNI and Minimal Interval Resonance Imaging in Alzheimer's Disease, MIRIAD). In test/retest reliability experiments, the proposed method yielded lower volume errors and significantly higher dice overlaps than the cross-sectional approach (volume errors: 1.55% vs 0.8%; dice overlaps: 0.945 vs 0.975). To diagnose AD, the discrimination ability of our proposal gave an area under the receiver operating characteristic (ROC) curve (AUC) [Formula: see text] 0.947 for the control vs AD, AUC [Formula: see text] 0.720 for mild cognitive impairment (MCI) vs AD, and AUC [Formula: see text] 0.805 for the control vs MCI.
- In situ nanostructured hydrogel of resveratrol for brain targeting: in vitro-in vivo characterization. [Journal Article]
- DDDrug Deliv Transl Res 2018 May 21
- The purpose of conducting the present research work was to develop resveratrol nanostructured in situ gel for the treatment of Alzheimer's disease. Resveratrol loaded lipid carrier was prepared by me...
The purpose of conducting the present research work was to develop resveratrol nanostructured in situ gel for the treatment of Alzheimer's disease. Resveratrol loaded lipid carrier was prepared by melt emulsification-probe sonication method, and the final product was evaluated for particle size (132 ± 11.90 nm), polydispersity index (0.209 ± 0.005), zeta potential (- 23 ± 3.79 mV), drug loading (9.26 ± 3.79%), and entrapment efficiency (74 ± 11.40%). Following incorporation of the resveratrol nanostructured lipid carrier in gellan gum and xanthan gum, in situ gel was formulated and characterized. The optimized in situ gel showed fivefold higher permeation across the nasal mucosa as compared to resveratrol suspension-based in situ gel. Finally, optimized in situ gel was evaluated using in vivo pharmacodynamic study by the scopolamine-induced amnesia model in rats using Morris Water Maze test. It showed significant improvement in memory function in rats treated with optimized in situ gel as compared to orally administered resveratrol suspension. The enhanced permeation across nasal mucosa and improved memory function suggest that the resveratrol nanostructured lipid carrier-based in situ gel could be an effective and promising approach for the treatment of Alzheimer's disease.
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- High Dose and Delayed Treatment with Bile Acids Ineffective in RML Prion-Infected Mice. [Journal Article]
- AAAntimicrob Agents Chemother 2018 May 21
- Prion diseases are a group of neurodegenerative diseases associated with the misfolding of the cellular prion protein (PrPC) into the infectious form (PrPSc). There are currently no treatments for pr...
Prion diseases are a group of neurodegenerative diseases associated with the misfolding of the cellular prion protein (PrPC) into the infectious form (PrPSc). There are currently no treatments for prion disease. Bile acids have the ability to protect hepatocytes from apoptosis and are neuroprotective in animal models of other protein folding neurodegenerative diseases including Huntington's, Parkinson's, and Alzheimer's disease. Importantly, bile acids are approved for clinical use in patients with cirrhosis, and have recently been shown to be safe and possibly effective in pilot trials of patients with amyotrophic lateral sclerosis (ALS). We previously reported that the bile acid, ursodeoxycholic acid (UDCA), given early in disease, prolonged incubation periods in male RML-infected mice. Here we expand on this result to include tauro-ursodeoxycholic acid (TUDCA) treatment trials and delayed UDCA treatment. We demonstrate that, despite a high dose of TUDCA given early in disease, there was no significant difference in incubation periods between treated and untreated cohorts, regardless of sex. In addition, delayed treatment with a high dose of UDCA resulted in a significant shortening of the average survival time for both male and female mice when compared to their sex-matched controls, with evidence of increased BiP, a marker of apoptosis, in treated female mice. Our findings suggest that treatment with high dose TUDCA provides no therapeutic benefit and that delayed treatment with high dose UDCA is ineffective and could potentially worsen outcomes.