- Phosphorylation of Serine 305 in Tau Inhibits Aggregation. [Journal Article]
- NLNeurosci Lett 2018 Nov 10
- Alzheimer's disease and other tauopathies are characterized by the brain accumulation of hyperphosphorylated aggregated tau protein forming pathological inclusions. Although elevated tau phosphorylat...
Alzheimer's disease and other tauopathies are characterized by the brain accumulation of hyperphosphorylated aggregated tau protein forming pathological inclusions. Although elevated tau phosphorylated at many amino acid residues is a hallmark of pathological tau, some evidence suggest that tau phosphorylation at unique sites, especially within its microtubule-binding domain, might inhibit aggregation. In this study, the effects of phosphorylation of two unique residues within this domain, serine 305 (S305) and serine 320 (S320), were examined in the context of established aggregation and seeding models. It was found that the S305E phosphomimetic significantly inhibited both tau seeding and tau aggregation in this model, while S320E did not. To further explore S305 phosphorylation in vivo, a monoclonal antibody (2G2) specific for tau phosphorylated at S305 was generated and characterized. Consistent with inhibition of tau aggregation, phosphorylation of S305 was not detected in pathological tau inclusions in Alzheimer's disease brain tissue. This study indicates that phosphorylation of unique tau residues can be inhibitory to aggregate formation, and has important implications for potential kinase therapies. Additionally, it creates new tools for observing these changes in vivo.
- Reliability, validity and minimal detectable change of 2-minute walk test, 6-minute walk test and 10-meter walk test in frail older adults with dementia. [Journal Article]
- EGExp Gerontol 2018 Nov 10
- CONCLUSIONS: The 2MWT, 6MWT and 10MeWT are reliable and valid measures in evaluating walking ability in frail older adults with dementia. The MDC95 of the walk tests has been established. The cueing system is feasible and reliable to facilitate the administration of the walk tests in this population group.
- Quantitative trait loci identification for brain endophenotypes via new additive model with random networks. [Journal Article]
- BBioinformatics 2018 Sep 01; 34(17):i866-i874
- The identification of quantitative trait loci (QTL) is critical to the study of causal relationships between genetic variations and disease abnormalities. We focus on identifying the QTLs associated ...
The identification of quantitative trait loci (QTL) is critical to the study of causal relationships between genetic variations and disease abnormalities. We focus on identifying the QTLs associated to the brain endophenotypes in imaging genomics study for Alzheimer's Disease (AD). Existing research works mainly depict the association between single nucleotide polymorphisms (SNPs) and the brain endophenotypes via the linear methods, which may introduce high bias due to the simplicity of the models. Since the influence of QTLs on brain endophenotypes is quite complex, it is desired to design the appropriate non-linear models to investigate the associations of genotypes and endophenotypes.
- Signs and Artifacts in Amyloid PET. [Journal Article]
- RRadiographics 2018 Nov-Dec; 38(7):2123-2133
- Establishing a diagnosis of Alzheimer dementia can be challenging, particularly early in the course of the disease. However, with disease-modifying therapies on the horizon, it is becoming increasing...
Establishing a diagnosis of Alzheimer dementia can be challenging, particularly early in the course of the disease. However, with disease-modifying therapies on the horizon, it is becoming increasingly important to achieve the correct diagnosis as soon as possible. In challenging presentations of dementia, such as patients with clinically atypical features or early-age onset of mild cognitive impairment, amyloid PET is a valuable tool in determining the diagnosis of Alzheimer dementia. Furthermore, preliminary data show that amyloid PET findings alter clinical management in patients who meet the appropriate use criteria. There are currently three U.S. Food and Drug Administration (FDA)-approved fluorine 18 (18F)-labeled radiopharmaceuticals that allow in vivo detection of cerebral amyloid deposition, which is a hallmark pathologic feature of Alzheimer dementia. Knowledge of the common imaging features among these three 18F-labeled radiopharmaceuticals in the normal and abnormal brain will enable the radiologist to more accurately interpret amyloid PET studies. As in other subspecialties of radiology, imaging signs in amyloid PET are helpful to distinguish if a region is normal or abnormal. This article reviews appropriate use criteria for amyloid PET, introduces the properties of the radiopharmaceuticals, explains the algorithmic approach to interpretation with examples of normal and abnormal amyloid PET scans with MRI correlation, and provides an atlas of regional amyloid PET signs and common artifacts. ©RSNA, 2018.
- The Potential of Information Technology to Navigate Caregiving Systems: Perspectives from Dementia Caregivers. [Journal Article]
- JGJ Gerontol Soc Work 2018 Nov 13; :1-19
- Technologies designed to support caregivers of adults with Alzheimer's disease and related dementias (AD/RD) have been developing at an increasingly rapid pace. However, little remains known about ca...
Technologies designed to support caregivers of adults with Alzheimer's disease and related dementias (AD/RD) have been developing at an increasingly rapid pace. However, little remains known about caregivers' perspectives on how technologies can and should help them navigate larger service systems they interact with to engage in caregiving. This study involved in-depth interviews and a beta test of an AD/RD caregiver app to learn more about how they currently use technologies and how potential technological features and functions can best meet their needs. Thematic findings suggest a conceptual model for designing AD/RD caregiver technologies. The findings suggest that eHealth and individual technologies may not fully meet the needs of caregivers as they navigate the larger systems within which they provide care. Findings highlight the need to develop technologies for caregivers that are effective, easy to use, and more widely disseminated - especially for caregivers from disadvantaged backgrounds.
- Protective effects of glucagon-like peptide-1 (GLP-1) analogue exenatide against glucose and fructose-induced neurotoxicity. [Journal Article]
- IJInt J Neurosci 2018 Nov 13; :1-24
- Diabetes mellitus (DM) is one of the most common metabolic disorders characterized by hyperglycemia due to insufficiency of insulin and/or insulin resistance. Clinical studies have revealed a higher ...
Diabetes mellitus (DM) is one of the most common metabolic disorders characterized by hyperglycemia due to insufficiency of insulin and/or insulin resistance. Clinical studies have revealed a higher risk of neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease in diabetic patients. Recently, glucagon-like peptide-1 (GLP-1) is an attractive potential treatment modality for various neurodegenerative diseases. In our study, we aimed to investigate whether exenatide, a GLP-1 analogue, has neuroprotective effects against glucose and fructose-induced toxicity in human SH-SY5Y neuroblastoma cell line. Neurotoxicity was induced by incubating SH-SY5Y cells with different doses (25-100 mM) of glucose and fructose for 24, 48 and 72 h. Following determination of the significant toxic doses of glucose and fructose, the cells were treated with various doses of exenatide (10-250 nM) in the presence or absence of glucose and fructose. Neurotoxicity was evaluated by MTT assay and Hoechst 33258 staining. Caspase-3 activity and the levels of advanced glycation end products (AGEs) were determined in the cytosolic fractions of treated cells. Our results demonstrated that both glucose and fructose treatments decreased cell viability in neuronal cells dose and time-dependently. Glucose and fructose-treated groups showed increased numbers of apoptotic cells, caspase-3 activity and AGEs levels. Treatment of the cells with exenatide significantly prevented cell death. The most prominent effect was observed at 100 nM exenatide-treated cultures. Our results suggest that high doses of glucose and fructose may lead to neurotoxicity, and exenatide may have protective effects against neuronal damage through its anti-apoptotic feature.
- Computational investigation of mechanistic insights of Aβ42 interactions against extracellular domain of nAChRα7 in Alzheimer's disease . [Journal Article]
- IJInt J Neurosci 2018 Nov 13; :1-39
- Amyloid beta (Aβ) 1-42, which is a basic constituent of amyloid plaques, binds with extracellular transmembrane receptor nicotine acetylcholine receptor α7 (nAChRα7) in Alzheimer's disease. In the cu...
Amyloid beta (Aβ) 1-42, which is a basic constituent of amyloid plaques, binds with extracellular transmembrane receptor nicotine acetylcholine receptor α7 (nAChRα7) in Alzheimer's disease. In the current study, a computational approach was employed to explore the active binding sites of nAChRα7 through Aβ 1-42 interactions and their involvement in the activation of downstream signaling pathways. Sequential and structural analyses were performed on the extracellular part of nAChRα7 to identify its core active binding site. Results showed that a conserved residual pattern and well superimposed structures were observed in all nAChRs proteins. Molecular docking servers were used to predict the common interactive residues in nAChRα7 and Aβ1-42 proteins. The docking profile results showed some common interactive residues such as Glu22, Ala42 and Trp171 may consider as the active key player in the activation of downstream signaling pathways. Moreover, the signal communication and receiving efficacy of best-docked complexes was checked through DynOmic online server. Furthermore, the results from molecular dynamic simulation experiment showed the stability of nAChRα7. The generated root mean square deviations and fluctuations (RMSD/F), solvent accessible surface area (SASA) and radius of gyration (Rg) graphs of nAChRα7 also showed its backbone stability and compactness, respectively. Taken together, our predicted results intimated the structural insight on the molecular interactions of beta amyloid protein involved in the activation of nAChRα7 receptor. In future, a better understanding of nAChRα7 and their interconnected proteins signaling cascade may be consider as target to cure Alzheimer's disease.
- Ablation of Amyloid Precursor Protein Increases Insulin Degrading Enzyme Levels and Activity in Brain and Peripheral Tissues. [Journal Article]
- AJAm J Physiol Endocrinol Metab 2018 Nov 13
- The amyloid precursor protein (APP) is a type-I transmembrane glycoprotein widely studied for its role as the source of β-amyloid peptide, accumulation of which is causal in at least some cases of Al...
The amyloid precursor protein (APP) is a type-I transmembrane glycoprotein widely studied for its role as the source of β-amyloid peptide, accumulation of which is causal in at least some cases of Alzheimer's disease (AD). APP is expressed ubiquitously and is involved in diverse biological processes. Growing bodies of evidence indicate connections between AD and somatic metabolic disorders related to type-2 diabetes, and App-/- mice show alterations in glycemic regulation. We find that App-/- have higher levels of insulin-degrading enzyme (IDE) mRNA, protein, and activity compared to wild-type controls. This regulation of IDE by APP was widespread across numerous tissues including liver, skeletal muscle, and brain as well as cell types within neural tissue including neurons, astrocytes, and microglia. RNAi-mediated knockdown of APP in the SIM-A9 microglia cell line elevated IDE levels. Fasting levels of blood insulin were lower in App-/- than App+/+ mice, but the former showed a larger increase in response to glucose. These low basal levels may enhance peripheral insulin sensitivity, as App-/- mice failed to develop impairment of glucose tolerance on a high-fat, high-sucrose ("western") diet. Insulin levels and insulin signaling were also lower in App-/- brain; synaptosomes prepared from App-/- hippocampus showed diminished insulin receptor phosphorylation compared to App+/+ mice when stimulated ex vivo. These findings represent a new molecular link connecting APP to metabolic homeostasis and demonstrate a novel role for APP as an upstream regulator of IDE in vivo.
- Heterogeneity in α-synuclein sub-types and their expression in cortical brain tissue lysates from Lewy body diseases and Alzheimer's disease. [Journal Article]
- NANeuropathol Appl Neurobiol 2018 Nov 13
- CONCLUSIONS: Taken together, these findings suggest that DLB have elevated levels of insoluble pS129-α-syn, but that increased levels of aqueous soluble o-α-syn and detergent soluble pS129-α-syn are also observed in PD and AD, suggesting different changes to α-syn across the spectrum of neurodegenerative proteopathies. This article is protected by copyright. All rights reserved.
New Search Next
- Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury: A Systematic Review and Meta-analysis. [Journal Article]
- JNJAMA Neurol 2018 Oct 22
- CONCLUSIONS: We report evidence that MRI markers of VBI have major clinical significance. This research prompts careful evaluation of the benefit-risk ratio for available prevention strategies in individuals with covert VBI.