Amyloid aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles is closely associated with Alzheimer’s disease (AD). Several molecular chaperones have been reported to bind Tau and impede its pathological aggregation. Recent findings of elevated levels of Hsp27 in the brains of patients with AD suggested its important role in pTau pathology. However, the molecular mechanism of Hsp27 in pTau aggregation remains poorly understood. Here, we show that Hsp27 partially co-localizes with pTau tangles in the brains of patients with AD. Notably, phosphorylation of Tau by microtubule affinity regulating kinase 2 (MARK2), dramatically enhances the binding affinity of Hsp27 to Tau. Moreover, Hsp27 efficiently prevents pTau fibrillation in vitro and mitigates neuropathology of pTau aggregation in a Drosophila tauopathy model. Further mechanistic study reveals that Hsp27 employs its N-terminal domain to directly interact with multiple phosphorylation sites of pTau for specific binding. Our work provides the structural basis for the specific recognition of Hsp27 to pathogenic pTau, and highlights the important role of Hsp27 in preventing abnormal aggregation and pathology of pTau in AD.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by irreversible cognitive decline with limited therapeutic approaches. We characterized a Drosophila model of amyloid pathology that expresses human amyloid-beta precursor protein (APP695) and β-site APP cleaving enzyme (BACE) in the nervous system. Our model recapitulates in vivo the age-dependent accumulation of BACE-derived C-terminal fragment (CTF) and amyloid plaques in the brain, one of the key pathological hallmarks of AD. Using this model, we assessed the effects on plaque formation of Nicotinamide mononucleotide adenylyltransferase (Nmnat), an evolutionarily conserved nicotinamide adenine dinucleotide (NAD+) synthase involved in cellular metabolism and neuroprotection. We compared the effects of overexpression of Drosophila Nmnat (dNmnat), human Nmnat1 (hNmnat1), human Nmnat2 (hNmnat2), and human Nmnat3 (hNmnat3), and observed that hNmnat1 has the highest efficacy in reducing amyloid aggregation and APP-CTF accumulation. Interestingly, we demonstrated that overexpression of hNmnat1 reduces amyloid plaques by promoting autophagic clearance. Our findings uncover a role of hNmnat1 in amyloid clearance and suggest an exciting neuroprotective potential of hNmnat1 in amyloid pathology.
Shoshana Shendelman declares a first-tier potential conflict as she owns equity in and receives a salary from Applied Therapeutics, Inc. Shoshana Shendelman is also a named inventor of the following patents and patent applications US 11,
Amyloid aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles is closely associated with Alzheimer’s disease (AD). Several molecular chaperones have been reported to bind Tau and impede its pathological aggregation. Recent findings of elevated levels of Hsp27 in the brains of patients with AD suggested its important role in pTau pathology. However, the molecular mechanism of Hsp27 in pTau aggregation remains poorly understood. Here, we show that Hsp27 partially co-localizes with pTau tangles in the brains of patients with AD. Notably, phosphorylation of Tau by microtubule affinity regulating kinase 2 (MARK2), dramatically enhances the binding affinity of Hsp27 to Tau. Moreover, Hsp27 efficiently prevents pTau fibrillation in vitro and mitigates neuropathology of pTau aggregation in a Drosophila tauopathy model. Further mechanistic study reveals that Hsp27 employs its N-terminal domain to directly interact with multiple phosphorylation sites of pTau for specific binding. Our work provides the structural basis for the specific recognition of Hsp27 to pathogenic pTau, and highlights the important role of Hsp27 in preventing abnormal aggregation and pathology of pTau in AD.
perhaps the largest movement of animals on Earth, is composed of mesopelagic species migrating vertically every night to feed in epipelagic depths and return to deeper water during the day. The objective of this study infers potential taxonomic identity of organisms in the DVM via their association with bacterioplankton signatures. High throughput sequencing of the 16S rRNA V4 region and the use of bioinformatics and statistics provided evidence to which bacteria appeared associated with either upward or downward vertical migration during two cycles. DNA was extracted from water samples and sequenced. Data analysis was performed using R Studio software. Our results confirm the vertical movement of bacterial taxa throughout the pelagic depths. The most abundant bacteria present during the Vertical Migration were of Genera Marinobacter, Alteromonas, Prochlorococcus, and class Gammaproteobacteria. These taxa occurred at depth of 320 meters which is the mesopelagic zone. Proteobacteria was only found during the vertical migration at mesopelagic depths, whereas Cyanobacteria was only found during the vertical migration at epipelagic depths. This indicates that these two phyla of bacteria are distinct to their respective zones. IntroductionThe earth's oceans hold vast amounts of water, with great depths and complex dynamics making them difficult to study. To better characterize the Gulf of Mexico, a relatively deep ocean basin, the DEEPEND consortium (www.deependconsortium.org) was formed. DEEPEND stands for DeepPelagic Nekton Dynamics. This consortium began after the Deepwater Horizon Oil Spill (DWHOS) in 2010. The BP/Deepwater Horizon (DWH) discharge in 2010 was the largest marine open water hydrocarbon discharge to date. The DWH well blowout at the seafloor discharged approximately 5 million barrels of oil and at least 250,000 metric tons of natural gas to the deep water (about 1,500m) of the Gulf of Mexico (Jove et al,).Teams of DEEPEND scientists go on cruises to collect water and organismal samples and bring them back to the lab for molecular studies. The last cruise the team went on was in May, and they
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