Alzheimer's disease pathology and the unfolded protein response : Prospective pathways and therapeutic targets

The authors would like to thank Alzheimer's Research UK (Grant refs: ARUK-PPG2014A-21 and ARUK-NSG2015-1 to BP and DK) who have provided support for relevant projects leading to this review.Peer reviewedPostprin

Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline

Acknowledgments We would like to gratefully acknowledge all donors and their families for the tissue provided for this study. Human tissue samples were supplied by the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK, the Alzheimer’s Society and the Medical Research Council, and sourced from the MRC London Neurodegenerative Diseases Brain Bank, the Manchester Brain Bank, the South West Dementia Brain Bank (SWDBB), the Newcastle Brain Tissue Resource and the Oxford Brain Bank. The Newcastle Brain Tissue Resource and Oxford Brain Bank are also supported by the National Institute for Health Research (NIHR) Units. The South West Dementia Brain Bank (SWDBB) receives additional support from BRACE (Bristol Research into Alzheimer’s and Care of the Elderly). Alz-50, CP13, MC-1 and PHF-1 antibodies were gifted from Dr. Peter Davies and brain lystates from BACE1−/−mice were obtained from Prof Mike Ashford. The work presented here was funded by Alzheimer’s Research UK (Grant refs: ARUKPPG2014A-21 and ARUK-NSG2015-1 to BP and DK and NIH/NIA grants NIH/NINDS R01 NS082730 and R01 AG044372 to NK)Peer reviewedPublisher PD

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Peer reviewedPostprin

Distinctive temporal profiles of detergent-soluble and -insoluble tau and Aβ species in human Alzheimer's disease

Alzheimer's disease (AD) pathology relevant proteins tau and beta-amyloid (Aβ) exist as an array of post-translationally modified and conformationally altered species with varying abundance, solubility and toxicity. Insoluble neurofibrillary tau tangles and Aβ plaques are end-stage AD hallmarks, yet may carry less disease significance compared to soluble species. At present, it is unclear how soluble and insoluble tau and Aβ relate to each other as well as to disease progression. Here, detergent soluble and insoluble fractions generated from post-mortem human temporal lobe samples (Brodmann area 21) were probed for tau and Aβ markers in immuno-dot assays. Measures were quantified according to diagnosis (AD cf. Non-AD), neuropathological severity, and correlated with disease progression (Braak stages). All markers were elevated within AD cases cf. non-AD controls (p &lt; 0.05) independent of solubility. However, when considered according to neuropathological severity, phospho-tau (detected via CP13 and AT8 antibodies) was elevated early within the soluble fraction (p &lt; 0.05 intermediate cf. low severity) and emerged only later within the insoluble fraction (p &lt; 0.05 high cf. low severity). In contrast, PHF1 phospho-tau, TOC1 reactive tau oligomers and amyloid markers rose within the two fractions simultaneously. Independent of solubility, cognitive correlations were observed for tau makers and for fibrillary amyloid (OC), however only soluble total Aβ was significantly correlated with intellectual impairment. Following the exclusion of end-stage cases, only soluble total Aβ remained correlated with cognition. The data indicate differential rates of protein aggregation during AD progression and confirm the disease relevance of early emerging soluble Aβ species.</p

Decreased specific star formation rates in AGN host galaxies

We investigate the location of an ultra-hard X-ray selected sample of active galactic nuclei (AGN) from the Swift Burst Alert Telescope (BAT) catalogue with respect to the main sequence (MS) of star-forming galaxies using Herschel-based measurements of the star formation rate (SFR) and M*'s from Sloan Digital Sky Survey photometry where the AGN contribution has been carefully removed. We construct the MS with galaxies from the Herschel Reference Survey and Herschel Stripe 82 Survey using the exact same methods to measure the SFR and M* as the Swift/BAT AGN. We find that a large fraction of the Swift/BAT AGN lie below the MS indicating decreased specific SFR (sSFR) compared to non-AGN galaxies. The Swift/BAT AGN are then compared to a high-mass galaxy sample (CO Legacy Database for GALEX Arecibo SDSS Survey, COLD GASS), where we find a similarity between the AGN in COLD GASS and the Swift/BAT AGN. Both samples of AGN lie firmly between star-forming galaxies on the MS and quiescent galaxies far below the MS. However, we find no relationship between the X-ray luminosity and distance from the MS. While the morphological distribution of the BAT AGN is more similar to star-forming galaxies, the sSFR of each morphology is more similar to the COLD GASS AGN. The merger fraction in the BAT AGN is much higher than the COLD GASS AGN and star-forming galaxies and is related to distance from the MS. These results support a model in which bright AGN tend to be in high-mass star-forming galaxies in the process of quenching which eventually starves the supermassive black hole itsel

Studies based on the Earley and Wolffer social studies vocabulary tests for grades IV, V, and VI.

Thesis (Ed.M.)--Boston Universit

Knock-in of Mutated hTAU Causes Insulin Resistance, Inflammation and Proteostasis Disturbance in a Mouse Model of Frontotemporal Dementia

Open Access via Springer Compact Agreement.Peer reviewedPublisher PD

Synaptic Loss, ER Stress and Neuro-inflammation Emerge Late in the Lateral Temporal Cortex and Associate with Progressive Tau Pathology in Alzheimer’s Disease

Acknowledgements We would like to deeply thank all donors and their families for the tissue provided for this study. Human tissue samples were supplied by the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK, the Alzheimer’s Society and the Medical Research Council, and sourced from the MRC London Neurodegenerative Diseases Brain Bank, the Manchester Brain Bank, the South West Dementia Brain Bank (SWDBB), the Newcastle Brain Tissue Resource and the Oxford Brain Bank. The Newcastle Brain Tissue Resource and Oxford Brain Bank are also supported by the National Institute for Health Research (NIHR) Units. The South West Dementia Brain Bank (SWDBB) receives additional support from BRACE (Bristol Research into Alzheimer’s and Care of the Elderly). Use of human tissue for this work was approved by Brains for Dementia Research from London – City and East NRES committee 08/H0704/128+5. The work presented here was funded by Alzheimer’s Research UK (Grant refs: ARUK-PPG2014A-21, ARUK-NSG2015-1, ARUK-NCG2017A-3 awarded to DK and BP). HB was supported by an Alzheimer’s Society Doctoral Training Centre grant (grant ref: 228) to BP. MK’s participation in the project was funded by ARUK Scotland Network pump priming award to DK and BP. Antibodies CP13 and PHF1 were generously provided by Prof. Peter Davies. TOC1 antibodies were a gift from Nicholas Kanaan at Michigan State University (originally created by Lester Binder at Northwestern University). Funding The work presented here was funded by Alzheimer’s Research UK (Grant refs: ARUK-PPG2014A-21, ARUK-NSG2015-1, ARUK-NCG2017A-3 awarded to DK and BP). HB was supported by an Alzheimer’s Society Doctoral Training Centre grant (grant ref:228) to BP. MK’s participation in the project was funded by ARUK Scotland Network pump priming award to DK and BP.Peer reviewedPublisher PD

MicroRNA Expression Profile in the Vitreous of Proliferative Diabetic Retinopathy Patients and Differences from Patients Treated with Anti-VEGF

Purpose: microRNAs (miRNAs) mediate the pathological mechanisms of diabetic retinopathy. In this study, we compared miRNA expression profiles in the vitreous between patients with proliferative diabetic retinopathy (PDR) and patients with a macular hole as non-diabetic controls, and between PDR patients treated with antivascular endothelial growth factor (VEGF) therapy and untreated PDR patients. Methods: Vitreous samples of non-diabetic and PDR patients were screened for miRNAs with quantitative polymerase chain reaction (qPCR) panels. miRNA candidates were validated in vitreous samples of a second, independent cohort. In addition, the effect of anti-VEGF therapy was investigated in the vitreous of a third study population consisting of PDR patients who had not received anti-VEGF therapy and PDR patients who had received preoperative anti-VEGF therapy. Results: During screening, seven miRNAs were found to be significantly higher in the vitreous of PDR patients, whereas two miRNAs were found to be significantly lower compared with non-diabetic controls. Validating the expression of these miRNAs in a second cohort resulted in the identification of six miRNAs that were expressed at significantly higher rates in the vitreous of PDR patients: hsa-miR-20a-5p, hsa-miR-23b3p, hsa-miR-142-3p, hsa-miR-185-5p, hsa-miR-326, and hsa-miR-362-5p. Among these six miRNAs, hsa-miR-23b-3p levels were lower in the anti-VEGF-treated group of PDR patients compared with untreated PDR patients. Conclusions: In this study, we identified six miRNAs that are expressed more highly in PDR patients and one miRNA that is expressed at a lower levels in anti-VEGF-treated PDR patients. Translational Relevance: miRNAs identified in the vitreous of PDR patients may improve our understanding of the mechanisms leading to PDR

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Models of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTauP301L + R406W) knock-in mouse was generated out of the previously characterised PLB1Triple mouse, and named PLB2Tau. After confirmation of an additional hTau species (~60 kDa) in forebrain samples, we identified age-dependent progressive Tau phosphorylation which coincided with the emergence of FTD relevant behavioural traits. In line with the non-cognitive symptomatology of FTD, PLB2Tau mice demonstrated early emerging (~6 months) phenotypes of heightened anxiety in the elevated plus maze, depressive/apathetic behaviour in a sucrose preference test and generally reduced exploratory activity in the absence of motor impairments. Investigations of cognitive performance indicated prominent dysfunctions in semantic memory, as assessed by social transmission of food preference, and in behavioural flexibility during spatial reversal learning in a home cage corner-learning task. Spatial learning was only mildly affected and task-specific, with impairments at 12 months of age in the corner learning but not in the water maze task. Electroencephalographic (EEG) investigations indicated a vigilance-stage specific loss of alpha power during wakefulness at both parietal and prefrontal recording sites, and site-specific EEG changes during non-rapid eye movement sleep (prefrontal) and rapid eye movement sleep (parietal). Further investigation of hippocampal electrophysiology conducted in slice preparations indicated a modest reduction in efficacy of synaptic transmission in the absence of altered synaptic plasticity. Together, our data demonstrate that the transgenic PLB2Tau mouse model presents with a striking behavioural and physiological face validity relevant for FTD, driven by the low level expression of mutant FTD hTau.</p