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Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer’s disease brain

Overview of attention for article published in Acta Neuropathologica Communications, March 2016
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  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (90th percentile)
  • High Attention Score compared to outputs of the same age and source (96th percentile)

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Title
Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer’s disease brain
Published in
Acta Neuropathologica Communications, March 2016
DOI 10.1186/s40478-016-0299-2
Pubmed ID
Authors

Ksenia Kurbatskaya, Emma C. Phillips, Cara L. Croft, Giacomo Dentoni, Martina M. Hughes, Matthew A. Wade, Safa Al-Sarraj, Claire Troakes, Michael J. O’Neill, Beatriz G. Perez-Nievas, Diane P. Hanger, Wendy Noble

Abstract

Alterations in calcium homeostasis are widely reported to contribute to synaptic degeneration and neuronal loss in Alzheimer's disease. Elevated cytosolic calcium concentrations lead to activation of the calcium-sensitive cysteine protease, calpain, which has a number of substrates known to be abnormally regulated in disease. Analysis of human brain has shown that calpain activity is elevated in AD compared to controls, and that calpain-mediated proteolysis regulates the activity of important disease-associated proteins including the tau kinases cyclin-dependent kinase 5 and glycogen kinase synthase-3. Here, we sought to investigate the likely temporal association between these changes during the development of sporadic AD using Braak staged post-mortem brain. Quantification of protein amounts in these tissues showed increased activity of calpain-1 from Braak stage III onwards in comparison to controls, extending previous findings that calpain-1 is upregulated at end-stage disease, and suggesting that activation of calcium-sensitive signalling pathways are sustained from early stages of disease development. Increases in calpain-1 activity were associated with elevated activity of the endogenous calpain inhibitor, calpastatin, itself a known calpain substrate. Activation of the tau kinases, glycogen-kinase synthase-3 and cyclin-dependent kinase 5 were also found to occur in Braak stage II-III brain, and these preceded global elevations in tau phosphorylation and the loss of post-synaptic markers. In addition, we identified transient increases in total amyloid precursor protein and pre-synaptic markers in Braak stage II-III brain, that were lost by end stage Alzheimer's disease, that may be indicative of endogenous compensatory responses to the initial stages of neurodegeneration. These findings provide insight into the molecular events that underpin the progression of Alzheimer's disease, and further highlight the rationale for investigating novel treatment strategies that are based on preventing abnormal calcium homeostasis or blocking increases in the activity of calpain or important calpain substrates.

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The data shown below were collected from the profiles of 5 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 167 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 167 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 35 21%
Researcher 22 13%
Student > Master 21 13%
Student > Bachelor 20 12%
Student > Doctoral Student 10 6%
Other 22 13%
Unknown 37 22%
Readers by discipline Count As %
Neuroscience 40 24%
Agricultural and Biological Sciences 30 18%
Biochemistry, Genetics and Molecular Biology 25 15%
Medicine and Dentistry 10 6%
Psychology 4 2%
Other 14 8%
Unknown 44 26%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 20. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 May 2023.
All research outputs
#1,634,178
of 23,668,780 outputs
Outputs from Acta Neuropathologica Communications
#158
of 1,442 outputs
Outputs of similar age
#28,517
of 302,526 outputs
Outputs of similar age from Acta Neuropathologica Communications
#2
of 32 outputs
Altmetric has tracked 23,668,780 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 93rd percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,442 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 13.1. This one has done well, scoring higher than 89% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 302,526 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 90% of its contemporaries.
We're also able to compare this research output to 32 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 96% of its contemporaries.