Pain-mediated cleavage of NR2B occurs from mid-stage AD. Alternatively, it

Pain-mediated cleavage of NR2B occurs from mid-stage AD. Alternatively, it is Rosiglitazone possible that an early compensatory response resulting in increased NR2B in Braak II-III tissues is overcome as AD develops. In addition, we observed loss of only post-synaptic proteins in supernatants from late-stage AD cortical homogenates, with the pre-synaptic marker synapsin 1 being increased at Braak stage III and returning to control levels at end-stage AD. This result is in discrepancy to previous findings showing reductions in synapsin-1 amounts in lamina 3 of the posterior cingulate cortex in Braak stage V-VI AD brain, relative to early Braak stage and non-cognitively impaired controls [62]. However, connections from the posterior cingulate are very different to those from the temporal cortex [56], and this may account for the difference in these findings. In addition, the relatively small sample set used in this study may have masked subtle changes in protein amounts during AD progression. Furthermore, the control group used in this study included some individuals younger than average in comparison to the experimental groups. This is believed not to have skewed the findings since these samples did not appear to differ significantly from older controls. However, it would be interesting in future work to assess the contribution ofKurbatskaya et al. Acta Neuropathologica Communications (2016) 4:Page 13 ofnormal aging to the changes described here, perhaps using resources such as that collected from the MRC-CFAS study [19] or the Lothian Birth Cohort [57].Acknowledgements We are grateful to Professor Peter Davies (Feinstein Institute for Medical Research, NY, USA) for his generous gift of tau antibodies. Funding This work was supported by Alzheimer’s Research UK (ARUK-ESG2014-2 to WN; ARUK-RF2014-2 to BGP-N), Rosetrees Trust (JS15/M367 to WN), BBSRC/Eli Lilly (BB/ K501219/1 to WN) and the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs, NC/K500343/1 to WN). Author details Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Rm1.25, 5 Cutcombe Road, Camberwell, London SE5 9RX, UK. 2King’s College London, MRC London Neurodegenerative Diseases Brain Bank, London, UK. 3Eli Lilly and Company, Erl Wood Manor, , Windlesham, Surrey GU20 6PH, UK.Conclusions In conclusion, in this study we have used postmortem human brain to examine protein changes in different stages of AD. We provide evidence to show that alterations in calpain activity occurs relatively PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/16989806 early in the disease process, concurrent with increased A1-42 production and activation of tau kinases, and prior to increased tau phosphorylation and loss of post-synaptic markers (Fig. 6d). Our findings therefore suggest that aberrant regulation of calpain is an important early step in disease development, supporting ongoing pre-clinical and clinical studies focused on correcting disrupted calcium channel activation and calpain activation in Alzheimer’s disease and related neurodegenerative conditions. Moreover, our results suggest that there are synaptic compensatory mechanisms during early Braak stages. Further experimentation may reveal the mechanisms underlying these events and perhaps indicate strategies to prolong this supposed endogenous neuroprotective response.Ethics approval and consent to participateReceived: 8 February 2016 Accepted: 15 Ma.