期刊
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
卷 39, 期 7, 页码 788-799出版社
WILEY-BLACKWELL
DOI: 10.1111/nan.12033
关键词
Alzheimer-type pathology; astrocytes; calcium; calcium/calmodulin-dependent kinase II alpha; calpain-10
资金
- Alzheimer's Research UK
- MRC [MR/J004308/1, U105292687]
- Department of Health
- UKNIHR Biomedical Research Centre for Ageing and Age-related Disease
- NIHR Cambridge Biomedical Research Centre
- Cambridgeshire and Peterborough NIHR CLAHRC
- Nottingham University Hospitals NHS Trust
- University of Sheffields
- Sheffields Teaching Hospitals NHS Foundation Trust
- Oxford Biomedical Research Centre
- Walton Centre NHS Foundation Trust, Liverpool
- MRC [MC_U105292687, MR/L016451/1, MR/L022656/1, G1100540, G0502157, G0400074, MR/J004308/1, G9901400, G0900652] Funding Source: UKRI
- Alzheimers Research UK [ART-PG2010-5] Funding Source: researchfish
- Medical Research Council [G0400074, G9901400, MR/J004308/1, MC_U105292687, G1100540, MR/L016451/1, MR/L022656/1, G0900652, G0502157] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10084] Funding Source: researchfish
Aims: Calcium dyshomeostasis is implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease. However, much of the previous research has focused on changes in neuronal calcium signalling. In a recent microarray study we identified dysregulation of several key signalling pathways including the Ca2+ signalling pathway in astrocytes as Alzheimer-type pathology developed. In this study we sought to determine the expression of calpain-10 and calcium/calmodulin-dependent kinase alpha (CamKII alpha) in relation to Alzheimer-type pathology in a population-based study. Methods: Using post mortem temporal cortex samples derived from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) ageing brain cohort we examined calpain-10 and CamKII alpha gene and protein expression using quantitative polymerase chain reaction and immunohistochemistry. Results: We demonstrate that astrocytic expression of calpain-10 is up-regulated, and CamKII alpha down-regulated with increasing Braak stage. Using immunohistochemistry we confirm protein expression of calpain-10 in astrocytes throughout the temporal cortex and demonstrate that calpain-10 immunoreactivity is correlated with both local and global measures of Alzheimer-type pathology. In addition, we identify a subpopulation of calpain-10 immunoreactive interlaminar astrocytes that extend processes deep into the cortex. CamKIIa is predominantly neuronal in localization and is associated with the presence of diffuse plaques in the ageing brain. Discussion: Dysregulated expression of key calcium signalling molecules occurs with progression of Alzheimer-type pathology in the ageing brain, highlighting the need for further functional studies of astrocytic calcium signalling with respect to disease progression.
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