title: Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer's disease brain.
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.
authors.affiliation: 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.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Kurbatskaya
authors.affiliation: 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.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Phillips
authors.affiliation: 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.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Croft
authors.affiliation: 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.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Dentoni
authors.affiliation: 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.
authors.forename: Martina M
authors.initials: MM
authors.lastname: Hughes
authors.affiliation: 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.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Wade
authors.affiliation: King's College London, MRC London Neurodegenerative Diseases Brain Bank, London, UK.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.affiliation: 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.|King's College London, MRC London Neurodegenerative Diseases Brain Bank, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Neill
authors.affiliation: 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.
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Perez-Nievas
authors.affiliation: 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.
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
authors.affiliation: 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. wendy.noble@kcl.ac.uk.
authors.forename: Wendy
authors.identifier: http://orcid.org/0000-0002-7898-4295
authors.initials: W
authors.lastname: Noble
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011180:Postmortem Changes; D013049:Spectrin / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D013049:Spectrin; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase; D002154:Calpain; D010751:Phosphopyruvate Hydratase
keywords: Alzheimer’s disease; Braak stage; Calpain; GSK-3; Postmortem brain; Synapse; Tau