Research Article Increased cerebrospinal fluid calpain activity and microparticle levels in Alzheimer’s disease Christoph Laske a,b, *, Konstantinos Stellos c,d , Ingrid Kempter e , Elke Stransky a , Walter Maetzler b,f , Ingrid Fleming e , Voahanginirina Randriamboavonjy e a Section for Dementia Research, Hertie-Institute of Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of T€ ubingen, T€ ubingen, Germany b DZNE, German Center for Neurodegenerative Diseases, T€ ubingen, Germany c Department of Cardiology, Centre of Internal Medicine III, Goethe University, Frankfurt am Main, Germany d Vascular Inflammation Group, Institute of Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Frankfurt am Main, Germany e Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany f Department of Neurodegeneration, Centerof Neurology, Hertie Institute for Clinical Brain Research, University of T€ ubingen, T€ ubingen, Germany Abstract Background: Calpain has been associated with the pathophysiology of Alzheimer’s disease (AD) and with apoptotic neuronal cell death leading to microparticles (MPs) formation. Methods: A total of 64 patients with AD and 52 age- and gender-matched cognitively healthy elderly controls were included in the study. We measured calpain activity and levels of MPs, amyloid beta (Ab1–42), h-tau, and p-tau181. Results: AD patients showed significantly increased calpain activity and higher levels of MPs in ce- rebrospinal fluid (CSF) and significantly decreased calpain activity and lower levels of MPs in serum and plasma compared with healthy controls. Combined assessment of calpain activity and Ab1–42 levels in CSF improved diagnostic accuracy as compared with singular or combined traditional CSF biomarkers of AD. Conclusions: This is the first study showing increased calpain activity and microparticle levels in CSF of AD patients. Calpain activity could represent a novel diagnostic and prognostic biomarker and promising treatment target for AD. Ó 2014 The Alzheimer’s Association. All rights reserved. Keywords: Alzheimer’s disease; Calpain activity; Microparticles; CSF; Serum; Plasma; Dementia 1. Introduction Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Aging populations in developed countries ensure that AD will reach epidemic proportions unless therapies are developed to cure or prevent it. Unfortu- nately, to date all “disease-modifying” experimental thera- pies for AD have failed to demonstrate significant clinical benefit in individuals with symptomatic AD. Thus, besides earlier start of treatment there is also need to identify new treatment targets in AD. The progressive formation of amyloid plaques and vascular deposits consisting of the 4 kD amyloid b-peptide (Ab) is considered a pathological hallmark of AD [1].Ab is generated from the amyloid precursor protein (APP) by enzymatic digestion involving b- and g-secretase activities [2]. Most b-secretase activity originates from a protease en- coded by the b-site APP-cleaving enzyme 1 gene (BACE1) [3]. Growing evidence indicates that BACE1 activity is significantly increased in the brain [4] and cerebrospinal fluid (CSF) [5,6], of sporadic AD patients. According to experimental findings in an animal model of AD, BACE1 expression is promoted by activation of calpain [7]. Conflict of interest: The authors have no potential conflicts of interest to declare. *Corresponding author. Tel.: 149-(0)7071-2982311; Fax: 149-(0) 7071-294141. E-mail address: christoph.laske@med.uni-tuebingen.de 1552-5260/$ - see front matter Ó 2014 The Alzheimer’s Association. All rights reserved. http://dx.doi.org/10.1016/j.jalz.2014.06.003 Alzheimer’s & Dementia - (2014) 1-10