Calcium dysregulation in Alzheimer’s disease: From mechanisms to therapeutic opportunities Jin-Tai Yu a,b , Raymond Chuen-Chung Chang c , Lan Tan a,b, * a Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province 266071, China b Department of Neurology, Qingdao Municipal Hospital, School of Medicine and Pharmaceutics, Ocean University of China, 266071, China c Laboratory of Neurodegenerative Diseases, Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong SAR, China Contents 1. Introduction ..................................................................................................... 241 2. Mechanisms linking calcium dysregulation to AD pathogenesis ............................................................ 241 2.1. Calcium dysregulation and aging ............................................................................... 241 2.2. Calcium dysregulation and synaptic dysfunction .................................................................. 241 2.3. Calcium dysregulation and mitochondrial dysfunction.............................................................. 243 2.4. Calcium dysregulation and presenilins .......................................................................... 243 2.5. Calcium dysregulation and Ab ................................................................................. 244 2.6. Calcium dysregulation and Tau phosphorylation .................................................................. 247 3. Calcium regulation as a therapeutic approach for AD: present and future .................................................... 248 3.1. Targeting calcium channels in the plasma membrane .............................................................. 248 3.1.1. Targeting receptor-operated calcium channels ............................................................ 248 Progress in Neurobiology 89 (2009) 240–255 ARTICLE INFO Article history: Received 12 April 2009 Received in revised form 28 July 2009 Accepted 31 July 2009 Keywords: Alzheimer’s disease Calcium Presenilins Amyloid-b Tau phosphorylation ABSTRACT Calcium is involved in many facets of neuronal physiology, including activity, growth and differentiation, synaptic plasticity, and learning and memory, as well as pathophysiology, including necrosis, apoptosis, and degeneration. Though disturbances in calcium homeostasis in cells from Alzheimer’s disease (AD) patients have been observed for many years, much more attention was focused on amyloid-b (Ab) and tau as key causative factors for the disease. Nevertheless, increasing lines of evidence have recently reported that calcium dysregulation plays a central role in AD pathogenesis. Systemic calcium changes accompany almost the whole brain pathology process that is observed in AD, including synaptic dysfunction, mitochondrial dysfunction, presenilins mutation, Ab production and Tau phosphorylation. Given the early and ubiquitous involvement of calcium dysregulation in AD pathogenesis, it logically presents a variety of potential therapeutic targets for AD prevention and treatment, such as calcium channels in the plasma membrane, calcium channels in the endoplasmic reticulum membrane, Ab- formed calcium channels, calcium-related proteins. The review aims to provide an overview of the current understanding of the molecular mechanisms involved in calcium dysregulation in AD, and an insight on how to exploit calcium regulation as therapeutic opportunities in AD. ß 2009 Elsevier Ltd. All rights reserved. Abbreviations: Ab, amyloid-b; AchE, acetylcholinesterase; AD, Alzheimer’s disease; AICD, APP carboxy-terminal intracellular domain; AIF, apoptosis-inducing factor; AMPA, amino-3-hydroxy-5-methyl-4-isoxazol propionate; APP, amyloid precursor protein; Ca 2+ /CaMKII, Ca 2+ /CaM-dependent protein kinase II; CALHM1, calcium homeostasis modulator 1; CCE, capacitative calcium entry; Cdk5, cyclin-dependent kinase 5; CypD, Cyclophilin D; ER, endoplasmic reticulum; FAD, familial Alzheimer’s disease; GSK3b, glycogen synthase kinase-3b; IP3R, inositol(1,4,5)-trisphosphate receptors; LTD, long-term depression; LTP, Long-term potentiation; MAPK, mitogen-activated protein kinase; mPTP, mitochondrial permeability transition pore; NFTs, neurofibrillary tangles; NMDA, N-methyl-D-aspartate; NSAIDs, non-steroidal anti-inflammatory drugs; PKA, protein kinase A; PKC, protein kinase C; PSs, presenilins; PtdS, phosphatidylserine; ROCCs, receptor-operated calcium channels; ROS, reactive oxygen species; RyR, ryanodine receptors; S-312-d, S-(+)-methy l4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitro-phenyl)thieno[2,3-b]pyridine-5-carboxylate; STIM1, stromal interaction molecule 1; S18986, (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide; SAD, spordic Alzheimer’s disease; SERCA pump, sarco-/endoplasmic reticulum calcium ATPase; SOCCs, store-operated calcium channels; VDCC, voltage-dependent chloride channel; VGCCs, voltage-gated calcium channels. * Corresponding author at: Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province 266071, China. Tel.: +86 532 8890 5659; fax: +86 532 8596 8434. E-mail address: dr.tanlan@163.com (L. Tan). Contents lists available at ScienceDirect Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio 0301-0082/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2009.07.009