The role of CD2AP in the Pathogenesis of Alzheimer's Disease
Qing-Qing Tao, Yu-Chao Chen, Zhi-Ying Wu*
Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China.
Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by irreversible decline in cognition with unclear pathogenesis. Recently, accumulating evidence has revealed that CD2 associated protein (CD2AP), a scaffolding molecule regulates signal transduction and cytoskeletal molecules, is implicated in AD pathogenesis. Several single nucleotide polymorphisms (SNPs) in CD2AP gene are associated with higher risk for AD and mRNA levels of CD2AP are decreased in peripheral lymphocytes of sporadic AD patients. Furthermore, CD2AP loss of function is linked to enhanced Aβ production, Tau-induced neurotoxicity, abnormal neurite structure modulation and reduced blood-brain barrier integrity. This review is to summarize the recent discoveries about the genetics and known functions of CD2AP. The recent evidence concerning the roles of CD2AP in the AD pathogenesis is summarized and CD2AP can be a promising therapeutic target for AD.
Figure 1. The chromosome location and schematic representation of the structural domains of CD2AP
A)CD2AP is located on chromosome 6 (6p12.3). B) The protein has three consecutive SH3 domains at the amino terminus. The middle region is a proline-rich sequence. The carboxy terminus contains a duplex helical structural region where has a binding site for the actin cytoskeleton.
Logue et al. 
American and European ancestry
Carrasquillo et al. 
ADGC combined analysis (Stage 1+2)
Naj et al. 
Hollingworth et al. 
Hollingworth et al. 
Tan et al. 
Miyashita et al. 
Four Consortia combined analysis (Stage 1+2)*
Lambert et al. 
Shulman et al. 
Vardarajan et al. 
Jiao et al. 
Jiao et al. 
Southeast China (Stage 1)
Tao et al. 
Southeast China (Stage 1+2)
Tao et al. 
Table 1 Associations between CD2AP and sporadic AD.
Figure 2. Possible mechanisms underlying CD2AP loss of function in the pathogenesis of sporadic AD
CD2AP loss of function is linked to enhanced Aβ metabolism, Tau-induced neurotoxicity, abnormal neurite structure modulation and reduced blood-brain barrier integrity.
Kirson NY, Desai U, Ristovska L, Cummings AK, Birnbaum HG, Ye W, et al. (2016). Assessing the economic burden of Alzheimer's disease patients first diagnosed by specialists. BMC Geriatr, 16: 138.
Lanoiselee HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, et al. (2017). APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med, 14: e1002270.
Kennedy JL, Farrer LA, Andreasen NC, Mayeux R, St George-Hyslop P (2003). The genetics of adult-onset neuropsychiatric disease: complexities and conundra? Science, 302: 822-826.
Laws SM, Hone E, Gandy S, Martins RN (2003). Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription. J Neurochem, 84: 1215-1236.
Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al. (2017). Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet, 49: 1373-1384.
Magi S, Castaldo P, Macri ML, Maiolino M, Matteucci A, Bastioli G, et al. (2016). Intracellular Calcium Dysregulation: Implications for Alzheimer's Disease. Biomed Res Int, 2016: 6701324.
Onyango IG, Dennis J, Khan SM (2016). Mitochondrial Dysfunction in Alzheimer's Disease and the Rationale for Bioenergetics Based Therapies. Aging Dis, 7: 201-214.
Wang ZX, Tan L, Yu JT (2015). Axonal transport defects in Alzheimer's disease. Mol Neurobiol, 51: 1309-1321.
Nisbet RM, Polanco JC, Ittner LM, Gotz J (2015). Tau aggregation and its interplay with amyloid-beta. Acta Neuropathol, 129: 207-220.
Zheng JY, Sun J, Ji CM, Shen L, Chen ZJ, Xie P, et al. (2017). Selective deletion of apolipoprotein E in astrocytes ameliorates the spatial learning and memory deficits in Alzheimer's disease (APP/PS1) mice by inhibiting TGF-beta/Smad2/STAT3 signaling. Neurobiol Aging.
Zheng H, Jia L, Liu CC, Rong Z, Zhong L, Yang L, et al. (2017). TREM2 Promotes Microglial Survival by Activating Wnt/beta-Catenin Pathway. J Neurosci, 37: 1772-1784.
Ubelmann F, Burrinha T, Salavessa L, Gomes R, Ferreira C, Moreno N, et al. (2017). Bin1 and CD2AP polarise the endocytic generation of beta-amyloid. EMBO Rep, 18: 102-122.
Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, et al. (2011). Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet, 43: 429-435.
Tao QQ, Liu ZJ, Sun YM, Li HL, Yang P, Liu DS, et al. (2017). Decreased gene expression of CD2AP in Chinese patients with sporadic Alzheimer's disease. Neurobiol Aging, 56: 212 e215-212 e210.
Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, et al. (2011). Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet, 43: 436-441.
Morgan K (2011). The three new pathways leading to Alzheimer's disease. Neuropathol Appl Neurobiol, 37: 353-357.
Dustin ML, Olszowy MW, Holdorf AD, Li J, Bromley S, Desai N, et al. (1998). A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell, 94: 667-677.
Cummins TD, Wu KZL, Bozatzi P, Dingwell KS, Macartney TJ, Wood NT, et al. (2018). PAWS1 controls cytoskeletal dynamics and cell migration through association with the SH3 adaptor CD2AP. J Cell Sci, 131.
Tolvanen TA, Dash SN, Polianskyte-Prause Z, Dumont V, Lehtonen S (2015). Lack of CD2AP disrupts Glut4 trafficking and attenuates glucose uptake in podocytes. J Cell Sci, 128: 4588-4600.
Sever S, Reiser J (2015). CD2AP, dendrin, and cathepsin L in the kidney. Am J Pathol, 185: 3129-3130.
Martin CE, Jones N (2018). Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond. Front Endocrinol (Lausanne), 9: 302.
Yaddanapudi S, Altintas MM, Kistler AD, Fernandez I, Moller CC, Wei C, et al. (2011). CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival. J Clin Invest, 121: 3965-3980.
Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O, et al. (1999). Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science, 286: 312-315.
Zhao J, Bruck S, Cemerski S, Zhang L, Butler B, Dani A, et al. (2013). CD2AP links cortactin and capping protein at the cell periphery to facilitate formation of lamellipodia. Mol Cell Biol, 33: 38-47.
Kirsch KH, Georgescu MM, Ishimaru S, Hanafusa H (1999). CMS: an adapter molecule involved in cytoskeletal rearrangements. Proc Natl Acad Sci U S A, 96: 6211-6216.
Panni S, Salvioli S, Santonico E, Langone F, Storino F, Altilia S, et al. (2015). The adapter protein CD2AP binds to p53 protein in the cytoplasm and can discriminate its polymorphic variants P72R. J Biochem, 157: 101-111.
Raju S, Kometani K, Kurosaki T, Shaw AS, Egawa T (2018). The adaptor molecule CD2AP in CD4 T cells modulates differentiation of follicular helper T cells during chronic LCMV infection. PLoS Pathog, 14: e1007053.
Zhang H, Zhang C, Tang H, Gao S, Sun F, Yang Y, et al. (2018). CD2-associated Protein Contributes to Hepatitis C Virus Propagation and Steatosis by Disrupting Insulin Signaling. Hepatology.
Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F, et al. (2011). Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study. Mol Neurodegener, 6: 54.
Tan L, Yu JT, Zhang W, Wu ZC, Zhang Q, Liu QY, et al. (2013). Association of GWAS-linked loci with late-onset Alzheimer's disease in a northern Han Chinese population. Alzheimers Dement, 9: 546-553.
Chung SJ, Lee JH, Kim SY, You S, Kim MJ, Lee JY, et al. (2013). Association of GWAS top hits with late-onset Alzheimer disease in Korean population. Alzheimer Dis Assoc Disord, 27: 250-257.
Chen H, Wu G, Jiang Y, Feng R, Liao M, Zhang L, et al. (2015). Analyzing 54,936 Samples Supports the Association Between CD2AP rs9349407 Polymorphism and Alzheimer's Disease Susceptibility. Mol Neurobiol, 52: 1-7.
Xiao Q, Liu ZJ, Tao S, Sun YM, Jiang D, Li HL, et al. (2015). Risk prediction for sporadic Alzheimer's disease using genetic risk score in the Han Chinese population. Oncotarget, 6: 36955-36964.
Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. (2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet, 45: 1452-1458.
Vardarajan BN, Ghani M, Kahn A, Sheikh S, Sato C, Barral S, et al. (2015). Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci. Ann Neurol, 78: 487-498.
Jiao B, Liu X, Zhou L, Wang MH, Zhou Y, Xiao T, et al. (2015). Polygenic Analysis of Late-Onset Alzheimer's Disease from Mainland China. PLoS One, 10: e0144898.
Shulman JM, Chen K, Keenan BT, Chibnik LB, Fleisher A, Thiyyagura P, et al. (2013). Genetic susceptibility for Alzheimer disease neuritic plaque pathology. JAMA Neurol, 70: 1150-1157.
Logue MW, Schu M, Vardarajan BN, Buros J, Green RC, Go RC, et al. (2011). A comprehensive genetic association study of Alzheimer disease in African Americans. Arch Neurol, 68: 1569-1579.
Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, et al. (2013). SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians. PLoS One, 8: e58618.
Li C, Ruotsalainen V, Tryggvason K, Shaw AS, Miner JH (2000). CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere. Am J Physiol Renal Physiol, 279: F785-792.
Vetrivel KS, Thinakaran G (2006). Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments. Neurology, 66: S69-73.
Guimas Almeida C, Sadat Mirfakhar F, Perdigao C, Burrinha T (2018). Impact of late-onset Alzheimer's genetic risk factors on beta-amyloid endocytic production. Cell Mol Life Sci, 75: 2577-2589.
Rosenberg RN, Lambracht-Washington D, Yu G, Xia W (2016). Genomics of Alzheimer Disease: A Review. JAMA Neurol, 73: 867-874.
Xu W, Tan L, Yu JT (2015). The Role of PICALM in Alzheimer's Disease. Mol Neurobiol, 52: 399-413.
Miyagawa T, Ebinuma I, Morohashi Y, Hori Y, Young Chang M, Hattori H, et al. (2016). BIN1 regulates BACE1 intracellular trafficking and amyloid-beta production. Hum Mol Genet, 25: 2948-2958.
Yin RH, Yu JT, Tan L (2015). The Role of SORL1 in Alzheimer's Disease. Mol Neurobiol, 51: 909-918.
Liao F, Jiang H, Srivatsan S, Xiao Q, Lefton KB, Yamada K, et al. (2015). Effects of CD2-associated protein deficiency on amyloid-beta in neuroblastoma cells and in an APP transgenic mouse model. Mol Neurodegener, 10: 12.
Cormont M, Meton I, Mari M, Monzo P, Keslair F, Gaskin C, et al. (2003). CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl. Traffic, 4: 97-112.
Shulman JM, Imboywa S, Giagtzoglou N, Powers MP, Hu Y, Devenport D, et al. (2014). Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms. Hum Mol Genet, 23: 870-877.
Ojelade SA, Lee TV, Giagtzoglou N, Shulman JM (2017). THE ALZHEIMER’S DISEASE SUSCEPTIBILITY GENE CD2AP REGULATES PRESYNAPTIC FUNCTION. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 13: P603.
Sun Y, Zhang H, Hu R, Sun J, Mao X, Zhao Z, et al. (2014). The expression and significance of neuronal iconic proteins in podocytes. PLoS One, 9: e93999.
Harrison BJ, Venkat G, Lamb JL, Hutson TH, Drury C, Rau KK, et al. (2016). The Adaptor Protein CD2AP Is a Coordinator of Neurotrophin Signaling-Mediated Axon Arbor Plasticity. J Neurosci, 36: 4259-4275.
Sweeney MD, Sagare AP, Zlokovic BV (2018). Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol, 14: 133-150.
Yates PA, Desmond PM, Phal PM, Steward C, Szoeke C, Salvado O, et al. (2014). Incidence of cerebral microbleeds in preclinical Alzheimer disease. Neurology, 82: 1266-1273.
Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, et al. (2016). Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab, 36: 216-227.
O'Keefe L, Denton D (2018). Using Drosophila Models of Amyloid Toxicity to Study Autophagy in the Pathogenesis of Alzheimer's Disease. Biomed Res Int, 2018: 5195416.
Li HL, Yang P, Liu ZJ, Sun YM, Lu SJ, Tao QQ, et al. (2015). Common variants at Bin1 are associated with sporadic Alzheimer's disease in the Han Chinese population. Psychiatr Genet, 25: 21-25.
Kuusela S, Wang H, Wasik AA, Suleiman H, Lehtonen S (2016). Tankyrase inhibition aggravates kidney injury in the absence of CD2AP. Cell Death Dis, 7: e2302.
Efthymiou AG, Goate AM (2017). Late onset Alzheimer's disease genetics implicates microglial pathways in disease risk. Mol Neurodegener, 12: 43.
Hickman S, Izzy S, Sen P, Morsett L, El Khoury J (2018). Microglia in neurodegeneration. Nat Neurosci, 21: 1359-1369.
Cao W, Zheng H (2018). Peripheral immune system in aging and Alzheimer's disease. Mol Neurodegener, 13: 51.
Srivatsan S, Swiecki M, Otero K, Cella M, Shaw AS (2013). CD2-associated protein regulates plasmacytoid dendritic cell migration, but is dispensable for their development and cytokine production. J Immunol, 191: 5933-5940.