The Alzheimer's disease risk factor CD2AP maintains blood-brain barrier integrity.

CD2-associated protein (CD2AP) is a leading genetic risk factor for Alzheimer's disease, but little is known about the function of CD2AP in the brain. We studied CD2AP(-/-) mice to address this question. Because CD2AP(-/-) mice normally die by 6 weeks from nephrotic syndrome, we used mice that also express a CD2AP transgene in the kidney, but not brain, to attenuate this phenotype. CD2AP-deficient mice had no behavioral abnormalities except for mild motor and anxiety deficits in a subset of CD2AP(-/-) mice exhibiting severe nephrotic syndrome, associated with systemic illness. Pentylenetetrazol (PTZ)-induced seizures occurred with shorter latency in CD2AP(-/-) mice, but characteristics of these seizures on electroencephalography were not altered. As CD2AP is expressed in brain-adjacent endothelial cells, we hypothesized that the shorter latency to seizures without detectably different seizure characteristics may be due to increased penetration of PTZ related to compromised blood-brain barrier integrity. Using sodium fluorescein extravasation, we found that CD2AP(-/-) mice had reduced blood-brain barrier integrity. Neither seizure severity nor blood-brain barrier integrity was correlated with nephrotic syndrome, indicating that these effects are dissociable from the systemic illness associated with CD2AP deficiency. Confirming this dissociation, wild-type mice with induced nephrotic syndrome maintained an intact blood-brain barrier. Taken together, our results support a role of CD2AP in mediating blood-brain barrier integrity and suggest that cerebrovascular roles of CD2AP could contribute to its effects on Alzheimer's disease risk.

[1]  Arthur Konnerth,et al.  Neuronal hyperactivity – A key defect in Alzheimer's disease? , 2015, BioEssays : news and reviews in molecular, cellular and developmental biology.

[2]  J. Schneider,et al.  Vascular contributions to cognitive impairment and dementia including Alzheimer's disease , 2015, Alzheimer's & Dementia.

[3]  J. Schneider,et al.  Central role for PICALM in amyloid–β blood–brain barrier transcytosis and clearance , 2015, Nature Neuroscience.

[4]  D. Hoffman,et al.  Tau-Dependent Kv4.2 Depletion and Dendritic Hyperexcitability in a Mouse Model of Alzheimer's Disease , 2015, The Journal of Neuroscience.

[5]  D. Holtzman,et al.  Effects of CD2-associated protein deficiency on amyloid-β in neuroblastoma cells and in an APP transgenic mouse model , 2015, Molecular Neurodegeneration.

[6]  A. C. Simões e Silva,et al.  The experimental model of nephrotic syndrome induced by Doxorubicin in rodents: an update , 2015, Inflammation Research.

[7]  C. Dickey,et al.  Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy , 2015, Acta neuropathologica communications.

[8]  Arthur W. Toga,et al.  Blood-Brain Barrier Breakdown in the Aging Human Hippocampus , 2015, Neuron.

[9]  A. Goate,et al.  Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis , 2015, Biological Psychiatry.

[10]  E. Roberson,et al.  Seizure resistance without parkinsonism in aged mice after tau reduction , 2014, Neurobiology of Aging.

[11]  T. Maniatis,et al.  An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex , 2014, The Journal of Neuroscience.

[12]  K. Arita,et al.  C-Type Natriuretic Peptide Modulates Permeability of the Blood–Brain Barrier , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[13]  S. Rosenthal,et al.  Late-Onset Alzheimer’s Disease Genes and the Potentially Implicated Pathways , 2014, Current Genetic Medicine Reports.

[14]  N. Perrimon,et al.  Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau-mediated mechanisms. , 2014, Human molecular genetics.

[15]  V. Tang,et al.  FSGS3/CD2AP is a barbed-end capping protein that stabilizes actin and strengthens adherens junctions , 2013, The Journal of cell biology.

[16]  R. Ransohoff,et al.  Development, maintenance and disruption of the blood-brain barrier , 2013, Nature Medicine.

[17]  Nick C Fox,et al.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease , 2013, Nature Genetics.

[18]  Jason J. Corneveaux,et al.  Genetic susceptibility for Alzheimer disease neuritic plaque pathology. , 2013, JAMA neurology.

[19]  Robert V Farese,et al.  Dissociation of Frontotemporal Dementia–Related Deficits and Neuroinflammation in Progranulin Haploinsufficient Mice , 2013, The Journal of Neuroscience.

[20]  A. Goate,et al.  Expression of Novel Alzheimer’s Disease Risk Genes in Control and Alzheimer’s Disease Brains , 2012, PloS one.

[21]  J. Cooper,et al.  CD2AP Links Cortactin and Capping Protein at the Cell Periphery To Facilitate Formation of Lamellipodia , 2012, Molecular and Cellular Biology.

[22]  Margaret A. Pericak-Vance,et al.  Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants , 2012, PLoS genetics.

[23]  Berislav V. Zlokovic,et al.  Apolipoprotein E controls cerebrovascular integrity via cyclophilin A , 2012, Nature.

[24]  E. Lundberg,et al.  Towards a knowledge-based Human Protein Atlas , 2010, Nature Biotechnology.

[25]  N. Ertekin-Taner.  Genetics of Alzheimer disease in the pre- and post-GWAS era , 2010, Alzheimer's Research & Therapy.

[26]  E. Lehtonen,et al.  CD2-associated protein is widely expressed and differentially regulated during embryonic development. , 2008, Differentiation; research in biological diversity.

[27]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[28]  P. Pavlidis,et al.  An ancestral haplotype defines susceptibility to doxorubicin nephropathy in the laboratory mouse. , 2006, Journal of the American Society of Nephrology : JASN.

[29]  A. Shaw,et al.  CD2-associated Protein (CD2AP) Expression in Podocytes Rescues Lethality of CD2AP Deficiency* , 2005, Journal of Biological Chemistry.

[30]  A. Shaw,et al.  CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere. , 2000, American journal of physiology. Renal physiology.

[31]  Y. Wang,et al.  Progressive adriamycin nephropathy in mice: sequence of histologic and immunohistochemical events. , 2000, Kidney international.

[32]  Michael Loran Dustin,et al.  Congenital nephrotic syndrome in mice lacking CD2-associated protein. , 1999, Science.

[33]  Patricia L. Widder,et al.  A Novel Adaptor Protein Orchestrates Receptor Patterning and Cytoskeletal Polarity in T-Cell Contacts , 1998, Cell.

[34]  H. Wiśniewski,et al.  Evidence for Blood‐Brain Barrier Changes in Senile Dementia of the Alzheimer Type (SDAT) , 1982, Annals of the New York Academy of Sciences.

[35]  David A Bennett,et al.  Epigenomics of Alzheimer's disease. , 2015, Translational research : the journal of laboratory and clinical medicine.

[36]  D. Blacker,et al.  Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database , 2007, Nature Genetics.

[37]  L. Rubin,et al.  The cell biology of the blood-brain barrier. , 1999, Annual review of neuroscience.