title: The Alzheimer's disease risk factor CD2AP maintains blood-brain barrier integrity.
abstract: 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.
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: J Nicholas
authors.initials: JN
authors.lastname: Cochran
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Rush
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Buckingham
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA eroberson@uab.edu.
authors.forename: Erik D
authors.initials: ED
authors.lastname: Roberson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004569:Electroencephalography; D005260:Female; D017353:Gene Deletion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009404:Nephrotic Syndrome / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins