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BRI2 (Itm2b) Inhibits A␤ Deposition in Vivo

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BRI2 (Itm2b) Inhibits A␤ Deposition in Vivo 6030 • The Journal of Neuroscience, June 4, 2008 • 28(23):6030–6036 Neurobiology of Disease BRI2 (ITM2b) Inhibits A␤ Deposition In Vivo Jungsu Kim,1 Victor M. Miller,1 Yona Levites,1 Karen Jansen West,1 Craig W. Zwizinski,1 Brenda D. Moore,1 Fredrick J. Troendle,1 Maralyssa Bann,1 Christophe Verbeeck,1 Robert W. Price,1 Lisa Smithson,1 Leilani Sonoda,1 Kayleigh Wagg,1 Vijayaraghavan Rangachari,1 Fanggeng Zou,1 Steven G. Younkin,1 Neill Graff-Radford,2 Dennis Dickson,1 Terrone Rosenberry,1 and Todd E. Golde1 Departments of 1Neuroscience and 2Neurology, Mayo Clinic College of Medicine, Mayo Clinic Jacksonville, Jacksonville, Florida 32224 AnalysesofthebiologiceffectsofmutationsintheBRI2(ITM2b)andtheamyloid␤precursorprotein(APP)genessupportthehypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer’s disease (AD) is associatedwithneurodegeneration.WehaveusedsomaticbraintransgenictechnologytoexpresstheBRI2andBRI2-A␤1–40transgenes in APP mouse models. Expression of BRI2-A␤1–40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild-type human BRI2 reduces cerebral A␤ deposition in an AD mouse model. Additional data indicate that the 23 aa peptide, Bri23, released from BRI2 by normal processing, is present in human CSF, inhibits A␤ aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of A␤ deposition in vivo. Key words: BRI2; ITM2b; amyloid ␤ protein; Alzheimer’s disease; somatic brain transgenesis; adeno-associated virus Introduction pathological and clinical similarities between FBD, FDD, and Familial British and Danish dementias (FBD and FDD, respec- Alzheimer’s disease (AD). Indeed, genetic analyses of FBD, FDD, tively) are neurodegenerative dementias pathologically charac- and familial forms of AD support a unifying pathologic mecha- terized by parenchymal preamyloid and amyloid deposits, cere- nism in which accumulation of amyloidogenic peptides triggers a bral amyloid angiopathy (CAA), neuronal loss, and complex pathological cascade leading to neurodegeneration neurofibrillary tangles (Ghiso et al., 2006). Two mutations in the (Golde, 2003). ITM2b gene encoding the BRI2 protein have been identified as Our interest in the BRI2 protein developed in the course of ␤ ␤ the cause of FBD and FDD. BRI2 is a 266-aa-long type 2 trans- studies using BRI2-A fusion proteins to express individual A membrane protein of unknown function. It is expressed at high peptides (McGowan et al., 2005; Kim et al., 2007). By crossing ␤ ␤ levels in the brain and cleaved by furin or furin-like proteases at BRI2-A 1–40 or BRI-A 1–42 transgenic mice with Tg2576 ␤ ␤ its C terminus to produce a 23 aa peptide (Bri2–23) (Kim et al., mice, we previously demonstrated that A 1–40 and A 42 have 1999; Choi et al., 2004) (Fig. 1B). Disease-causing mutations opposing effects on amyloid deposition (McGowan et al., 2005; result in the production of C-terminally extended 277 aa mutant Kim et al., 2007). To study the anti-amyloidogenic effect of ␤ ␤ BRI2 proteins, which are cleaved at the normal furin processing A 1–40 in another amyloid precursor protein (APP) mouse site to generate distinct 34 aa peptides (ABri in FBD and ADan in model, we used recombinant adeno-associated virus 1 (rAAV1)- ␤ FDD) that accumulate in the brains of affected patients (Vidal et mediated gene transfer to deliver the BRI2-A 1–40 and BRI2 al., 1999, 2000). Notably, synthetic ABri and ADan undergo rapid transgenes to the brains of postnatal day 0 (P0) TgCRND8 hAP- aggregation and fibrillization into amyloid, and they are neuro- PKM670/671NLϩV717F APP mice (Levites et al., 2006b). This meth- toxic (Gibson et al., 2005; Ghiso et al., 2006). Thus, there are clear odology of gene transfer, which we have termed somatic brain transgenesis, leads to consistent widespread and permanent ex- pression of the transgene in forebrain and hippocampal neurons Received Feb. 28, 2008; revised May 2, 2008; accepted May 4, 2008. (Fig. 1A) and enables one to rapidly and cost-effectively evaluate This work was supported by the National Institutes of Health–National Institute on Aging (NIA) Grant R01 the effects of transgene expression on the amyloid deposition AG18454 (T.E.G.) and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program phenotype (Levites et al., 2006b). (T.E.G.); Robert and Clarice Smith Postdoctoral Fellowship (B.D.M., V.M.M.); Development Award 0535185N from the American Heart Association (V.R.); and The Mayo Foundation. We thank Dr. Eileen McGowan for providing the BRI2cDNA.WeacknowledgethetechnicalassistanceofLindaRousseau,VirginiaPhillips,MonicaCasey-Castanedes, Materials and Methods and John Gonzales in the Neuropathology Laboratory at Mayo Clinic Jacksonville, which is supported by the NIA rAAV1 construction and preparation. rAAV1 expressing BRI2, BRI2- Grants AG25711, AG17216, and AG03949 (D.D.). A␤1–40, BRI2del244–266, nonspecific single-chain variable fragment This article is freely available online through the J Neurosci Open Choice option. (scFv ns), or enhanced green fluorescent protein (eGFP), under the con- Correspondence should be addressed to either Terrone Rosenberry (regarding A␤/Bri2-23 aggregation studies) ␤ or Todd E. Golde (all other correspondence), Department of Neuroscience, Mayo Clinic College of Medicine, Mayo trol of the cytomegalovirus enhancer/chicken actin (CBA) promoter Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, E-mail: [email protected] or were generated by calcium-phosphate transfection of pAM/CBA-pI- [email protected]. WPRE-BGH, rAAV1 cis-plasmid pH21 (AAV1 helper plasmid), and DOI:10.1523/JNEUROSCI.0891-08.2008 pF⌬6 into a HEK293 cell line. rAAV1-scFv ns construct was reported Copyright © 2008 Society for Neuroscience 0270-6474/08/286030-07$15.00/0 previously (Levites et al., 2006b). At 48 h after transfection, cells were Kim et al. • BRI (ITM2b) Inhibits A␤ Deposition In Vivo J. Neurosci., June 4, 2008 • 28(23):6030–6036 • 6031 Figure 1. BRI2 expression inhibits A␤ deposition in vivo. A, Somatic brain transgenesis results in consistent transduction of forebrain and hippocampal neurons. rAAV1-EGFP was delivered into cerebral ventricles of newborn mice (4 ϫ 10 9 genomes per mouse), and widespread EGFP expression was detected by immunohistochemistry with an anti-GFP antibody at ϳ1 month of age. The top panel is a saline-injected control, and the next six panels are representative of three separate somatic brain transgenic experiments performed on four different litters using two different rAAV1-EGFP preparations. Note that the forebrain and hippocampus are routinely transduced, whereas hindbrain structures (e.g., cerebellum) are more variably transduced. B, Schematic of BRI2-fusion constructs. BRI2 and BRI2-A␤1–40 are cleaved by furin and other kex2 proteases to release Bri2–23 and A␤1–40, respectively. C, P0 TgCRND8 mice were transduced by the intracerebroventricular injection of rAAV1-BRI2 (n ϭ 8) or BRI2-A␤1–40 (n ϭ 11). Total brain A␤ levels (pooled values of the SDS-soluble and SDS-insoluble FA extracts) from 3-month-old mice were analyzed by A␤ end-specific ELISA. Control refers to both noninjected and PBS-injected mice (n ϭ 8). D, Cortical sections of 3-month-old mice were immunostained with anti-A␤1–16 antibody 33.1.1. Sections representing the mice with the median levels of biochemical A␤ deposition are shown. CAA was not increased by the BRI transgenes and was almost completely absent in the TgCRND8 mice at 3 months of age. Magnification, 200ϫ. E, Amyloid plaque burdens and thioflavin (Thio S)-positive plaques were quantified from the stitched images of whole cerebral cortex. Cored plaques, identified by Thio S staining, were counted individually. **p Ͻ 0.01 versus no injection control (ANOVA). lysed in the presence of 0.5% sodium deoxycholate and 50 U/ml benzo- 2006; Levites et al., 2006b). Briefly, P0 pups were cryoanesthetized on ice nase (Sigma) by repeated rounds of freeze/thaws at Ϫ80°C and Ϫ20°C. for 5 min. Two microliters of AAV1 construct (1 ϫ 10 12 genome parti- The virus was isolated using a discontinuous Iodixanol gradient and then cles/ml) were bilaterally injected into the cerebral ventricle of newborn affinity purified on a HiTrap HQ column (GE Healthcare). Samples were mice using a 10 ml Hamilton syringe with a 30 gauge needle. The pups eluted from the column and buffer exchanged to PBS using an Amicon were placed on a heating pad until they recovered from cryoanesthesia Ultra 100 Centrifugation device (Millipore). The genomic titer of each and then returned to their mother for further recovery. Negative control virus was determined by quantitative PCR using the ABI 7900 (Applied groups (total n ϭ 20) were noninjection (n ϭ 4), PBS injection (n ϭ 4), Biosystems). The viral DNA samples were prepared by treating the virus eGFP (n ϭ 5), and nonspecific scFv (n ϭ 7) groups. Experimental groups with DNase I (Invitrogen), heat inactivating the enzyme, and then digest- were BRI2-A␤1–40 (n ϭ 11), BRI2 (n ϭ 8), and BRI2del244–266 (n ϭ ing the protein coat with Proteinase K (Invitrogen), followed by a second 13). Biochemical and histochemical A␤ loads in the control groups were heat inactivation. Samples were compared against a standard curve of equivalent. All animal procedures were approved by Mayo Clinic Insti- supercoiled plasmid. tutional Animal Care and Use Committee in accordance with National rAAV1 injection to neonatal mice. TgCRND8 mice expressing mutant Institutes of Health (NIH) guidelines. human APP (KM670/671NL and V717F) gene under the control of ham- Quantification of amyloid deposition. Hemibrains were immersion ster prion promoter were reported previously (Chishti et al., 2001). fixed in 10% formalin then processed for paraffin embedding. Brain Hemizygous male TgCRND8 mice were crossed with female B6C3F1 tissue sections (5 ␮m) were immunostained with the anti-total A␤ anti- wild-type mice.
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