Journal
JOURNAL OF NEUROSCIENCE
Volume 28, Issue 23, Pages 6030-6036Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0891-08.2008
Keywords
BRI2; ITM2b; amyloid beta protein; Alzheimer's disease; somatic brain transgenesis; adeno-associated virus
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Funding
- NIA NIH HHS [P01 AG025531, P01 AG003949, R01 AG018454, P50 AG025711, P01 AG025531-030001, R01 AG018454-07A2, R01 AG18454, P01 AG017216] Funding Source: Medline
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Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid beta precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer's disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-A beta 1-40 transgenes in APP mouse models. Expression of BRI2-A beta 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 beta 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 beta aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of A beta deposition in vivo.
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