Article

Generation and Initial Characterization of FDD Knock In Mice

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
PLoS ONE (Impact Factor: 3.23). 11/2009; 4(11):e7900. DOI: 10.1371/journal.pone.0007900
Source: PubMed

ABSTRACT

Mutations in the integral membrane protein 2B, also known as BRI(2), a type II trans-membrane domain protein cause two autosomal dominant neurodegenerative diseases, Familial British and Danish Dementia. In these conditions, accumulation of a C-terminal peptide (ABri and ADan) cleaved off from the mutated precursor protein by the pro-protein convertase furin, leads to amyloid deposition in the walls of blood vessels and parenchyma of the brain. Recent advances in the understanding of the generation of amyloid in Alzheimer's disease has lead to the finding that BRI(2) interacts with the Amyloid Precursor Protein (APP), decreasing the efficiency of APP processing to generate Abeta. The interaction between the two precursors, APP and BRI(2), and possibly between Abeta and ABri or ADan, could be important in influencing the rate of amyloid production or the tendency of these peptides to aggregate.
We have generated the first BRI(2) Danish Knock-In (FDD(KI)) murine model of FDD, expressing the pathogenic decamer duplication in exon 6 of the BRI(2) gene. FDD(KI) mice do not show any evident abnormal phenotype, with normal brain histology and no detectable amyloid deposition in blood vessel walls or parenchyma.
This new murine mouse model will be important to further understand the interaction between APP and BRI(2), and to provide insights into the molecular basis of FDD.

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    • "All experimental mice were male F2 hybrid mice on a C57BL/6 Â 129 background and generated and maintained at the Animal facility of the Albert Einstein College of Medicine. F1 ApoE3 and ApoE4 targeted replacement mice, in which the endogenous mouse ApoE gene was replaced by human ApoE3 or ApoE4, respectively , under the control of the mouse ApoE promoter (Knouff et al., 1999; Sullivan et al., 1997), were crossed with F1 FDD KI mice carrying one mutant and one wild type BRI2/ITM2b allele (Giliberto et al., 2009) to generate four genotypes (ApoE3, FDD KI /ApoE3, ApoE4, and FDD KI /ApoE4) of F2 mice (n = 16–25 per genotype). Upon weaning, all mice were implanted with electronic chips (PharmaSeq, Monmouth Junction, NJ) subcutaneously on the tail for identification purposes, and their identity was checked regularly during testing periods. "
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    ABSTRACT: Mutations in Amyloid β Precursor Protein (APP) and in genes that regulate APP processing -such as PSEN1/2 and ITM2b/BRI2- cause familial dementia, such Familial Alzheimer disease (FAD), Familial Danish (FDD) and British (FBD) dementias. The ApoE gene is the major genetic risk factor for sporadic AD. Three major variants of ApoE exist in humans (ApoE2, ApoE3, and ApoE4), with the ApoE4 allele being strongly associated with AD. ITM2b/BRI2 is also a candidate regulatory node genes predicted to mediate the common patterns of gene expression shared by healthy ApoE4 carriers and late-onset AD patients not carrying ApoE4. This evidence provides a direct link between ITM2b/BRI2 and ApoE4. To test whether ApoE4 and pathogenic ITM2b/BRI2 interact to modulate learning and memory, we crossed a mouse carrying the ITM2b/BRI2 mutations that causes FDD knocked-in the endogenous mouse Itm2b/Bri2 gene (FDDKI mice) with human ApoE3 and ApoE4 targeted replacement mice. The resultant ApoE3, FDDKI/ApoE3, ApoE4, FDDKI/ApoE4 male mice were assessed longitudinally for learning and memory at 4, 6, 12, and 16-17 months of age. The results showed that ApoE4-carrying mice displayed spatial working/short-term memory deficits relative to ApoE3-carrying mice starting in early middle age, while long-term spatial memory of ApoE4 mice was not adversely affected even at 16-17 months, and that the FDD mutation impaired working/short-term spatial memory in ApoE3 -carrying mice and produced impaired long-term spatial memory in ApoE4-carrying mice in middle age. The present results suggest that the FDD mutation may differentially affect learning and memory in ApoE4 carriers and non-carriers.
    Full-text · Article · Nov 2015 · Neurobiology of Learning and Memory
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    • "When this transgenic animal was crossed with tau-P301S transgenic mice (Tg-Tau P301S), there was an increase of tau accumulation, phosphorylation and caspase cleavage of tau at Asp421 [15]. A knock-in (KI) mouse, carrying the FDD mutation in endogenous BRI2 has also been generated although it did not show detectable brain abnormalities [16]. In addition, two other transgenic lines that overexpress BRI2 containing the FDD mutation have been produced [17]. "
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    ABSTRACT: Familial British and Familial Danish dementias (FBD and FDD, respectively) are associated with mutations in the BRI2 gene. Processing of the mutated BRI2 protein leads to the accumulation in the brain of the 34-mer amyloid Bri (ABri) and amyloid Dan (ADan) peptides, accompanied by neurofibrillary tangles. Recently, transgenic mice successfully reproduced different aspects of FDD, while modeling of FBD in vivo has been more difficult. In this work we have modeled FBD and FDD in Drosophila and tested the hypothesis that ABri and ADan are differentially neurotoxic. By using site-directed insertion, we generated transgenic lines carrying ABri, ADan, Bri2-23 (the normal product of wild-type BRI2 processing) and amyloid-beta (Abeta) 1-42 as a well-characterized neurotoxic peptide, alone or with a His-tag. Therefore, we avoided random insertion effects and were able to compare levels of accumulation accurately. Peptides were expressed with the GAL4-Upstream Activating Sequence (UAS) system using specific drivers. Despite low levels of expression, toxicity in the eye was characterized by mild disorganization of ommatidia and amyloid peptides accumulation. The highest toxicity was seen for ADan, followed by Abeta42 and ABri. Pan-neuronal expression in the CNS revealed an age-dependent toxicity of amyloid peptides as determined by the ability of flies to climb in a geotaxis paradigm when compared to Bri2-23. This effect was stronger for ADan, detected at 7 days post-eclosion, and followed by ABri and Abeta42, whose toxicity became evident after 15 and 21 days, respectively. Histological analysis showed mild vacuolization and thioflavine-S-negative deposits of amyloid peptides. In contrast, the over-expression of amyloid peptides in the specific subset of lateral neurons that control circadian locomotor activity showed no toxicity. Our results support the differential neurotoxicity of ADan and ABri in the Drosophila eye and CNS at low expression levels. Such differences may be partially attributed to rates of aggregation and accumulation. In the CNS, both peptides appear to be more neurotoxic than wild-type Abeta42. These Drosophila models will allow a systematic and unambiguous comparison of differences and similarities in the mechanisms of toxicity of diverse amyloid peptides associated with dementia.
    Full-text · Article · Jan 2014 · Molecular Neurodegeneration
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    • "In FDD patients, cleavage of the BRI2 mutant protein leads to the release of the longer ADan peptide [8]. To model FDD we generated FDDKI mice that like FDD patients [8], carry one wild type Bri2/Itm2b allele and the other one has the Danish mutation [12]. FDDKI mice develop synaptic and memory deficits due to loss of Bri2 protein, but do not develop amyloidosis [13]. "
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    ABSTRACT: Mutations in ß and genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPß and ß-CTF. ß-CTF is cleaved by gamma-secretase to produce Aß. A knock-in mouse model of FDD, called FDD, shows deficits in memory and synaptic plasticity, which can be attributed to sAPPß/ß-CTF but not Aß. We have investigated further the pathogenic function of ß-CTF focusing on Thr of ß-CTF because phosphorylation of Thr is increased in AD cases. We created a knock-in mouse bearing a ThrAla mutation ( mice) that prevents phosphorylation at this site. This mutation prevents the development of memory and synaptic plasticity deficits in FDD mice. These data are consistent with a role for the carboxyl-terminal APP domain in the pathogenesis of dementia and suggest that averting the noxious role of Thr is a viable therapeutic strategy for human dementias.
    Full-text · Article · Feb 2013 · PLoS ONE
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