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


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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    • "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.
    Molecular Neurodegeneration 01/2014; 9(1):5. DOI:10.1186/1750-1326-9-5 · 6.56 Impact Factor
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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.
    PLoS ONE 02/2013; 8(2):e57120. DOI:10.1371/journal.pone.0057120 · 3.23 Impact Factor
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    • "Abnormal processing of BRI2 can lead to a decrease in m-BRI2 levels and accumulation of murine amyloid β precursor protein (Aβpp) C-terminal fragments [58], which together with mutant tau may cause synaptic dysfunction in Tg-FDD-Tau mice, independent of the presence of ADan oligomers. Work done using knock-in mice with the Danish mutation (FDD-KI) and the British mutation (FBD-KI) in the murine Bri2 gene, and with mice with a knock-out of one allele of murine Bri2 (Bri2+/−) has shown that these mice exhibit abnormal synaptic plasticity and memory deficits that is independent of the presence of the amyloid peptides [31], [59]–[61]. The finding of a reduction of m-Bri2 in synaptic membranes of FDDKI/+ mice in the absence of ADan and tau deposition is consistent with the hypothesis that FDD may begin as a synaptic disease, associated with a Bri2 loss of function [31]. "
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    ABSTRACT: Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease caused by a 10-nucleotide duplication-insertion in the BRI(2) gene. FDD is clinically characterized by loss of vision, hearing impairment, cerebellar ataxia and dementia. The main neuropathologic findings in FDD are the deposition of Danish amyloid (ADan) and the presence of neurofibrillary tangles (NFTs). Here we investigated tau accumulation and truncation in double transgenic (Tg-FDD-Tau) mice generated by crossing transgenic mice expressing human Danish mutant BRI(2) (Tg-FDD) with mice expressing human 4-repeat mutant Tau-P301S (Tg-Tau). Compared to Tg-Tau mice, we observed a significant enhancement of tau deposition in Tg-FDD-Tau mice. In addition, a significant increase in tau cleaved at aspartic acid (Asp) 421 was observed in Tg-FDD-Tau mice. Tg-FDD-Tau mice also showed a significant decrease in synaptophysin levels, occurring before widespread deposition of fibrillar ADan and tau can be observed. Thus, the presence of soluble ADan/mutant BRI(2) can lead to significant changes in tau metabolism and synaptic dysfunction. Our data provide new in vivo insights into the pathogenesis of FDD and the pathogenic pathway(s) by which amyloidogenic peptides, regardless of their primary amino acid sequence, can cause neurodegeneration.
    PLoS ONE 02/2013; 8(2):e56426. DOI:10.1371/journal.pone.0056426 · 3.23 Impact Factor
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