TY - JOUR
T1 - Memory deficits of british dementia knock-in mice are prevented by Aβ-precursor protein haploinsufficiency
AU - Tamayev, Robert
AU - D'Adamio, Luciano
PY - 2012/4/18
Y1 - 2012/4/18
N2 - Familial British Dementia (FBD) is caused by an autosomal dominant mutation in the BRI2/ITM2B gene (Vidal et al., 1999). FBD KI mice are a model ofFBDthat is genetically congruous to the human disease, because they carry one mutant and one wild-type Bri2/Itm2b allele. Analysis of these mice has shown that the British mutation causes memory impairments due to loss of Bri2 function (Tamayev et al., 2010b). BRI2 is a physiologic inhibitor of processing of the Aβ-precursor protein (APP; Matsuda et al., 2008), a gene associated with Alzheimer's disease (Bertram et al., 2010). Here we show that APP haploinsufficiency prevents memory dysfunctions seen in FBDKI mice. This genetic suppression is consistent with a role for APP in the pathogenesis of memory deficits. Moreover, it provides compelling evidence that the memory dysfunctions caused by the British BRI2 mutant are dependent on endogenous APP and that BRI2 and APP functionally interact. This evidence establishes a mechanistic connection between Familial British and Alzheimer's dementias.
AB - Familial British Dementia (FBD) is caused by an autosomal dominant mutation in the BRI2/ITM2B gene (Vidal et al., 1999). FBD KI mice are a model ofFBDthat is genetically congruous to the human disease, because they carry one mutant and one wild-type Bri2/Itm2b allele. Analysis of these mice has shown that the British mutation causes memory impairments due to loss of Bri2 function (Tamayev et al., 2010b). BRI2 is a physiologic inhibitor of processing of the Aβ-precursor protein (APP; Matsuda et al., 2008), a gene associated with Alzheimer's disease (Bertram et al., 2010). Here we show that APP haploinsufficiency prevents memory dysfunctions seen in FBDKI mice. This genetic suppression is consistent with a role for APP in the pathogenesis of memory deficits. Moreover, it provides compelling evidence that the memory dysfunctions caused by the British BRI2 mutant are dependent on endogenous APP and that BRI2 and APP functionally interact. This evidence establishes a mechanistic connection between Familial British and Alzheimer's dementias.
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U2 - 10.1523/JNEUROSCI.5193-11.2012
DO - 10.1523/JNEUROSCI.5193-11.2012
M3 - Article
C2 - 22514310
AN - SCOPUS:84859776703
SN - 0270-6474
VL - 32
SP - 5481
EP - 5485
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 16
ER -