An autosomal dominant mutation in the BRI2/ITM2B gene causes Familial Danish Dementia (FDD). We have generated a mouse model of FDD, called FDDKI, genetically congruous to the human disease. These mice carry one mutant and one wild type Bri2/Itm2b allele, like FDD patients. Analysis of FDDKI mice and samples from human patients has shown that the Danish mutation causes loss of Bri2 protein. FDDKI mice show synaptic plasticity and memory impairments. BRI2 is a physiological interactor of amyloid-beta protein precursor (AbetaPP), a gene associated with Alzheimer's disease, which inhibits processing of AbetaPP. AbetaPP/Bri2 complexes are reduced in synaptic membranes of FDDKI mice. Consequently, AbetaPP metabolites derived from processing of AbetaPP by beta-, ±-, and ³-secretases are increased in Danish dementia mice. AbetaPP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for AbetaPP-metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that AbetaPP and BRI2 functionally interact. Here, we have investigated whether AbetaPP processing is altered in FDD patients' brain samples. We find that the levels of several AbetaPP metabolites, including Abeta, are significantly increased in the brain sample derived from an FDD patient. Our data are consistent with the findings in FDDKI mice, and support the hypothesis that the neurological effects of the Danish form of BRI2 are caused by toxic AbetaPP metabolites, suggesting that Familial Danish and Alzheimer's dementias share common pathogenic mechanisms.
Increased AbetaPP processing in familial Danish dementia patientsmory deficits in a mouse model of dementia
2011
Abstract
An autosomal dominant mutation in the BRI2/ITM2B gene causes Familial Danish Dementia (FDD). We have generated a mouse model of FDD, called FDDKI, genetically congruous to the human disease. These mice carry one mutant and one wild type Bri2/Itm2b allele, like FDD patients. Analysis of FDDKI mice and samples from human patients has shown that the Danish mutation causes loss of Bri2 protein. FDDKI mice show synaptic plasticity and memory impairments. BRI2 is a physiological interactor of amyloid-beta protein precursor (AbetaPP), a gene associated with Alzheimer's disease, which inhibits processing of AbetaPP. AbetaPP/Bri2 complexes are reduced in synaptic membranes of FDDKI mice. Consequently, AbetaPP metabolites derived from processing of AbetaPP by beta-, ±-, and ³-secretases are increased in Danish dementia mice. AbetaPP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for AbetaPP-metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that AbetaPP and BRI2 functionally interact. Here, we have investigated whether AbetaPP processing is altered in FDD patients' brain samples. We find that the levels of several AbetaPP metabolites, including Abeta, are significantly increased in the brain sample derived from an FDD patient. Our data are consistent with the findings in FDDKI mice, and support the hypothesis that the neurological effects of the Danish form of BRI2 are caused by toxic AbetaPP metabolites, suggesting that Familial Danish and Alzheimer's dementias share common pathogenic mechanisms.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
