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-â protein precursor (AâPP), a gene associated with Alzheimer's disease, which inhibits processing of AâPP. AâPP/Bri2 complexes are reduced in synaptic membranes of FDDKI mice. Consequently, AâPP metabolites derived from processing of AâPP by â-, á-, and ã-secretases are increased in Danish dementia mice. AâPP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for AâPP-metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that AâPP and BRI2 functionally interact. Here, we have investigated whether AâPP processing is altered in FDD patients' brain samples. We find that the levels of several AâPP metabolites, including Aâ, 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 AâPP metabolites, suggesting that Familial Danish and Alzheimer's dementias share common pathogenic mechanisms.
Adaptor Proteins, Signal Transducing Alzheimer Disease