The upper three-phase region in the system SiO 2 -H 2 O

Abstract

<h3>ABSTRACT</h3> Familial British and Danish dementia (FBD and FDD) are two neurodegenerative disorders caused by mutations in the <i>Integral membrane protein 2B (ITM2b)</i>. BRI2, the protein encoded by <i>ITM2b</i>, tunes excitatory synaptic transmission at both pre- and post-synaptic terminus. Too, BRI2 interacts with and modulates proteolytic processing of Amyloid-β precursor Protein (APP), whose mutations cause familial forms of Alzheimer disease (FAD). To study pathogenic mechanism triggered by the Danish mutation we generated rats carrying the Danish mutation into the rat <i>Itm2b</i> gene (<i>Itm2b</i>^<i>D</i> rats). Given the BRI2/APP interaction and the widely accepted relevance of human Aβ, a proteolytic product of APP, to AD, <i>Itm2b</i>^<i>D</i> rats were engineered to express two humanized <i>App</i> alleles, to produce human Aβ. Here, we studied young <i>Itm2b</i>^<i>D</i> rats to investigate early pathogenic changes. We found that peri-adolescent <i>Itm2b</i>^<i>D</i> rats present subtle changes in human Aβ levels along with decreased spontaneous glutamate release and AMPAR-mediated responses but increased short-term synaptic facilitation in the hippocampal Schaeffer-collateral pathway. These changes are like those observed in adult mice producing rodent Aβ and carrying either the Danish or British mutations into the mouse <i>Itm2b</i> gene. Collectively, the data show that the pathogenic Danish mutation alters the physiological function of BRI2 at glutamatergic synapses; these functional alterations are detected across species and occur early in life. Future studies will be needed to determine whether this phenomenon represents an early pathogenic event in human dementia.