title: Deletion of the γ-secretase subunits Aph1B/C impairs memory and worsens the deficits of knock-in mice modeling the Alzheimer-like familial Danish dementia.
abstract: Mutations in BRI2/ITM2b genes cause Familial British and Danish Dementias (FBD and FDD), which are pathogenically similar to Familial Alzheimer Disease (FAD). BRI2 inhibits processing of Amyloid precursor protein (APP), a protein involved in FAD pathogenesis. Accumulation of a carboxyl-terminal APP metabolite -ß-CTF- causes memory deficits in a knock-in mouse model of FDD, called FDDKI.We have investigated further the pathogenic function of ß-CTF studying the effect of Aph1B/C deletion on FDDKI mice. This strategy is based on the evidence that deletion of Aph1B/C proteins, which are components of the γ-secretase that cleaves ß-CTF, results in stabilization of ß-CTF and a reduction of Aβ. We found that both the FDD mutation and the Aph1B/C deficiency mildly interfered with spatial long term memory, spatial working/short-term memory and long-term contextual fear memory. In addition, the Aph1BC deficiency induced deficits in long-term cued fear memory. Moreover, the two mutations have additive adverse effects as they compromise the accuracy of spatial long-term memory and induce spatial memory retention deficits in young mice. Overall, the data are consistent with a role for β-CTF in the genesis of memory deficits.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Biundo
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Research Institute on Addictions University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Keita
authors.initials: K
authors.lastname: Ishiwari
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Dolores
authors.initials: D
authors.lastname: Del Prete
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal; D002386:Cataract / Q000235:genetics / Q000473:pathology*; D002524:Cerebellar Ataxia / Q000235:genetics / Q000473:pathology*; D003638:Deafness / Q000235:genetics / Q000473:pathology*; D003704:Dementia / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation
chemical_list: D053829:Amyloid Precursor Protein Secretases
keywords: APP; Alzheimer; Danish dementia; Gerotarget; Itm2b-bri2; gamma-secretase