Oncotarget

Research Papers: Gerotarget (Focus on Aging):

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

Fabrizio Biundo, Keita Ishiwari, Dolores Del Prete and Luciano D’Adamio _

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Oncotarget. 2016; 7:11923-11944. https://doi.org/10.18632/oncotarget.7389

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Abstract

Fabrizio Biundo1, Keita Ishiwari1,2, Dolores Del Prete1 and Luciano D’Adamio1

1 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America

2 Research Institute on Addictions University at Buffalo, Buffalo, New York, United States of America

Correspondence to:

Luciano D’Adamio, email:

Keywords: APP, Itm2b-bri2, Alzheimer, Danish dementia, gamma-secretase, Gerotarget

Received: December 18, 2015 Accepted: February 08, 2016 Published: March 01, 2016

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.


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