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, Luciano D'Adamio

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 -β-CTF- causes memory deficits in a knock-in mouse model of FDD, called FDDKI. We have investigated further the pathogenic function of β-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 β-CTF, results in stabilization of β-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.

Original languageEnglish (US)
Pages (from-to)11923-11944
Number of pages22
JournalOncotarget
Volume7
Issue number11
DOIs
StatePublished - Mar 15 2016

Fingerprint

Amyloid Precursor Protein Secretases
Memory Disorders
Long-Term Memory
Amyloid beta-Protein Precursor
Mutation
Fear
Alzheimer Disease
Protein C
Short-Term Memory
Genes
Spatial Memory
Familial Danish dementia
Proteins

Keywords

  • Alzheimer
  • APP
  • Danish dementia
  • Gamma-secretase
  • Gerotarget
  • Itm2b-bri2

ASJC Scopus subject areas

  • Oncology

Cite this

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. / Biundo, Fabrizio; Ishiwari, Keita; Del Prete, Dolores; D'Adamio, Luciano.

In: Oncotarget, Vol. 7, No. 11, 15.03.2016, p. 11923-11944.

Research output: Contribution to journalArticle

@article{985feef2000642ae98bf1fb6985b444d,
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 -β-CTF- causes memory deficits in a knock-in mouse model of FDD, called FDDKI. We have investigated further the pathogenic function of β-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 β-CTF, results in stabilization of β-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.",
keywords = "Alzheimer, APP, Danish dementia, Gamma-secretase, Gerotarget, Itm2b-bri2",
author = "Fabrizio Biundo and Keita Ishiwari and {Del Prete}, Dolores and Luciano D'Adamio",
year = "2016",
month = "3",
day = "15",
doi = "10.18632/oncotarget.7389",
language = "English (US)",
volume = "7",
pages = "11923--11944",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "11",

}

TY - JOUR

T1 - 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

AU - Biundo, Fabrizio

AU - Ishiwari, Keita

AU - Del Prete, Dolores

AU - D'Adamio, Luciano

PY - 2016/3/15

Y1 - 2016/3/15

N2 - 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 -β-CTF- causes memory deficits in a knock-in mouse model of FDD, called FDDKI. We have investigated further the pathogenic function of β-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 β-CTF, results in stabilization of β-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.

AB - 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 -β-CTF- causes memory deficits in a knock-in mouse model of FDD, called FDDKI. We have investigated further the pathogenic function of β-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 β-CTF, results in stabilization of β-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.

KW - Alzheimer

KW - APP

KW - Danish dementia

KW - Gamma-secretase

KW - Gerotarget

KW - Itm2b-bri2

UR - http://www.scopus.com/inward/record.url?scp=84962885325&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962885325&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.7389

DO - 10.18632/oncotarget.7389

M3 - Article

C2 - 26942869

AN - SCOPUS:84962885325

VL - 7

SP - 11923

EP - 11944

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 11

ER -