An Intracellular Threonine of Amyloid-β Precursor Protein Mediates Synaptic Plasticity Deficits and Memory Loss

Franco Lombino, Fabrizio Biundo, Robert Tamayev, Ottavio Arancio, Luciano D'Adamio

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Mutations in Amyloid-ß Precursor Protein (APP) and BRI2/ITM2b genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPß and ß-CTF. ß-CTF is cleaved by gamma-secretase to produce Aß. A knock-in mouse model of FDD, called FDDKI, shows deficits in memory and synaptic plasticity, which can be attributed to sAPPß/ß-CTF but not Aß. We have investigated further the pathogenic function of ß-CTF focusing on Thr668 of ß-CTF because phosphorylation of Thr668 is increased in AD cases. We created a knock-in mouse bearing a Thr668Ala mutation (APPTA mice) that prevents phosphorylation at this site. This mutation prevents the development of memory and synaptic plasticity deficits in FDDKI mice. These data are consistent with a role for the carboxyl-terminal APP domain in the pathogenesis of dementia and suggest that averting the noxious role of Thr668 is a viable therapeutic strategy for human dementias.

Original languageEnglish (US)
Article numbere57120
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 22 2013

Fingerprint

Neuronal Plasticity
dementia
Amyloid beta-Protein Precursor
Memory Disorders
Threonine
amyloid
threonine
Plasticity
Phosphorylation
mutation
Data storage equipment
phosphorylation
mice
Bearings (structural)
Mutation
Dementia
Amyloid Precursor Protein Secretases
Flavin-Adenine Dinucleotide
proteins
pathogenesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

An Intracellular Threonine of Amyloid-β Precursor Protein Mediates Synaptic Plasticity Deficits and Memory Loss. / Lombino, Franco; Biundo, Fabrizio; Tamayev, Robert; Arancio, Ottavio; D'Adamio, Luciano.

In: PLoS One, Vol. 8, No. 2, e57120, 22.02.2013.

Research output: Contribution to journalArticle

Lombino, Franco ; Biundo, Fabrizio ; Tamayev, Robert ; Arancio, Ottavio ; D'Adamio, Luciano. / An Intracellular Threonine of Amyloid-β Precursor Protein Mediates Synaptic Plasticity Deficits and Memory Loss. In: PLoS One. 2013 ; Vol. 8, No. 2.
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