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Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice.

In the brain of Alzheimer's disease (AD) patients, neurotoxic amyloid peptides accumulate and are deposited as senile plaques. A major therapeutic strategy aims to decrease production of amyloid peptides by inhibition of gamma-secretase. Presenilins are polytopic transmembrane proteins that are essential for gamma-secretase activity during development and in amyloid production. By loxP/Cre-recombinase-mediated deletion, we generated mice with postnatal, neuron-specific presenilin-1 (PS1) deficiency, denoted PS1(n-/-), that were viable and fertile, with normal brain morphology. In adult PS1(n-/-) mice, levels of endogenous brain amyloid peptides were strongly decreased, concomitant with accumulation of amyloid precursor protein (APP) C-terminal fragments. In the cross of APP[V717I]xPS1 (n-/-) double transgenic mice, the neuronal absence of PS1 effectively prevented amyloid pathology, even in mice that were 18 months old. This contrasted sharply with APP[V717I] single transgenic mice that all develop amyloid pathology at the age of 10-12 months. In APP[V717I]xPS1 (n-/-) mice, long-term potentiation (LTP) was practically rescued at the end of the 2 hr observation period, again contrasting sharply with the strongly impaired LTP in APP[V717I] mice. The findings demonstrate the critical involvement of amyloid peptides in defective LTP in APP transgenic mice. Although these data open perspectives for therapy of AD by gamma-secretase inhibition, the neuronal absence of PS1 failed to rescue the cognitive defect, assessed by the object recognition test, of the parent APP[V717I] transgenic mice. This points to potentially detrimental effects of accumulating APP C99 fragments and demands further study of the consequences of inhibition of gamma-secretase activity. In addition, our data highlight the complex functional relation of APP and PS1 to cognition and neuronal plasticity in adult and aging brain.

Pubmed ID: 11978821


  • Dewachter I
  • Reversé D
  • Caluwaerts N
  • Ris L
  • Kuipéri C
  • Van den Haute C
  • Spittaels K
  • Umans L
  • Serneels L
  • Thiry E
  • Moechars D
  • Mercken M
  • Godaux E
  • Van Leuven F


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

May 1, 2002

Associated Grants


Mesh Terms

  • Alzheimer Disease
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor
  • Animals
  • Aspartic Acid Endopeptidases
  • Basic Helix-Loop-Helix Transcription Factors
  • Brain
  • Cognition Disorders
  • Crosses, Genetic
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Electric Stimulation
  • Endopeptidases
  • Hippocampus
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Long-Term Potentiation
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neuronal Plasticity
  • Neurons
  • Peptide Fragments
  • Phenotype
  • Plaque, Amyloid
  • Presenilin-1
  • RNA, Messenger
  • Recognition (Psychology)
  • Repressor Proteins