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Related Experiment Videos

APP processing and synaptic plasticity in presenilin-1 conditional knockout mice.

H Yu1, C A Saura, S Y Choi

  • 1Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.

Neuron
|September 25, 2001
PubMed
Summary
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Presenilin-1 (PS1) knockout in adult mouse forebrains reduced beta-amyloid (Abeta) generation and caused mild spatial memory deficits, without impacting Notch signaling.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Presenilin-1 (PS1) is a key component of gamma-secretase, involved in amyloid precursor protein (APP) processing.
  • Dysregulation of PS1 and Abeta production is implicated in Alzheimer's disease pathogenesis.
  • Understanding PS1's role in the adult brain is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the specific role of presenilin-1 (PS1) in the adult forebrain.
  • To determine the effects of PS1 inactivation on amyloid-beta (Abeta) generation and cognitive function.
  • To assess the impact on Notch signaling pathways.

Main Methods:

  • Development of a conditional knockout (cKO) mouse model for PS1, with inactivation restricted to the postnatal forebrain.

Related Experiment Videos

  • Analysis of amyloid precursor protein (APP) carboxy-terminal fragments and beta-amyloid (Abeta) peptide generation in the cerebral cortex.
  • Evaluation of Notch downstream effector gene expression (Hes1, Hes5, Dll1).
  • Assessment of synaptic transmission, long-term potentiation (LTP), and long-term depression (LTD) at hippocampal CA1 synapses.
  • Behavioral testing to evaluate long-term spatial memory.

    • Main Results:

    • PS1 cKO mice were viable with no gross abnormalities.
    • Differential accumulation of APP carboxy-terminal fragments and reduced Abeta generation were observed in the cerebral cortex.
    • Expression of Notch downstream genes remained unaffected.
    • Synaptic plasticity (basal transmission, LTP, LTD) at hippocampal CA1 synapses was normal.
    • Significant, albeit subtle, deficits in long-term spatial memory were detected in PS1 cKO mice.

    Conclusions:

    • Postnatal forebrain inactivation of PS1 leads to decreased Abeta generation.
    • PS1 inactivation in the adult cerebral cortex results in subtle cognitive deficits, specifically in spatial memory.
    • These effects occur independently of alterations in Notch downstream gene expression.