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Memory impairment in transgenic Alzheimer mice requires cellular prion protein

David A Gimbel1, Haakon B Nygaard, Erin E Coffey

  • 1Cellular Neuroscience, Neurodegeneration, and Repair Program, Yale University School of Medicine, New Haven, Connecticut 06536, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|May 7, 2010
PubMed

Insights

Cellular prion protein (PrP(C)) is essential for amyloid-beta (Abeta) to impair cognitive function in Alzheimer's disease (AD) models. Removing PrP(C) in AD mice prevents memory loss, even with Abeta plaques present.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Prion and Amyloid Diseases

Background:

  • Soluble amyloid-beta (Abeta) oligomers are implicated in Alzheimer's disease (AD) pathophysiology.
  • Abeta oligomers bind to cellular prion protein (PrP(C)), a process required for Abeta's suppression of synaptic plasticity.

Purpose of the Study:

  • To investigate if PrP(C) is essential for Abeta-induced cognitive deficits in a mouse model of AD.
  • To determine the necessity of PrP(C) for AD-related phenotypes, including synaptic dysfunction and mortality.

Main Methods:

  • Generated transgenic AD mice (APPswe/PSen1DeltaE9) lacking PrP(C) (Prnp-/-).
  • Assessed Abeta levels, astrogliosis, 5-HT axonal degeneration, synaptic marker loss, and spatial learning/memory.
  • Compared cognitive function and neuropathology between AD mice with and without PrP(C).

Main Results:

  • PrP(C) absence did not alter APP expression, Abeta levels, or astrogliosis in AD mice.
  • Deletion of PrP(C) rescued 5-HT axonal degeneration, synaptic marker loss, and early death in AD mice.
  • AD mice lacking PrP(C) showed no spatial learning or memory impairment, despite Abeta plaque accumulation.

Conclusions:

  • PrP(C) is crucial for Abeta-induced cognitive impairment in this AD model.
  • The interaction between Abeta and PrP(C) is necessary to dissociate Abeta accumulation from behavioral deficits.
  • Targeting the PrP(C)-Abeta interaction may offer a therapeutic strategy for AD cognitive decline.

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