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Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice.

Hyemyung Seo1, Ole Isacson

  • 1Neuroregeneration Laboratories, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. hseo@mclean.harvard.edu

Experimental Neurology
|May 5, 2005
PubMed
Summary

Ts65Dn mice, a model for Down syndrome, exhibit cognitive deficits and cholinergic neuron degeneration. Elevated amyloid precursor protein (APP) levels correlate with these deficits, suggesting a link between APP and cognitive impairment.

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Area of Science:

  • Neuroscience
  • Genetics
  • Pathology

Background:

  • Down syndrome is associated with cognitive deficits and neuropathological changes.
  • Amyloid precursor protein (APP) plays a role in neuronal function and is implicated in neurodegenerative diseases.

Purpose of the Study:

  • To investigate APP-related cellular and biochemical changes in Ts65Dn mice, a model for Down syndrome.
  • To correlate these changes with cognitive deficits observed in Ts65Dn mice.

Main Methods:

  • Ts65Dn mice and littermates (LM) were assessed at 1-2, 4, and 12 months of age.
  • Cognitive function was evaluated using the Morris water maze.
  • Cellular and biochemical analyses focused on cholinergic neurons, choline acetyltransferase (ChAT) activity, and APP levels in the hippocampus.

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Main Results:

  • Ts65Dn mice displayed cognitive deficits at 4 and 12 months.
  • Progressive degeneration of septohippocampal cholinergic neurons (ChAT-positive) was observed in Ts65Dn mice by 12 months.
  • Elevated hippocampal APP protein levels were found in Ts65Dn mice at 12 months compared to LM.
  • Both Ts65Dn mice and LM showed abnormal responses to M1 agonist treatment regarding APP, NGF, and BDNF levels.

Conclusions:

  • Ts65Dn mice exhibit age-related behavioral deficits, hippocampal APP elevations, and cholinergic pathology.
  • The combination of elevated APP and cholinergic system degeneration is critical to the cognitive deficits in Ts65Dn mice.
  • These findings highlight the utility of Ts65Dn mice for studying Down syndrome-related neuropathology and cognitive impairment.