Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities.

Abstract

Transgenic mice made by crossing animals expressing mutant amyloid precursor protein (APPswe) to mutant presenilin 1 (PS1dE9) allow for incremental increases in Abeta42 production and provide a model of Alzheimer-type amyloidosis. Here, we examine cognition in 6- and 18-month old transgenic mice expressing APPswe and PS1dE9, alone and in combination. Spatial reference memory was assessed in a standard Morris Water Maze task followed by assessment of episodic-like memory in Repeated Reversal and Radial Water maze tasks. We then used factor analysis to relate changes in performance in these tasks with cholinergic markers, somatostatin levels, and amyloid burden. At 6 months of age, APPswe/PS1dE9 double-transgenic mice showed visible plaque deposition; however, all genotypes, including double-transgenic mice, were indistinguishable from nontransgenic animals in all cognitive measures. In the 18-month-old cohorts, amyloid burdens were much higher in APPswe/PS1dE9 mice with statistically significant but mild decreases in cholinergic markers (cortex and hippocampus) and somatostatin levels (cortex). APPswe/PS1dE9 mice performed all cognitive tasks less well than mice from all other genotypes. Factor and correlation analyses defined the strongest correlation as between deficits in episodic-like memory tasks and total Abeta loads in the brain. Collectively, we find that, in the APPswe/PS1dE9 mouse model, some form of Abeta associated with amyloid deposition can disrupt cognitive circuits when the cholinergic and somatostatinergic systems remain relatively intact; and that episodic-like memory seems to be more sensitive to the toxic effects of Abeta.

• Authors: Alena Savonenko, Guilian M Xu, Tatiana Melnikova, Johanna L Morton, Victoria Gonzales, Molly P F Wong, Donald L Price, Fai Tang, Alicja L Markowska, David R Borchelt
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 18 Issue 3 Pg. 602-17 (Apr 2005) ISSN: 0969-9961 [Print] United States
• PMID: 15755686 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Membrane Proteins
• Neurotransmitter Agents
• PSEN1 protein, human
• Presenilin-1
• Somatostatin
• Acetylcholine

Topics

• Acetylcholine (biosynthesis, genetics)
• Alzheimer Disease (genetics, metabolism, physiopathology)
• Amyloid beta-Peptides (biosynthesis, genetics, metabolism)
• Amyloid beta-Protein Precursor (biosynthesis, genetics)
• Animals
• Female
• Humans
• Male
• Maze Learning (physiology)
• Membrane Proteins (biosynthesis, genetics)
• Memory Disorders (genetics, metabolism)
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurotransmitter Agents (biosynthesis, genetics)
• Presenilin-1
• Reaction Time (physiology)
• Somatostatin (biosynthesis, genetics)