Delayed amyloid plaque deposition and behavioral deficits in outcrossed A beta PP/PS1 mice

作者：Couch Brian A; Kerrisk Meghan E; Kaufman Adam C; Nygaard Haakon B; Strittmatter Stephen M; Koleske Anthony J^*

来源：Journal of Comparative Neurology, 2013, 521(6): 1395-1408.

DOI：10.1002/cne.23239

• amyloid-beta precursor protein
• hippocampus
• novel object recognition
• presenilin-1
• radial-arm water maze
• strain background
• Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative dementia characterized by amyloid plaque accumulation, synapse/dendrite loss, and cognitive impairment. Transgenic mice expressing mutant forms of amyloid- precursor protein (APP) and presenilin-1 (PS1) recapitulate several aspects of this disease and provide a useful model system for studying elements of AD progression. APP/PS1 mice have been previously shown to exhibit behavioral deficits and amyloid plaque deposition between 49 months of age. We crossed APP/PS1 animals with mice of a mixed genetic background (C57BL/6 x 129/SvJ) and investigated the development of AD-like features in the resulting outcrossed mice. The onset of memory-based behavioral impairment is delayed considerably in outcrossed APP/PS1 mice relative to inbred mice on a C57BL/6 background. While inbred APP/PS1 mice develop deficits in radial-arm water maze performance and novel object recognition as early as 8 months, outcrossed APP/PS1 mice do not display defects until 18 months. Within the forebrain, we find that inbred APP/PS1 mice have significantly higher amyloid plaque burden at 12 months than outcrossed APP/PS1 mice of the same age. Surprisingly, inbred APP/PS1 mice at 8 months have low plaque burden, suggesting that plaque burden alone cannot explain the accompanying behavioral deficits. Analysis of APP processing revealed that elevated levels of soluble A correlate with the degree of behavioral impairment in both strains. Taken together, these findings suggest that animal behavior, amyloid plaque deposition, and APP processing are sensitive to genetic differences between mouse strains. J. Comp. Neurol., 521:13951408, 2013.

• 出版日期2013-4-15