Cognitive correlates of Abeta deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes.
Several transgenic mouse models of Alzheimer's disease (AD) have been developed that exhibit beta-amyloid (Abeta) neuropathology and behavioural deficits. However, not all studies have investigated the relationship between the development of cognitive impairment and neuropathology. Therefore, temporal changes in cognition were investigated in male and female double-mutant APPswexPS1.M146V (TASTPM) transgenic mice using an object recognition test and correlated with the development of cerebral Abeta neuropathology. Both male and female TASTPM mice exhibited similar significant cognitive impairment at 6, 8 and 10 months of age in the object recognition test, compared to wild-type littermates. There was no such cognitive impairment at 3 or 4 months of age. Quantitative immunohistochemistry using a battery of Abeta antibodies demonstrated that cerebral Abeta deposition was first apparent in 3-month-old mice, and it increased with age. The early appearance of cerebral Abeta deposits in the double-transgenic TASTPM mice supports the evidence that mutations in the PS1 gene accelerate Abeta deposition. The cerebral Abeta load was greater in female than in male TASTPM mice at all ages investigated. In the electron microscope, mature Abeta plaques comprising a fibrillar core surrounded by degenerating neurites and reactive glia were first observed in the cortex of TASTPM mice at 6 months of age, the same age at which cognitive impairment became apparent. These results suggest that the cognitive impairment in TASTPM mice is related to the disruption of neural connectivity and not simply Abeta deposition, which first occurs 3 months earlier.
Howlett
David R
DR
Neurology and GI CEDD, GlaxoSmithKline Research and Development Limited, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK. david_howlett-1@gsk.com
Richardson
Jill C
JC
Austin
Angela
A
Parsons
Andrew A
AA
Bate
Simon T
ST
Davies
D Ceri
DC
Gonzalez
M Isabel
MI
D000367:Age Factors; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron / Q000379:methods; D009154:Mutation; D009483:Neuropsychological Tests; D058225:Plaque, Amyloid / Q000378:metabolism / Q000648:ultrastructure; D053764:Presenilin-1; D012727:Sex Characteristics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D053764:Presenilin-1