Cognitive correlates of Aβ deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes

Abstract

Several transgenic mouse models of Alzheimer's disease (AD) have been developed that exhibit β-amyloid (Aβ) 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 APPswe×PS1.M146V (TASTPM) transgenic mice using an object recognition test and correlated with the development of cerebral Aβ 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 Aβ antibodies demonstrated that cerebral Aβ deposition was first apparent in 3-month-old mice, and it increased with age. The early appearance of cerebral Aβ deposits in the double-transgenic TASTPM mice supports the evidence that mutations in the PS1 gene accelerate Aβ deposition. The cerebral Aβ load was greater in female than in male TASTPM mice at all ages investigated. In the electron microscope, mature Aβ 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 Aβ deposition, which first occurs 3 months earlier.