| Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by the pathophysiology of amyloid plaques, neurofibrillary tangles, and neuronal loss. In order to study AD, numerous mouse models have been created using the genetic mutations from familial AD (FAD), an early-onset form of this disease. One such mouse model is called the 5xFAD. The 5xFAD mouse model has significant neocortical neuronal loss by 12 months of age, preceded by intraneuronal amyloid beta (Abeta) and plaque deposition. We created a bigenic AD mouse model by crossing the 5xFAD with the "H-line" YFP mouse model to produce transgenic fluorescence in neocortical layer 5 pyramidal neurons. We used in vivo two-photon microscopy and ex vivo confocal microscopy to characterize our new "5XY" bigenic mouse model. In vivo imaging of the 5XY mice revealed an appearance of axonal dystrophies, with two distinct morphologies, simple swelling and rosette dystrophy, in the early stages of the disease progression. Plaque growth was followed over 4 weeks, and significant growth was seen between weekly imaging sessions. In addition to axonal dystrophy appearance and plaque growth, we were able to follow spine stability in 4-month old 5XY mice, which revealed no significant loss of spines. 5XY mice also showed a striking shrinkage of the neocortex at older ages (12-14 months). When brain sections from 2-, 4-, and 6-month old 5XY mice were examined using confocal microscopy, there was a significant loss of spine density in the basal layers of the neocortex in 6-month old mice. Our data suggest that spine loss is an early event in the degeneration of the neocortical neurons, and a likely contributor to the cognitive impairments reported previously in the 5xFAD mouse model. The 5XY mouse model may be a valuable tool for studying specific events in the degeneration of the neocortex. |
