Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ(42) accumulation and Caspase-3 activation

BACKGROUND: Although the mechanism of neuron loss in Alzheimer’s disease (AD) is enigmatic, it is associated with cerebral accumulation of Aβ(42). The 5XFAD mouse model of amyloid deposition expresses five familial AD (FAD) mutations that are additive in driving Aβ(42) overproduction. 5XFAD mice exhibit intraneuronal Aβ(42) accumulation at 1.5 months, amyloid deposition at 2 months, and memory deficits by 4 months of age. RESULTS: Here, we demonstrate by unbiased stereology that statistically significant neuron loss occurs by 9 months of age in 5XFAD mice. We validated two Aβ(42)-selective antibodies by immunostaining 5XFAD; BACE1(−/−) bigenic brain sections and then used these antibodies to show that intraneuronal Aβ(42) and amyloid deposition develop in the same regions where neuron loss is observed in 5XFAD brain. In 5XFAD neuronal soma, intraneuronal Aβ(42) accumulates in puncta that co-label for Transferrin receptor and LAMP-1, indicating endosomal and lysosomal localization, respectively. In addition, in young 5XFAD brains, we observed activated Caspase-3 in the soma and proximal dendrites of intraneuronal Aβ(42)-labeled neurons. In older 5XFAD brains, we found activated Caspase-3-positive punctate accumulations that co-localize with the neuronal marker class III β-tubulin, suggesting neuron loss by apoptosis. CONCLUSIONS: Together, our results indicate a temporal sequence of intraneuronal Aβ(42) accumulation, Caspase-3 activation, and neuron loss that implies a potential apoptotic mechanism of neuron death in the 5XFAD mouse.