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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.

Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation