Abstract
BackgroundAlthough the mechanism of neuron loss in Alzheimer’s disease (AD) is enigmatic, it is associated with cerebral accumulation of Aβ42. The 5XFAD mouse model of amyloid deposition expresses five familial AD (FAD) mutations that are additive in driving Aβ42 overproduction. 5XFAD mice exhibit intraneuronal Aβ42 accumulation at 1.5 months, amyloid deposition at 2 months, and memory deficits by 4 months of age.ResultsHere, we demonstrate by unbiased stereology that statistically significant neuron loss occurs by 9 months of age in 5XFAD mice. We validated two Aβ42-selective antibodies by immunostaining 5XFAD; BACE1−/− bigenic brain sections and then used these antibodies to show that intraneuronal Aβ42 and amyloid deposition develop in the same regions where neuron loss is observed in 5XFAD brain. In 5XFAD neuronal soma, intraneuronal Aβ42 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 Aβ42-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.ConclusionsTogether, our results indicate a temporal sequence of intraneuronal Aβ42 accumulation, Caspase-3 activation, and neuron loss that implies a potential apoptotic mechanism of neuron death in the 5XFAD mouse.
Highlights
The mechanism of neuron loss in Alzheimer’s disease (AD) is enigmatic, it is associated with cerebral accumulation of Aβ42
Our results suggest that apoptotic processes are present in 5 familial AD mutations (5XFAD) mice beginning at 4 months, before the start of neuronal death at 6 months, in the same brain regions that exhibit intraneuronal Aβ42, amyloid plaques, and neuron loss
Our data is consistent with previous studies, except we have demonstrated that significant 5XFAD neuron loss begins at an earlier age than previously reported [16]
Summary
The mechanism of neuron loss in Alzheimer’s disease (AD) is enigmatic, it is associated with cerebral accumulation of Aβ42. Frank neuron loss has been observed in two aggressive amyloid plaque transgenic mouse models that exhibit accumulation of intraneuronal Aβ42 prior to plaque formation: the 5XFAD and APPSLPS1K1 lines [10,11]. These transgenic models express multiple FAD mutations that additively increase Aβ42 production. These characteristics make 5XFAD mice a robust model for investigating the role of intraneuronal Aβ42 in neuron loss
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