As highlighted in the news story, Abramowski and colleagues chose a risky approach in generating mice directly expressing Aβ40 or 42, thereby likely precluding the normal trafficking and localization of Aβ. While we have shied away from studying Aβ biology with such models, reports using different Aβ constructs are nevertheless providing some interesting results. In a study published in Neuron in 2005, McGowan et al. also used artificial constructs, but in their case to secrete Aβ. Interestingly, both the McGowan and Abramowski studies support that Aβ40 can be protective, since coexpression of either the secreted or intracellular Aβ40 with the corresponding Aβ42 constructs reduced brain Aβ42 levels. The present study also underscores how toxic intraneuronal Aβ42 can be compared to the just two-amino-acid-shorter Aβ40. Moreover, in contrast to rising Aβ42 levels in Aβ42 overexpression APP48 mice, Aβ40 levels did not rise in brains of the Aβ40 overexpressing mouse. Intriguingly, pan-neuron expression of Aβ42, but not Aβ40, led to neurodegeneration, particularly of hippocampal...  Read more

As highlighted in the news story, Abramowski and colleagues chose a risky approach in generating mice directly expressing Aβ40 or 42, thereby likely precluding the normal trafficking and localization of Aβ. While we have shied away from studying Aβ biology with such models, reports using different Aβ constructs are nevertheless providing some interesting results. In a study published in Neuron in 2005, McGowan et al. also used artificial constructs, but in their case to secrete Aβ. Interestingly, both the McGowan and Abramowski studies support that Aβ40 can be protective, since coexpression of either the secreted or intracellular Aβ40 with the corresponding Aβ42 constructs reduced brain Aβ42 levels. The present study also underscores how toxic intraneuronal Aβ42 can be compared to the just two-amino-acid-shorter Aβ40. Moreover, in contrast to rising Aβ42 levels in Aβ42 overexpression APP48 mice, Aβ40 levels did not rise in brains of the Aβ40 overexpressing mouse. Intriguingly, pan-neuron expression of Aβ42, but not Aβ40, led to neurodegeneration, particularly of hippocampal pyramidal neurons.

The current paper describes seeing no extracellular plaques in their intracellular Aβ42 mice, whereas McGowan et al. showed many plaques. Abramowski et al. also note that the Aβ42-secreting mice of McGowan et al. had no obvious behavioral decline or neurodegeneration, while their APP48 mice had both neurodegeneration and functional impairment, albeit motor impairment (given hippocampal cell loss, it would be interesting to look at cognition and memory). From these results, one could conclude that intraneuronal Aβ42 may be toxic, but doesn’t cause typical AD pathology. Yet, looking carefully at Fig. 6H, there clearly is labeling of Aβ42 that does not overlap with MAP2, and even looks plaque-like (MAP2 typically does also label neuron soma). Importantly, a different transgenic mouse model expressing pyro-glut Aβ3-42 was shown to develop diffuse plaques next to marked intraneuronal labeling (Wirths et al., 2009). Interestingly, Abramowski and colleagues describe an age-related Aβ42 increase in neuritic threads, but a decrease in lysosomal granules in APP48 mice. These results parallel what has been described in human Down's syndrome and AD brains, as well as in APP mutant transgenic mice.

Despite the artificial nature of their constructs, the different models reproduce various aspects of AD, often complementary between studies. The complementarity suggests that both intra- and extracellular Aβ play a role in AD pathogenesis.

References:
Wirths O, Breyhan H, Cynis H, Schilling S, Demuth HU, Bayer TA. Intraneuronal pyroglutamate-Abeta 3-42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathol. 2009 Oct;118(4):487-96. Abstract

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