Research paperThe cytoplasmic nuclear shuttling of Beclin 1 in neurons with Alzheimer's disease-like injury

- Aβ1-42 treatment led to nuclear translocation of Beclin 1 in cultured PC12 cells.
- Caspase 3 inhibitor blocked the nuclear translocation of Beclin 1 induced by Aβ1-42.
- Beclin 1 mutation (146/149aa) was resistant to Aβ1-42-induced nuclear translocation.
- The nuclear translocation of Beclin 1 was detected in AD mice brain.

The abnormal expression of the autophagy-related protein Beclin 1 has been implicated in Alzheimer's disease (AD) brains, whereas the precise involvement of Caspase-mediated Beclin 1 cleavage in AD neurons has not yet been fully clarified. In this study, we investigated the distribution of Beclin 1 fragments in neurons with AD-like injury. Our results demonstrated that Beclin 1 was expressed in neurons but not in astrocytes in both neuron-glia co-cultures and in cortical tissue slices. The full length and C-terminal fragments of human Beclin 1 was mainly expressed in cytoplasm, while the N-terminal fragment of Beclin 1 was predominantly localized in nucleus. Compared to amyloid-β (Aβ)42-1 treatment control, exposure of PC12 cells or cortical neurons to Aβ1-42 resulted in cell injury, with the appearance of neuritic shortening, reduced nuclear diameter in PC12 cells, beading formation and fragmentation in cortical neurons. A partial nuclear translocation of Beclin 1 was detected in cells incubated with Aβ1-42, which could be inhibited by the administration of pan-Caspase inhibitor or Caspase 3 specific inhibitor. Moreover, Beclin 1 mutation at 146/149 sites was resistant to Aβ1-42-induced nuclear translocation. The nuclear translocation of Beclin 1 could also been detected in the brains of 12-month-old APPSwe/PS1dE9 transgenic mice. Our findings suggest that after Caspase 3-mediated Beclin 1 cleavage at 146/149 sites, the N-terminal fragments of Beclin 1 may partially translocate into nuclei in neurons subjected to AD-like injury.