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

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) treatment control, exposure of PC12 cells or cortical neurons to Aβ 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 Aβ, 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 Aβ-induced nuclear translocation. The nuclear translocation of Beclin 1 could also been detected in the brains of 12-month-old APP/PS1 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.