Alzheimer’s disease (AD) has been considered as an age-related diseases, which always occurs in late stage of life of elderly people. However, Yan Zhang’s group from College of Life Sciences, Peking University, found that familial AD mouse model showed the defects in neuronal development, protein trafficking and axon initial segment (AIS) function in very early stage. Ankyrin G (AnkG) is an adaptor protein, playing a significant role in maintaining filtering function at the AIS.

Yan Zhang’s group has reported that the level of miR-342-5p is increased significantly in familial AD mouse model. AnkG one of the targets of miR-342-5p is downregulated. In APP/PS1, PS1ΔE9 and PS1-M146V mice, the level of miR342-5p is found increased dramatically, due to the upregulated of β-catenin, c-Myc and interferon regulatory factor (IRF)-9. MiR-342-5p is able to interact with the region of AnkG 3’ UTR directly. These results has been published on Cell Reports before. The decreased level of AnkG caused by changes of the microRNAs could be the reason of axon pathology found in AD patients and mouse models. Defects of AIS filtering mechanisms in AD mouse models lead to many proteins which supposed to be on soma and dendrites mis-localize into axons, such as NR2B, subunit of neurotransmitter receptor NMDA. Distributions of some proteins related to the initiation of action potential, which should be concentrated in AIS, is also affected, such as NaV1.6. These results reveal that defects of AIS filtering mechanisms may contribute to the AD pathology. Further studies have confirmed that over-expression of AnkG can rescue the cognition of AD mice. These results indicate that in familial AD carriers, neurons show deficient in early development stages.

Xiaqin Suna, Yu Wua, Mingxue Gua, Zhuo Liua, Yuanlin Mab, Jun Lib, and Yan Zhanga（2014）Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models,  PNAS , 14271–14276, doi: 10.1073/pnas.1411837111