Selective filtering defect at the axon initial segment in Alzheimer s disease mouse models. Yu Wu

Transcription

1 Selective filtering defect at the axon initial segment in Alzheimer s disease mouse models Yu Wu

2 Alzheimer s Disease (AD) Mouse models: APP/PS1, PS1δE9, APPswe, hps1 Wirths, O. et al, Acta neuropathologica (2006) 111,

3 MicroRNAs (mirnas) Non-coding RNAs Over 1,000 identified mirnas Interact with the complementary mrna sequences Target degradation or translation repression

4 Upregulation of mir 342 5p in the Hippocampus of AD Transgenic Mice 7 mirnas were upregulated 7 mirnas were downregulated mir-342-5p showed an ~22-fold upregulation

5 Ankyrin G (AnkG) mrna 3 UTR was a Target of mir 342 5p Complementary sequences for mir-342-5p are present in the 3 UTR of AnkG mrna in both mouse and human.

6 AnkG Plays a Critical Role at the Axon Initial Segment (AIS) AnkG has been associated with the AIS filtering and protein trafficking.

7 AnkG Plays a Critical Role at the Axon Initial Segment (AIS)

8 AnkG Plays a Critical Role at the Axon Initial Segment (AIS)

9 AnkG Plays a Critical Role at the Axon Initial Segment (AIS)

10 AnkG Downregulation Induces Impaired Selective Filtering Machinery at AIS 10kDa 70kDa dextran

11 AnkG Downregulation Induces Impaired Selective Filtering Machinery at AIS

12 AnkG Downregulation Induces Impaired Selective Filtering Machinery at AIS

13 AnkG Downregulation Induces Impaired Selective Filtering Machinery at AIS

14 AnkG Downregulation Induces Impaired Selective Filtering Machinery at AIS

15 AnkG Downregulation Induces Impaired Selective Filtering Machinery at AIS

16 Impaired AIS Filtering Might Underlie Functional Defects in APP/PS1 Neurons

17 Impaired AIS Filtering Might Underlie Functional Defects in APP/PS1 Neurons

18 Impaired AIS Filtering Induced Synaptic and Cognitive Defects in APP/PS1 Mice

19 Summary

20

21 Synapse Synaptic Plasticity Learning Memory etc.

22 Myelin Plasticity Fields R. D. (2015). Nat. Rev. Neurosci. 16,

23 Myelin Plasticity Myelin Sheath Formed by oligodendrocytes in central nervous system (CNS) Important for the propagation of action potential along axon Naked at axon initial segment (AIS) and nodes of Ranvier

24 Myelin Plasticity Myelin plasticity Structure of myelin Structure of nodes of Ranvier Length of internode Unmyelinated-axon Fields R. D. (2015). Nat. Rev. Neurosci. 16, 756

25 Relative Researches

26 Active CNS Myelination is Required for Motor Skill Learning WT mouse Seven nights self-training P-Myrf (-/-) mouse Seven nights self-training

27 Active CNS Myelination is Required for Motor Skill Learning

28 Running Stimulates OP Proliferation and OL Production

29 Relative Researches

30 Longitudinal Studies of Structural Changes in Gray and White Matter with Learning

31 Thanks for your attention!

32 AnkG mrna 3 UTR was a Target of mir 342 5p

33 AnkG mrna 3 UTR was a Target of mir 342 5p BD(Binding Domain)

34 AnkG mrna 3 UTR Direct Binds with mir 342 5p RNase protection assay RNase protection assay *

35 Downregulation of AnkG in AD Transgenic Mice Associated with PS1 Mutant The downregulation of AnkG was due to either accelerated degradation or reduced protein expression at the translation level.

36 AnkG mrna 3 UTR was a Target of mir 342 5p Luciferase Reporter Assays

37 Aβ is derived from the APP after β and γ secretase cleavages Presenilin1 β Amyloid Hypothesis and Alzheimer s Disease, Xiaqin Sun and Yan Zhang

38 Upregulation of mir 342 5p in AD Transgenic Mice

39 Upregulation of mir 342 5p in AD Transgenic Mice Associated with PS1 Mutant WT WT APP/PS1 APP/PS1 APPswe APPswe hps1 hps1 PS1 E9 PS1 E9 PS1 M146V PS1 M146V