Geon 11. Regulation of 4R:3R Tau Ratio by miR-132 Alzheimer

In a healthy adult human brain, the levels of 4-repeat (4R) and 3-repeat (3R) Tau proteins are approximately equal. The previous chapter has explained how elevation in the total Tau level or 4R:3R Tau ratio may result in hyperexcitability, which is an early sign of Alzheimer's disease (AD). This chapter will discuss how the 4R:3R Tau ratio is normally regulated.

miR-132 is Implicated in Neurodegeneration

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Figure 11-1. An example of microRNA (in red) and its precursor (with hairpin loop). [Source: Wikipedia]

As described in Chapter 5, Tau isoforms can be produced from a single gene through alternative RNA splicing. The 4R Tau includes the repeat encoded by exon 10. Recently, microRNAs have been demonstrated to play important roles in the regulation of gene expression. A microRNA is a small non-coding RNA molecule (~ 22 nucleotides), created from the genomic DNA. The human genome may encode at least 800 microRNAs (Bentwich et al., 2005). They are named with the prefix "miR" followed by a dash and a number. A suffix, -3p or -5p, may also be included, specifying whether the mature microRNA originates from the 3' or 5' arm of its precursor.

The mature microRNA interacts with its target (the mRNA of a protein) within a structure called RNA-induced silencing complex (RISC). For perfect or nearly perfect complementarity between a microRNA and its mRNA target, the interaction within RISC will result in mRNA degradation. For partial complementarity, the translation of the target mRNA will be repressed (Ye et al., 2016).

miR-132 targets the mRNA of both Tau protein and a splicing factor, polypyrimidine tract-binding protein 2 (PTBP2). Thus, miR-132 regulates not only the total Tau level, but also the ratio between 4R and 3R Tau. miR-132 deficiency has been shown to cause increased Tau expression and higher 4R:3R Tau ratio (Smith et al., 2011; Smith et al., 2015). It is implicated in AD (Cogswell et al., 2008; Hébert et al., 2013; Lau et al., 2013), and other 4R tauopathies such as progressive supranuclear palsy (Smith et al., 2011) and Huntington's disease (HD) (Johnson and Buckley, 2009).

miR-132 is Up-regulated by BDNF

Brain-Derived Neurotrophic Factor (BDNF) is an essential protein in the central nervous system. It plays critical roles in cell differentiation, survival, and synaptic plasticity. Low level of BDNF is linked to AD, HD, and other brain-related disorders (Adachi et al., 2014). A growing body of evidence suggests that BDNF exerts its beneficial effects via up-regulation of miR-132 (Numakawa et al., 2011; Zheng et al., 2013; Marler et al., 2014) which, in addition to the regulation of Tau expression, also plays important roles in synaptic plasticity (Ryan et al., 2015). The link between miR-132 and BDNF explains why in AD and other neurodegenerative disorders both miR-132 and BDNF are reduced.

The Release and Production of BDNF

During synaptic transmission, the Ca2+ influx through voltage-gated calcium channels at the presynaptic axon terminal triggers the release of neurotransmitters stored in synaptic vesicles (see this article). Like other neurotransmitters, BDNF is also stored in synaptic vesicles and released by neural activity. However, the Ca2+ influx through voltage-gated calcium channels alone is insufficient to trigger BDNF release. The Ca2+ entry via presynaptic NMDA receptors is also required (Park et al., 2014).

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Figure 11-2. The BDNF-TrkB signaling pathways which induce the production of plasticity-related molecules, including BDNF and miR-132. [Source: Cunha et al., 2010]

The released BDNF may bind with its receptor, tropomyosin-related kinase B (TrkB), located on either presynaptic or postsynaptic membranes. Three main pathways have been elucidated: PLCγ, PI3K and ERK (Figure 11-2). They all lead to the activation of the transcription factor CREB that regulates transcription of genes essential for synaptic plasticity. The PI3K pathway may also activate mTOR for protein translation from mRNA. Transcriptions of both BDNF and miR-132 genes are regulated by CREB (Zheng et al., 2012; Wanet et al., 2012; Yi et al., 2014). Thus, BDNF can stimulate its own production and increase the level of miR-132. After BDNF is produced in the cell body, they are packaged into vesicles and transported to presynapses, not postsynapses (Andreska et al., 2014).

 

Author: Frank Lee
First published: June 16, 2015
Last updated: June 26, 2017