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 and why AD begins in the entorhinal cortex.

miR-132 is Implicated in Neurodegeneration


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.

A number of microRNAs are involved in the regulation of the 4R:3R Tau ratio, including miR-132, miR-124, miR-9, and miR-137 (Smith et al., 2011). Among them, miR-132 is down-regulated in AD (Cogswell et al., 2008; H├ębert et al., 2013; Lau et al., 2013), as well as other 4R tauopathies such as progressive supranuclear palsy (Smith et al., 2011) and Huntington's disease (HD) (Johnson and Buckley, 2009). Lower miR-132 level increases the 4R:3R Tau ratio and the total Tau level (Smith et al., 2011). Its down-regulation may result in hyperexcitability (see Chapter 10).

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.

Why AD Begins in Entorhinal Cortex


Figure 11-2. Transient reduction of miR-132 after LTP induction. The miR-132 level is reduced at 20 minutes, but recovers in 5 hours. [Source: Joilin et al., 2014]

The entorhinal cortex (EC) and its neighboring hippocampus are crucial for learning and memory. The two regions normally contain abundant miR-132 and BDNF. In the absence of neuronal activity, miR-132 is responsible for suppressing the expression of the proteins involved in synaptic plasticity. Upon induction of long term potentiation (LTP), miR-132 is down-regulated, allowing expression of plasticity-related molecules (Joilin et al., 2014). The miR-132 level recovers about 5 hours after LTP induction (Figure 11-2). This recovery may result from BDNF stimulation, which also induces the production of other plasticity-related molecules during the late-phase LTP (Figure 11-3).


Figure 11-3. The BDNF-TrkB signaling pathways which induce the production of plasticity-related molecules, including BDNF and miR-132. [Source: Cunha et al., 2010]

LTP may occur in several different brain areas. The above results were observed at the perforant path synapses which are the most heavily engaged with LTP. The perforant path lies between EC and hippocampus. It comprises the axons that extend from EC. In the above experiments, the perforant path synapse is formed between the EC axon (presynaptic) and the granule cell (postsynaptic) in the dentate gyrus of the hippocampus. LTP causes miR-132 reduction in the granule cells. Although this reduction is normally temporary, could neurodegeneration arises from the low level of BDNF that fails to induce full recovery of miR-132? If this is the case, why AD begins in the entorhinal cortex, rather than hippocampus?

After BDNF is produced in the cell body, they are packaged into vesicles and transported to presynapses, not postsynapses (Andreska et al., 2014). The presynaptic BDNF release from the vesicles promotes LTP (Jia et al., 2010; Park et al., 2014). Hence, BDNF is consumed in the presynaptic neuron during LTP. For the perforant path synapses, this implies that the BDNF level in EC could be reduced by LTP. On the other hand, the BDNF released into the synaptic cleft may stimulate its own production (Zheng and Wang , 2009; Cunha et al., 2010) in both presynaptic and postsynaptic neurons because the BDNF receptor, TrkB, is present in both presynaptic and postsynaptic membranes. AD begins when the supply of BDNF cannot meet demand.

In EC, the miR-132 level will decrease with BDNF, resulting in hyperexcitability of the EC cells that contain the perforant path fibers. This pathogenic mechanism is consistent with the observation that alterations in myelination patterns at the perforant path precede the appearance of amyloid plaque and neurofibrillary tangles (Desai et al., 2009).


Author: Frank Lee
First published: June 16, 2015
Last updated: July 20, 2015