|Alzheimer > 11. BDNF Deficiency Down-regulates miR-132|
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 has been shown to associate with neurodegenerative disorders, including Alzheimer's disease (AD) (Yasutake et al., 2006; Jiao et al., 2016), Parkinson's disease (PD) (Howells et al., 2000), amyotrophic lateral sclerosis (ALS) (He et al., 2013), Huntington's disease (HD) (Zuccato and Cattaneo, 2007) and frontotemporal dementia (FTD) (Ventriglia et al., 2013; Zanardini et al., 2016). In cognitively normal adults, the level of BDNF decreases with age (Li et al., 2009). This may explain why age is a risk factor for neurodegeneration.
This chapter will discuss how BDNF deficiency may lead to various diseases. It will be shown that the microRNA, miR-132 (Chapter 10), plays a crucial role in differentiating pathologies that characterize distinct disorders: Tau pathology is associated with tauopathy; α-synuclein pathology with PD; TDP-43 pathology with ALS and Tau-negative FTD.
miR-132 Is Down-regulated in Tauopathy
Tauopathy is a class of diseases that exhibit Tau pathology (Tau hyperphosphorylation and neurofibrillary tangles). As discussed in previous chapters, miR-132 deficiency may increase total and 4R-Tau level, thereby promoting tauopathy. Indeed, miR-132 is down-regulated in various tauopathies, including AD (Lau et al., 2013; El Fatimy et al., 2018), progressive supranuclear palsy (PSP) (Smith et al., 2011), HD (Johnson and Buckley, 2009; Lee et al., 2011; Fukuoka et al., 2018) and Tau-positive FTD (Hébert et al., 2013).
miR-132 is also down-regulated in Tau-negative FTD (FTLD-TDP) and ALS that exhibit TDP-43 pathology (Chen-Plotkin et al., 2012; Freischmidt et al., 2013). It has been shown that miR-132 regulates not only the expression of Tau protein, but also TMEM106B (Chen-Plotkin et al., 2012), which is implicated in both FTLD-TDP and ALS (Vass et al., 2011). miR-132 deficiency leads to TMEM106B upregulation, thereby resulting in TDP-43 pathology, possibly through impaired TDP-43 clearance (Nicholson and Rademakers, 2016).
miR-132 is up-regulated in PD (Lungu et al., 2013), which exhibits little Tau pathology compared to PSP (Schonhaut et al., 2017). Instead, PD is characterized by Lewy Bodies comprising phosphorylated α-synuclein at serine-129 (S129) (Sato et al., 2011; Oueslati, 2016). GSK-3β has been shown to phosphorylate α-synuclein at S129 (Credle et al., 2015). This demonstrates the importance of GSK-3β in PD (see Appendix C). The next section will show that the BDNF-induced signaling pathways can inhibit GSK-3β activity and enhance miR-132 expression. Thus, BDNF deficiency would augment GSK-3β activity to exacerbate PD or down-regulate miR-132 to aggravate other neurodegenerative disorders.
BDNF Signaling Pathways
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. 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).
The released BDNF may bind to its receptor, tropomyosin-related kinase B (TrkB), located on either presynaptic or postsynaptic membranes. Three main pathways have been elucidated: PLCγ, PI3K and Ras (Cunha et al., 2010). They all lead to the activation of the transcription factor CREB (Figure 11-1) that regulates transcription of a variety of genes, including miR-132 and BDNF itself (Wanet et al., 2012; Yi et al., 2014; Zheng et al., 2012). Thus, BDNF can stimulate its own production and increase the level of miR-132. The PI3K pathway may also activate mechanistic target of rapamycin (mTOR) whose principal function is translation of mRNA into a protein. mTOR activation has been shown to increase Tau protein level (Caccamo et al., 2013; Tang et al., 2013; Tang et al., 2015). Therefore, the BDNF/PI3K/mTOR pathway can increase Tau level which, as discussed in Chapter 7, may lead to Tau pathology. Then, how can BDNF deficiency increases the risk of tauopathy?
Beneficial Effects of miR-132
It has been suggested that BDNF could exert its beneficial effects via up-regulation of miR-132 (Numakawa et al., 2011). A microRNA may inhibit the expression of its target mRNA either by promoting mRNA degradation or by repressing protein translation (Chapter 10). miR-132 has been shown to reduce the total Tau protein level by targeting Tau mRNA and decrease 4R-Tau by targeting a splicing factor, PTBP2 (Chapter 10). Therefore, upregulation of miR-132 by BDNF can reduce the risk of Tau pathology. As mentioned above, miR-132 can also reduce the expression of TMEM106B, which is involved in the clearance of TDP-43. Hence, miR-132 upregulation can also mitigate TDP-43 pathology.
It is important to note that expression of the Tau gene (MAPT) is regulated by the transcription factors SP1 and AP2, not CREB (Caillet-Boudin et al., 2015). If the Tau gene were transcribed by CREB, BDNF would also increase Tau mRNA. This would negate the beneficial effects of BDNF via up-regulation of miR-132.
Author: Frank Lee