Geon 13. Therapeutic Strategies Alzheimer

On the basis of the pathogenesis proposed in Chapter 12, therapeutic strategies for Alzheimer's disease (AD) may target BDNF, miR-132 or mTOR.

Pros and Cons of BDNF

BDNF has been suggested for the treatment of AD and other neurological disorders (Nagahara and Tuszynski, 2011). Early BDNF treatment by gene delivery was shown to ameliorates cell loss in the entorhinal cortex of APP transgenic mice (Nagahara et al., 2013). However, therapeutic delivery of recombinant human BDNF to affected neurons faces several challenges such as short in vivo half-life, low permeability through the blood-brain barrier and high manufacturing costs (Géral et al., 2013). More importantly, BDNF may activate mTOR (Chapter 11, Figure 11-3), which could be the "ultimate risk factor" for most human diseases (Appendix D). While BDNF is essential for neuronal development and synaptic plasticity, it may cause several types of cancer (Lam et al., 2011; Yang et al., 2013; Okugawa et al., 2013).

Pros and Cons of miR-132

A growing body of evidence suggests that BDNF exerts its beneficial effects via up-regulation of the microRNA, miR-132 (Numakawa et al., 2011; Zheng et al., 2013; Marler et al., 2014), which may repress Tau expression (Smith et al., 2011; Smith et al., 2015), even when mTOR activity is increased by BDNF. Hence, miR-132 could be a promising target. Recently, exosomes have emerged as a powerful drug delivery system (Alvarez-Erviti et al., 2011; Kalani et al., 2014). Exosomes are the smallest naturally-occurring membranous vesicles, involved in cell-to-cell communication (Cervio et al., 2015). They may carry a variety of proteins, lipids, non-coding RNAs, mRNA, and microRNA. For drug delivery, their membrane can be modified to enhance tissue-specific targeting. Since exosomes are produced in natural biological systems, immunogenicity is low. Furthermore, exosomes can cross the blood-brain barrier (El Andaloussi et al., 2013).

In contrast to BDNF, miR-132 serves as a tumor suppressor (Zhang et al., 2014; Wang et al., 2014; Liu et al., 2015; Jiang et al., 2015). However, miR-132 could inhibit autophagy (a degradation pathway for removing dysfunctional cellular components), thereby promoting pathological cardiac hypertrophy (Ucar et al., 2012).

Pros of Physical Exercise

The easiest way to produce BDNF is exercise (Coelho et al., 2014). During exercise, the speed of blood flow increases, producing greater shear stress on the wall of blood vessels. This in turn activates polycystin-2 (a mechanosensitive calcium channel) in the cilia of vascular endothelial cells which form the linings of the blood vessels (AbouAlaiwi et al., 2009). Ca2+ entry into the endothelial cells through polycystin-2 may stimulate the production of nitric oxide (NO), which is a hydrophobic molecule, capable of passing through the cell membrane and diffusing to other cells. NO up-regulates BDNF in target cells (Chen et al., 2005), possibly via the NO/sGC/cGMP pathway (Chalimoniuk et al., 2015; Furini et al., 2010).

BDNF can activate mTOR. The exercise-induced mTOR activation is helpful for building stronger muscles. However, hyperactive mTOR has three major detrimental effects (Appendix D): (1) over-production of Tau proteins (leading to hyperexcitability), (2) inhibition of autophagy (resulting in accumulation of dysfunctional cellular components), and (3) augment of proliferation and suppression of apoptosis (promoting tumor growth). In the brain, BDNF elevation usually up-regulates miR-132 which may translocate to other parts of the body through bloodstream or exosomes. As discussed above, miR-132 can suppress Tau production and tumor growth, but exacerbate autophagy inhibition. Fortunately, physical exercise can enhance autophagy by counteracting the inhibitory effect of mTOR activation (Medina et al., 2015).

The Beneficial Actions of Melatonin

Melatonin is a powerful antioxidant. It can also exert beneficial effects by acting on its receptors: MT1 and MT2 (Jenwitheesuk et al., 2014). The major benefits of this magnificent hormone are highlighted below.

  • Melatonin increases BDNF production (Imbesi et al., 2008; Zhang et al., 2013; Rudnitskaya et al., 2015).
  • Melatonin suppresses NF-κB activation, thereby attenuating inflammation (Negi et al., 2011).
  • Melatonin is a "smart" modulator of sirtuins (e.g. SIRT1): it increases sirtuin activities in normal cells via its antioxidant property (Ramis et al., 2015), but reduces sirtuin expression level in cancer cells (Bizzarri et al., 2013). Sirtuins are histone deacetylases (HDACs) that catalyze histone deacetylation (removal of an acetyl group). They can also deacetylate other proteins, particularly p53 which plays a crucial role in carcinogenesis. Acetylation is indispensable for p53 activation (Tang et al., 2008). Activated sirtuins may promote expression of autophagy regulatory proteins (e.g. Atg proteins) to enhance autophagic degradation of dysfunctional cellular components (Salminen and Kaarniranta, 2009). In cancer cells, melatonin treatment decreases SIRT1 level and up-regulates acetylated-p53 to inhibit tumor growth (Cheng et al., 2013; Proietti et al., 2014).

The increase of BDNF by melatonin is mediated by its receptors, rather than its antioxidant property (Imbesi et al., 2008). The novel antidepressant, agomelatine, acts on both melatonin and 5-HT2C receptors. Administration of agomelatine also significantly increases the BDNF level (Soumier et al., 2009; Calabrese et al., 2011; Gumuslu et al., 2014).

mTOR Inhibitors

The following is a list of mTOR inhibitors that do not need prescription.

BDNF and miR-132 As Biomarkers

Biomarkers are useful for the diagnosis of diseases, especially if they are available in the blood. BDNF can cross the blood-brain barrier and enter the bloodstream (Pan et al., 1998). In AD patients, the serum BDNF level decreases (Yasutake et al., 2006). However, for individuals with mild cognitive impairment (MCI), the serum miR-132 level is significantly elevated (Xie et al., 2015), which appears to contradict with other reports that miR-132 expression in neurons decreases in AD patients (Hébert et al., 2013; Lau et al., 2013).

In the absence of neuronal activity, miR-132 is responsible for suppressing the expression of plasticity-related proteins by binding with their mRNAs. These bound miR-132 molecules are not present in the blood. The neuronal activity may somehow cause miR-132 to dissociate from mRNA, allowing the expression of plasticity-related proteins. The free miR-132 could then enter the bloodstream. As mentioned in Chapter 12, hyperexcitability is an early sign of AD. Hence, at the early stage of AD, the miR-132 level in the blood could be elevated even though its expression level in neurons is reduced.

 

Author: Frank Lee
First published: May 23, 2015
Last updated: October 13, 2015