Alzheimer  >   12. The BDNF Cascade Hypothesis of Alzheimer's Disease

Based on the evidence presented in previous chapters, a pathogenic cascade for Alzheimer's disease (AD) is emerging. That is, the age-dependent BDNF deficiency will cause miR-132 down-regulation (Chapter 11), leading to elevated total and 4R Tau protein (Chapter 10), and consequently resulting in Tau pathology (Chapter 6 and Chapter 9). This model will be referred to as "BDNF Cascade Hypothesis" (Figure 12-1). Further evidence is provided in this chapter.


Figure 12-1. The BDNF Cascade Hypothesis for Alzheimer's disease. See text for details.

BDNF Deficiency

In addition to aging (Li et al., 2009), glucocorticoid elevation (Suri and Vaidya, 2013; Wosiski-Kuhn et al., 2014), estrogen deficiency (Carbone and Handa, 2013) and melatonin deficiency (Imbesi et al., 2008; Zhang et al., 2013; Rudnitskaya et al., 2015) may also reduce BDNF level. The glucocorticoid level increases under psychological stress, which is a risk factor for AD via Tau hyperphosphorylation (Rissman, 2009; Sotiropoulos et al., 2011; Sotiropoulos and Sousa, 2015).

APP/PS Overexpression

In familial AD, one of three genes is mutated: APP, PSEN1 and PSEN2, encoding amyloid precursor protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2), respectively. In the past several decades, thousands of experimental studies have been using transgenic mice overexpressing mutant APP/PS to investigate the pathogenesis of AD. The results appeared to support the Amyloid Cascade Hypothesis. However, the APP/PS overexpression has been shown to up-regulates a microRNA, miR-342-5p, which in turn down-regulates the expression of Ankyrin-G (Sun et al., 2014). Injection of Ankyrin-G into the APP transgenic mice reduces β-amyloid pathology (Santuccione et al., 2013). Therefore, the pathology observed in the APP/PS transgenic mice could arise from down-regulation of Ankyrin-G leading to hyperexcitability (Chapter 8).

mTOR and Hyperexcitability

Upon activation, the mechanistic target of rapamycin (mTOR) stimulates the synthesis of a variety of proteins, including Tau (Caccamo et al., 2013; Tang et al., 2013; Tang et al., 2015). Compelling evidence indicates that excessive Tau expression can cause hyperexcitability (Chapter 7). Therefore, hyperactive mTOR can result in hyperexcitability. This novel mechanism is now well documented (see this article). While hyperexcitability could arise from alteration at synapses, the hyperactive mTOR does not necessarily lead to changes in synaptic transmission (Lasarge and Danzer, 2014; Wang et al., 2015). Furthermore, rapamycin (a potent mTOR inhibitor) ameliorates Tau pathology (Caccamo et al., 2013; Ozcelik et al., 2013; Kolosova et al., 2013), suggesting that the mTOR-induced hyperexcitability plays an important role in Tau pathology.

mTOR can be activated by a diverse range of signals: glucose (Blagosklonny, 2013), cytokines (Lee et al., 2007), protein misfolding (Qian et al., 2010), etc. mTOR could be the ultimate risk factor for most human diseases (see Appendix D). Diabetes (excess glucose), inflammation (aberrant cytokine activation) and vitamin D deficiency are known to be the risk factors for AD. They all converge to the activation of mTOR.

Hyperexcitability and Ca2+ Overload

Hyperexcitability may result in excessive Ca2+ entry into the neuron through various Ca2+-permeable channels such as NMDA receptors at synapses and T-type calcium channels at the axon initial segment (AIS) (Debanne et al., 2011). The Ca2+ overload can damage neurons via three major pathways.

  1. Calpain activation. Ca2+ may activate calpain which regulates two important kinases involved in Tau phosphorylation, GSK-3β and Cdk5 (Chapter 7). Hyperactive GSK-3β can exert deleterious effects on axonal transport, neurite outgrowth, long-range coupling and neuronal excitability by phosphorylating various targets (see this article).
  2. Oxidative stress. The reciprocal interactions between Ca2+-induced reactive oxygen species (ROS) and ROS-modulated Ca2+ upsurge may aggravate oxidative stress (Peng and Jou, 2010; Görlach et al., 2015), which has been demonstrated to promote the production of Aβ (Zhao and Zhao, 2013; Arimon et al., 2015). Therefore, the Aβ pathology is likely to be one of many consequences of BDNF deficiency. Further details are discussed in the next chapter.
  3. Caspase activation. Severe Ca2+ overload may activate caspases, resulting in apoptosis (Pinton et al., 2008).


Author: Frank Lee
First published: May 23, 2015
Last updated: July 22, 2019