Geon 12. The Pathogenesis of Alzheimer's Disease Alzheimer

Figure 12-1. The proposed pathogenic cascade for Alzheimer's disease. See text for details.

The pathogenic cascade for Alzheimer's disease (AD) is summarized in Figure 12-1. Each step is discussed below.

BDNF Deficiency

During long term potentiation (LTP), brain-derived neurotrophic factor (BDNF) is released from presynapses, not postsynapses (Andreska et al., 2014; Jia et al., 2010; Park et al., 2014). Therefore, LTP consumes BDNF stored in presynapses. BDNF will decrease if its production cannot meet demand. AD begins in entorhinal cortex because it contains the presynaptic neurons of the perforant path synapses which are heavily engaged with LTP. Further details are explained in Chapter 11.

In addition to LTP, 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).

miR-132 Deficiency

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). BDNF deficiency also results in miR-132 deficiency, as observed in AD brains (Cogswell et al., 2008; Hébert et al., 2013). Further studies suggest that miR-132 plays a rather upstream role in the pathogenic cascade for AD (Lau et al., 2013).

miR-132 is essential for the regulation of Tau expression. Reduction of miR-132 increases the total Tau level, especially the 4-repeat (4R) Tau (Smith et al., 2011; Smith et al., 2015), which can cause hyperexcitability by interfering with the binding between microtubules and Ankyrin-G (Chapter 9 and Chapter 10). In animal models, Tau reduction or knockout has been demonstrated to attenuate hyperexcitability (Holth et al., 2013; DeVos et al., 2013; Li et al., 2014).

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 9), rather than the mutant APP/PS.

mTOR and Hyperexcitability

The mechanistic (or mammalian) target of rapamycin (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. Upon activation, mTOR promotes the synthesis of a variety of proteins, including Tau (Caccamo et al., 2013; Tang et al., 2013; Tang et al., 2015). As described above, Tau elevation may cause hyperexcitability. Therefore, hyperactive mTOR can result in hyperexcitability. This novel mechanism is now well documented (see Epilepsy and mTOR). 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 could be the ultimate risk factor for most human diseases. Diabetes, inflammation and vitamin D deficiency are known to be the risk factors for AD. They all converge to the activation of mTOR (see Appendix D).

Hyperexcitability and Ca2+ Overload

Hyperexcitability is an early sign of AD (Dickerson et al., 2005; Putcha et al., 2011). It is likely to be the primary cause of toxicity since injection of Aβ oligomers into APP/PS1 transgenic mice suppresses axonal transport defects (Stokin et al., 2008), rather than increases as the Amyloid Cascade Hypothesis would predict. The APP/PS1 transgenic mice exhibit hyperexcitability (Chapter 7) whereas Aβ injection reduces excitability through AMPAR endocytosis, or more severely, synapse loss (Chapter 6).

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 two different pathways.

  1. Mitochondrial dysfunction. Ca2+ may enter mitochondria, resulting in oxidative stress (Peng and Jou, 2010), which is toxic to the neuron.
  2. Calpain activation. Ca2+ may activate calpain which regulates two major kinases involved in Tau phosphorylation (see below).

Calpain and Tau Hyperphosphorylation


Figure 12-2. The role of calpain in Tau hyperphosphorylation. GSK-3β and Cdk5 are two major protein kinases that can phosphorylate multiple sites on the Tau protein. (A) Calpain may activate GSK-3β by removing its inhibitory domain. (B) Calpain may convert normal Cdk5 activity into pathological Cdk5 hyperactivity by cleaving p35 to p25.

Calpain is a Ca2+-dependent protease that cleaves proteins (Ferreira, 2012). Activation of calpain by high Ca2+ concentration may act on a variety of proteins, including GSK-3β and p35 (Figure 12-2). GSK-3β has the capability to phosphorylate multiple sites on the Tau protein. It can be activated by calpain through removal of its inhibitory domain (Goñi-Oliver et al., 2007). The mTOR-induced Tau hyperphosphorylation involves GSK-3β (Caccamo et al., 2013).

The cyclin dependent kinase 5 (Cdk5) plays multiple roles in neuron development, neuronal survival, phosphorylation of cytoskeletal proteins and synaptic plasticity. The kinase is normally activated by the protein p35 or p39. High Ca2+ concentration activates calpain which cleaves p35 to p25, forming a more stable yet hyperactive Cdk5/p25 complex (Shukla et al., 2011). Kinase is a type of enzyme that catalyzes protein phosphorylation. Cdk5 may target the Tau protein, resulting in Tau hyperphosphorylation (Kimura et al., 2014). On the other hand, the Cdk5/p25 complex can also phosphorylate STAT3 (signal transducer and activator of transcription 3), promoting the expression of BACE1 (Wen et al., 2008), which is the β-secretase involved in the production of beta amyloid (Aβ) peptides (Chapter 4).

Toxicity Triggered by Tau Hyperphosphorylation

Microtubules are highly negatively charged. Phosphorylation is a process that adds a negatively charged phosphate group (PO43−) to a protein. Hence, hyperphosphorylation will reduce Tau's binding affinity and cause Tau to dissociate from the microtubule. The free hyperphosphorylated Tau may misfold (Luna-Muñoz et al., 2007), promoting mTOR activation. Furthermore, the dissociation of Tau may result in microtubule disassembly, disrupting microtubule transport of important molecules and eventually leading to neuronal death.

The free hyperphosphorylated Tau can also pass the AIS barrier (Li et al., 2011) and migrate to dendrites where they may trigger microtubule severing by TTLL6 and spastin (Zempel et al., 2013). Without intact microtubules to transport necessary components, synapses will be lost.

Beta Amyloid and Oxidative Stress

Numerous studies have suggested that oxidative stress promotes the production of beta amyloid (Aβ) (Zhao and Zhao, 2013; Arimon et al., 2015), which may contribute to spine loss as discussed in Chapter 6. In addition to oxidative level, Aβ production also depends on the constitutive expression of associated proteins (amyloid precursor protein, β and γ secretase) which, as suggested from the findings in aged monkeys (Heuer et al., 2012), could be the highest in neocortex and lower in allocortex (including entorhinal cortex and hippocampus). Thus, in AD, Aβ deposits appear first (Phase 1) in neocortex when the oxidative levels at both neocortex and allocortex are still mild. Only when the allocortex is under severer oxidative stress (Phase 2) can Aβ deposits be observed in this brain region (Thal et al., 2002).

Although Aβ may accelerate pathology progression by causing spine loss, mounting evidence indicates that AD is not initiated by Aβ.

  1. AD begins in entorhinal cortex but Aβ deposits appear first in neocortex (Thal et al., 2002).
  2. To date, all AD clinical trials based on Aβ as a therapeutic target have failed.
  3. In a transgenic animal model, alterations in myelination patterns at the perforant path precede the appearance of amyloid plaque and neurofibrillary tangles (Desai et al., 2009).
  4. Neuroprotective effects of BDNF in rodent and primate models of AD are independent of Aβ (Nagahara et al., 2009; Nagahara et al., 2013).
  5. In the accelerated-senescence nontransgenic rats, called OXYS rats, Aβ deposits occur later than synapse loss, neuronal death, mitochondrial abnormalities, and Tau hyperphosphorylation (Stefanova et al., 2015).


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