|Alzheimer > 13. Beta Amyloid (Aβ) Pathology|
Amyloid plaques comprising beta amyloid (Aβ) and neurofibrillary tangles (NFTs) composed of Tau protein are the hallmarks of Alzheimer's disease (AD). Over the last three decades, researchers have been debating whether AD originates from Aβ or Tau. The "Amyloid Cascade Hypothesis" postulated that AD was initiated by aggregates of Aβ and thus Aβ should be a good therapeutic target (Hardy and Higgins, 1992). Many drugs were developed on the basis of this hypothesis. Unfortunately, to date, all AD clinical trials based on this idea have failed (Kametani and Hasegawa, 2018). A growing number of studies found that the Tau protein could play a more important role in the pathogenesis of AD (Rapoport et al., 2002; Schönheit et al., 2004; Kametani and Hasegawa, 2018). According to the BDNF Cascade Hypothesis proposed in Chapter 12, Aβ pathology is a consequence of oxidative stress resulting from Ca2+ overload.
Oxidative Stress Stimulates Aβ Production
Numerous studies have demonstrated that oxidative stress promotes the production of Aβ (Zhao and Zhao, 2013; Arimon et al., 2015). In addition to oxidative level, Aβ production also depends on the constitutive expression of relevant proteins (amyloid precursor protein, β and γ secretase) which, as revealed from the studies of 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 severe oxidative stress (Phase 2) can significant Aβ deposits be observed in this brain region (Thal et al., 2002).
Synaptic Targeting of Aβ Oligomers
Aβ oligomers (AβOs) are more toxic than amyloid plaques (Cline et al., 2018). However, they generally do not cause neuronal death, but interfere specifically with synaptic function (Lacor et al., 2004; Nimmrich and Ebert, 2009). A number of AβO receptors have been identified, including cellular prion protein (PrPc), α7 nicotinic acetylcholine receptor, p75 neurotrophin receptor, beta-adrenergic receptors, Eph receptors, paired immunoglobulin-like receptor B and its human ortholog receptor (LilrB2) (Xia et al., 2016). Among them, the AβO/PrPc signaling pathway (Figure 13-1) concurred with the largest body of evidence on AβO toxicity.
The extracellular AβO may bind PrPc to induce metabotropic glutamate receptors 5 (mGluR5) signaling (Um et al., 2012; Um et al., 2013), which leads to increased Ca2+ level in the cytosol (see this article) and subsequently stimulates synergistic coactivation of Fyn (a tyrosine kinase in the Src family) and Pyk2 (Heidinger et al., 2002; Brody and Strittmatter, 2018). Both Fyn and Pyk2 can augment GSK-3β activity by phosphorylating it at tyrosine-216 (Lesort et al., 1999; Hartigan et al., 2001; Brody and Strittmatter, 2018). Hyperactive GSK-3β is detrimental to various cellular processes, including synaptic function (Jaworski et al., 2019). This mechanism resembles the toxicity exerted by extracellular α-synuclein oligomers (see Appendix C). The mechanism agrees with the findings that Aβ toxicity depends largely on
It has been well established that Aβ toxicity also requires the presence of Tau protein (Rapoport et al., 2002; Ittner et al., 2010; Roberson et al., 2011). Tau is normally located in the axon due to the existence of a barrier at the axon initial segment (Li et al., 2011). Hyperphosphorylated Tau may pass the barrier and mislocalize to dendrites where it could augment GSK-3β activity by promoting Fyn/Pyk2 coactivation. In line with this hypothesis, Pyk2 has been demonstrated to associate with hyperphosphorylated Tau, thereby enhancing Fyn/Pyk2 coactivation (Li and Götz, 2018). Tau is also a substrate of Fyn. Thus, Tau may serve as a linker between Pyk2 and Fyn, facilitating their coactivation.
NMDA receptors (NMDARs) were thought to play a role in Aβ toxicity. However, conflicting results have been reported on whether NMDARs are responsible for the Aβ-mediated spine loss (Müller et al., 2018). The next chapter will show that coactivation of Fyn and Pyk2 leads to CRMP2 hyperphosphorylation which could be the major cause of spine loss.
Evidence Against Amyloid Cascade Hypothesis
Aβ oligomers have been shown to reduce BDNF level (Tong et al., 2004; Garzon and Fahnestock, 2007; DaRocha-Souto et al., 2012). Therefore, based on the BDNF Cascade Hypothesis, Aβ oligomers may accelerate AD progression. However, the AβO/BDNF cascade is only one of many pathways that can cause BDNF deficiency. Mounting evidence indicates that AD is not initiated by Aβ aggregates.
Furthermore, Aβ should be able to drive Tau pathology (NFTs) if AD originates from Aβ aggregates (Selkoe and Hardy, 2016). In the past three decades, the Aβ proponents have been trying to demonstrate this prediction experimentally, but all failed by using traditional modeling systems. In 2011, a novel technology, called induced pluripotent stem cell (iPSC), was found to have great potential in modeling AD (Yagi et al., 2011). However, the original iPSC system still failed to recapitulate Tau pathology. In the following years, researchers continued to improve the modeling systems. A 3D cell culture system finally succeeded in producing robust NFTs. Why is 3D cell culture a better system for modeling AD? The answer lies in the 4R-Tau (D'Avanzo et al., 2015):
This finding is in excellent agreement with the BDNF Cascade Hypothesis (Chapter 12), wherein the elevated total and/or 4R-Tau is crucial for the pathogenesis of AD. Strikingly, by studying the expression profile of Tau proteins in different brain regions, it was found that the expression level of 3R-Tau was comparable in the hippocampus, entorhinal cortex (EC), frontal cortex, parietal-temporal cortex, occipital-temporal cortex, striatum, thalamus, olfactory bulb and cerebellum, but the expression level of 4R-Tau was the highest in EC (Hu et al., 2017).
Author: Frank Lee