Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease

Abstract

The so-called amyloid hypothesis, that the accumulation and deposition of oligomeric or fibrillar amyloid β (Aβ) peptide is the primary cause of Alzheimer's disease (AD), has been the mainstream concept underlying AD research for over 20 years. However, all attempts to develop Aβ-targeting drugs to treat AD have ended in failure. Here, we review recent findings indicating that the main factor underlying the development and progression of AD is tau, not Aβ, and we describe the deficiencies of the amyloid hypothesis that have supported the emergence of this idea.

Keywords: APP; Alzheimer's disease; Aβ; PHF; amyloid; tau.

Figure 1

Schematic illustration of the structure and metabolism of APP and its derivatives. Dark blue arrows indicate cleavage sites. α-Secretase (TACE/ADAM) (Buxbaum et al., ; Lammich et al., 1999) cleaves the α-site and β-secretase (BACE1, Vassar et al., 1999) cleaves the β-site, affording N-terminal fragments, sAPPα and sAPP β, and C-terminal fragments, C83 and C99, respectively. C83 and C99 are further cleaved at the γ-sites by γ-secretase complex, which includes presenilin-1, nicastrin, Aph-1 and Pen2 (Capell et al., ; De Strooper et al., ; Yu et al., ; Francis et al., ; Goutte et al., ; Takasugi et al., 2003). AICD and p3/Aβ are produced and released from the membrane. In the normal physiological state, α-secretase cleaves 90% or more of APP and the remaining APP is cleaved by β-secretase. Therefore, the major products in this APP metabolic pathway are sAPPα, C83, p3, and AICD, and Aβ is a minor product. AICD is rapidly degraded (Cupers et al., ; Kopan and Ilagan, ; Kametani and Haga, 2015). Thus, mutations found in familial AD, especially presenilin mutations, may affect the formation and processing of a variety of products. A part of APP sequence including Aβ is shown. Asterisks indicate APP mutations that have been identified in familial AD. These pathogenetic mutations of APP cluster near the α-secretase, β-secretase and γ-secretase cleavage sites. These mutations cause accumulation of APP C-terminal fragments (Tesco et al., ; Wiley et al., ; Xu et al., 2016a), and such accumulation has been found even in sporadic AD brains (Pera et al., 2013). Furthermore, mutations in presenilin, a constitutive protein of the γ-secretase complex, reduce γ-secretase activity (Chen et al., ; Walker et al., ; Bentahir et al., ; Shen and Kelleher, ; Xia et al., 2015). Decrease in the catalytic capacity of γ-secretase, which would lead to an increase of APP C-terminal fragments, facilitates the pathogenesis in sporadic and familial AD (Svedruzic et al., 2015).

Figure 2

Schematic illustration of functional sites of tau. Six tau isoforms are expressed in the adult human brain as a result of mRNA alternative splicing, with or without exons 2, 3, and 10. Exon 10 contains the microtubule-binding region. Insertion of exon 10 affords 4-repeat (4R) tau isoforms, while 3-repeat (3R) tau isoforms are produced without exon 10 (Goedert et al., 1989a). Major tau phosphorylation sites identified in PHF-tau from AD brains are shown. Microtubule binding regions R3 and R4 form the core of tau fibrils (PHF and SF) (Taniguchi-Watanabe et al., ; Fitzpatrick et al., 2017).

Figure 3

Proposed sequence of major pathogenic events leading to AD. Aβ amyloidosis and tau pathology are regarded as independent pathological events. AD is APP trigger tauopathy.