Role of Amyloid-β and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade

Abstract

The "Amyloid Cascade Hypothesis" has dominated the Alzheimer's disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.

Keywords: Amyloid-β peptide; amyloid-β protein precursor; oligomers; synaptic dysfunction; tau.

Fig. 1.

Oligomeric tau is present in the CSF of AD patients and healthy individuals. A) Western blot showing total tau levels in CSF samples of healthy individuals (HC) and probable AD patients (higher magnification view of the lower molecular weight bands on the lower part of the panel. Different band intensity is quantified on the right graph (31–38 kDa: p = 0.009, 50–54 kDa: p = 0.003, 74–78 kDa: p = 0.04, 100–104 kDa: p = 0.002 and 120–150 kDa: p = 0.003). CSF specimens from subjects listed in Table 1 were thoroughly mixed, de-identified, and underwent one freeze-thaw cycle before standard aliquoting in 1.5 ml portions in polypropylene screw-cap tubes and storage at −80° C. To verify the oligomerization status of tau, we ran samples on western blots. Immunoreactivity toward total tau was measured in each of the CSF aliquots. Equal amounts of protein (8 μg) were fractionated by Tris-Acetate gradient gels (3–8%) and transferred to nitrocellulose membranes (Millipore). Tau immunoreactivity was detected using anti-total tau polyclonal antibody (1:2000; Epitomics). Immunoblot data were quantified by measuring the band intensity using imaging software (NIH ImageJ). Statistical analyses were performed by ANOVA plus post-hoc multiple comparisons test using Prism (GraphPad) software. B) Immunoreactivity for total tau in samples from probable AD patients reduced with β-mercaptoethanol (βME). βME zeroed the high molecular weight signal revealed by tau antibodies while intensifying the signals in the monomeric range.

Fig. 2.

Different views of Aβ and tau interaction in AD pathogenesis. The Amyloid Cascade Hypothesis has dominated the AD field for several years. This picture describes how it has been updated over time from the beginning (A), to the discovery of genetic mutations involving both Aβ and tau production (B), to a more complex vision recognizing oligomers as the toxic Aβ species (C). Notably, in A-C Aβ acts upstream tau. D) According to our novel vision, both oligomers of Aβ and tau exert a neurotoxic effect mediated by AβPP leading to synaptic and memory dysfunction. AβPP also mediates oligomers entrance into neurons and glial cells, a mechanism probably contributing to the spreading of the disease throughout the brain.