Re-Arranging the Puzzle between the Amyloid-Beta and Tau Pathology: An APP-Centric Approach

Abstract

After several years of research in the field of Alzheimer's disease (AD), it is still unclear how amyloid-beta (Aβ) and Tau, two key hallmarks of the disease, mediate the neuropathogenic events that lead to AD. Current data challenge the "Amyloid Cascade Hypothesis" that has prevailed in the field of AD, stating that Aβ precedes and triggers Tau pathology that will eventually become the toxic entity in the progression of the disease. This perspective also led the field of therapeutic approaches towards the development of strategies that target Aβ or Tau. In the present review, we discuss recent literature regarding the neurotoxic role of both Aβ and Tau in AD, as well as their physiological function in the healthy brain. Consequently, we present studies suggesting that Aβ and Tau act independently of each other in mediating neurotoxicity in AD, thereafter, re-evaluating the "Amyloid Cascade Hypothesis" that places Tau pathology downstream of Aβ. More recent studies have confirmed that both Aβ and Tau could propagate the disease and induce synaptic and memory impairments via the amyloid precursor protein (APP). This finding is not only interesting from a mechanistic point of view since it provides better insights into the AD pathogenesis but also from a therapeutic point of view since it renders APP a common downstream effector for both Aβ and Tau. Subsequently, therapeutic strategies that act on APP might provide a more viable and physiologically relevant approach for targeting AD.

Keywords: Tau; amyloid cascade hypothesis; amyloid-beta; amyloid-precursor protein.

Figure 1

A revised view of the relationship between APP, Aβ, and Tau. Based on the “Amyloid Cascade Hypothesis”, amyloid-beta (Aβ) peptides generated after cleavage of the amyloid precursor protein (APP) by β-secretase-1 (BACE-1) are the main toxic species in Alzheimer’s disease (AD). Based on this original view regarding the pathogenesis of AD, Aβ peptides will trigger Tau pathology, leading to the progression of the disease due to neuronal loss, plasticity, and memory deficits. This view was updated after the discovery that oligomeric Aβ (oAβ) and oligomeric Tau (oTau) are responsible for the neurotoxicity in AD, rather than their insoluble deposits referred to as amyloid plaques and neurofibrillary tangles (NFTs), respectively. Nevertheless, more recent findings challenge this hypothesis and suggest that the pathogenesis of oAβ and oTau occurs independently and not in sequence as was suggested by the “Amyloid Cascade Hypothesis”. Specifically, our revised hypothesis proposes that oAβ and oTau act in parallel and via APP to induce plasticity and memory deficits. Both oAβ and oTau bind to APP, and their expression is important for the intraneuronal uptake of both peptides, rendering APP a common target for both oAβ and oTau.