Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease

Abstract

One of the defining pathological features of Alzheimer disease (AD) is the intraneuronal accumulation of tau. The tau that forms these accumulations is altered both posttranslationally and conformationally, and there is now significant evidence that soluble forms of these modified tau species are the toxic entities rather than the insoluble neurofibrillary tangles. However there is still noteworthy debate concerning which specific pathological forms of tau are the contributors to neuronal dysfunction and death in AD. Given that increases in aberrant forms of tau play a role in the neurodegeneration process in AD, there is growing interest in understanding the degradative pathways that remove tau from the cell, and the selectivity of these different pathways for various forms of tau. Indeed, one can speculate that deficits in a pathway that selectively removes certain pathological forms of tau could play a pivotal role in AD. In this review we will discuss the different proteolytic and degradative machineries that may be involved in removing tau from the cell. How deficits in these different degradative pathways may contribute to abnormal accumulation of tau in AD will also be considered. In addition, the issue of the selective targeting of specific tau species to a given degradative pathway for clearance from the cell will be addressed.

Keywords: autophagy; degradation; proteasome; proteolysis; tau.

Figure 1

Proteolytic processing of tau. Under pathological and physiological conditions, tau undergoes cleavage at many distinct proteolytic sites by a myriad of proteases. The action of these proteases can lead to both protection and/or exacerbation of pathology. For example, cleavage of tau by caspase (Casp) 3, caspase-6, calpain (Calp), and thrombin (Thrm) leads to the production of toxic fragments of tau that exacerbate pathology. On the other hand, cleavage of tau by PSA, Htra1, and – in some circumstances – caspase-3, may facilitate its degradation, which may protect neurons from AD-related neuronal death.

Figure 2

Physiological degradation of tau. Tau is degraded by both the proteasome and autophagy systems. Targeting of tau to either system may be determined by the extent and nature of post-translational modifications, the folding state, the level of aggregation, and its interaction with chaperone proteins or ubiquitin ligases. Monomeric tau is natively unfolded making it a likely target for the 20S proteasome. Monomeric tau also interacts with the E3 ligase, CHIP, which can lead to its ubiquitylation and degradation via the 26S proteasome or autophagy. Certain cleavage products and phosphorylated forms of tau, as well as, monoubiquitylated tau and tau aggregates are selectively degraded by autophagy.

Figure 3

Alzheimer disease-related disruption of tau degradation. Impairment of protein degradation is a known component of both familial and sporadic AD. Familial AD-related mutations of PS1 are linked to impairment of lysosomal acidification and/or fusion to the autophagosome, while sporadic factors leading to similar impairments have not yet been elucidated. Impairment of the lysosome/autophagosome leads to accumulation of dysfunctional autophagic vacuoles (AVs), cytosolic p62, and aggregates of tau. Dysfunction of autophagy further inhibits the proteasome, possibly via accumulation of p62, which can be a chaperone for both systems. P62 is usually recycled via autophagy and accumulates in the cytosol when autophagy is impaired. Hypothetically, this allows p62 to compete with other proteasome chaperones thus inhibiting proteasomal degradation. Further, accumulation of aggregated proteins has also been shown to inhibit the proteasome. Taken together, this could lead to accumulation of soluble tau, and thus more proteolytic processing and further aggregate. Hence, a vicious cycle of degradative pathway impairment and tau accumulation/aggregation may contribute to the neurodegenerative processes in AD.