Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Abstract

Recent investigations into the etiology and pathogenesis of Alzheimer's disease (AD) in the past few years have expanded to include previously unexplored and/or disconnected aspects of AD and related conditions at both the cellular and systemic levels of organization. These include how AD-associated abnormalities affect the cell cycle and neuronal differentiation state and how they recruit signal transduction, membrane trafficking and protein transcytosis mechanisms to produce a neurotoxic syndrome capable of spreading itself throughout the brain. The recent expansion of AD research into intercellular and new aspects of cellular degenerative mechanisms is causing a systemic re-evaluation of AD pathogenesis, including the roles played by well-studied elements, such as the generation of Aβ and tau protein aggregates. It is also changing our view of neurodegenerative diseases as a whole. Here we propose a conceptual framework to account for some of the emerging aspects of the role of tau in AD pathogenesis.

Monoaminergic neuropathology in Alzheimer’s disease

“…This finding strengthens cytoskeletal abnormalities as a possible pivotal mechanism in neurodegeneration in AD (Terry, 1996; Šimić et al, 1998a), and positioned AD as the most important secondary tauopathy (as the tau-coding MAPT geneitself is not mutated), while mutations in the MAPT gene subsequently identified into a new group of diseases now called primary tauopathies. In the years to follow, both in vitro and in vivo studies have shown that reducing endogeneous tau ameliorates Aβ-induced deficits (Roberson et al, 2007; Bhatia and Hall, 2013; for review see Wang and Mandelkow, 2016), which provided compelling evidence that tau is sufficient and necessary for Aβ-induced neurodegeneration.…”

Tangles, Toxicity, and Tau Secretion in AD – New Approaches to a Vexing Problem

“…These include the appearance of cell cycle markers (64) and ectopically sprouting axonlike processes (NTs) emerging from the dendrites (45, 65–67) during the development of neurofibrillary lesions in neurodegenerative tauopathies. Dendritic NTs in particular suggest that tau functions in the development of axonal identity may play a role in the early stages of AD where they may reflect damage to mechanisms that maintain the terminally differentiated neuronal state (68, 69). The “fetal” (3R0N) tau isoform is the shortest three repeat tau isoform with the lowest binding affinity for MTs (30), possibly reflecting the far greater importance of tau N-terminal interactions and functions during development relative to the role tau plays in the mature CNS.…”

“…Overexpression of tau in culture causes cells to secrete exosomes containing tau that has been phosphorylated at several proline-directed sites (106), possibly as a protective response to high concentrations of membrane-associated tau (206). Overall, it appears that tau may be secreted via multiple mechanisms from neurons in tauopathy, including microvesicle shedding, exosomal secretion via endocytosis and fusion with multivesicular bodies, and exophagy, a pathway involving the diversion of autophagosomes to exosomes (69, 81, 134, 207). Uptake mechanisms into trans-synaptic and adjacent cells have been characterized in even less detail that have tau secretion pathways.…”

“…The key element in this hypothesis is an endocytosis-associated mechanism that depends on tau-fyn interaction, induces tau oligomerization and is potentiated by both the activity of excitotoxicity-prone synapses and the progressive failure of tau to segregate normally to the axon in tauopathy pathogenesis, which increases the exposure of dendritic elements to tau, thereby amplifying perisynaptic tau toxicity [Ref. (69), also see Figure 2F]. The potential importance of changes in neuronal differentiation state to tau toxicity was recently underscored by a study of changes in gene regulation in two separate cohorts of early onset AD patients (237).…”

Epigenetic dysregulation of brainstem nuclei in the pathogenesis of Alzheimer’s disease: looking in the correct place at the right time?

“…From a genetic perspective AD can be classified into two subtypes, familial or sporadic, and while the symptomatology and the progression of both forms are comparable, the etiology is fundamentally different [12]. Familial AD accounts for only 5–10 % of the disease cases and is related to the existence of genetic mutations in specific genes, such as those encoding amyloid precursor protein ( APP ) and presenilin ( PSEN ) 1 ( PSEN1 ) and PSEN2 [13–20], which are all involved in the production of Aβ.…”