The importance of tau phosphorylation for neurodegenerative diseases

Abstract

Fibrillar deposits of highly phosphorylated tau are a key pathological feature of several neurodegenerative tauopathies including Alzheimer's disease (AD) and some frontotemporal dementias. Increasing evidence suggests that the presence of these end-stage neurofibrillary lesions do not cause neuronal loss, but rather that alterations to soluble tau proteins induce neurodegeneration. In particular, aberrant tau phosphorylation is acknowledged to be a key disease process, influencing tau structure, distribution, and function in neurons. Although typically described as a cytosolic protein that associates with microtubules and regulates axonal transport, several additional functions of tau have recently been demonstrated, including roles in DNA stabilization, and synaptic function. Most recently, studies examining the trans-synaptic spread of tau pathology in disease models have suggested a potential role for extracellular tau in cell signaling pathways intrinsic to neurodegeneration. Here we review the evidence showing that tau phosphorylation plays a key role in neurodegenerative tauopathies. We also comment on the tractability of altering phosphorylation-dependent tau functions for therapeutic intervention in AD and related disorders.

Keywords: Alzheimer’s disease; extracellular; function; oligomers; phosphorylation; tau.

Figure 1

The human tau gene and six protein isoforms. (A) The six isoforms of human CNS tau. Exons 2 and 3 (E2 and E3) encode two different inserts of 28 amino acids near the N-terminus of tau. Absence of E2 and E3 gives rise to 0N tau isoforms, whereas inclusion of E2 produces 1N and inclusion of both E2 and E3 results in 2N tau isoforms. M1–M4 represent the four imperfect-repeat microtubule-binding domains, M2 being encoded by exon 10. Lack of M2 results in the formation of 3R tau and M2 inclusion results in 4R tau isoforms. The proline-rich domain in the center of the tau polypeptide is indicated. Alternative-splicing produces tau isoforms of 352–441 amino acids, as indicated. (B) Positioning of phosphorylation sites on tau from Alzheimer brain. Approximately 45 phosphorylation sites have been identified, these are found predominantly in the proline-rich domain and the regions flanking the microtubule-binding domain.

Figure 2

The impact of phosphorylation on tau functions in different cell locations. The figure shows the functions of tau in different cellular compartments that are influenced by tau phosphorylation, and that likely contribute to the development or progression of neurodegenerative tauopathies.