"Don't Phos Over Tau": recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer's disease and other tauopathies

Abstract

Phosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer's disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.

Keywords: Alzheimer’s disease; Cerebrospinal fluid; Frontotemporal lobar degeneration; Kinase inhibitor; Phosphatase activator; Plasma; Tau immunotherapy; Tau phosphorylation; Tauopathy.

Fig. 1

Schematic showing 2N4R tau (441 amino acids), the longest isoform expressed in human brain. Tau protein contains major structural domains including N-terminal domain with N1 and N2 inserts, proline rich region, four major microtubule-binding repeats (R1-R4), and C-terminal domain. The N1, N2 and R2 regions can be alternatively spliced in the human brain resulting in 6 isoforms: 0N3R, 1N3R, 2N3R, 0N4R, 1N4R, and 2N4R. The position of identified phosphorylation sites found in AD brains are shown [–5]

Fig. 2

Tau pathological inclusions associated with neurodegenerative diseases stained with antibodies specific for p-tau. Neurofibrillary tangles (A) and neuritic plaques (B) in AD stained with antibody AT8 that reacts with tau phosphorylated at Ser202 and Thr205. Tufted astrocytes (C) in PSP stained with antibody AT8. Antibody 3G12 specific for tau phosphorylated at Ser208 depicts neurofibrillary tangles (D) and neuritic plaques (E, asterisks) in AD. Astrocytic plaques (F) in CBD stained with antibody AT8. Scale bar = 60 μm

Fig. 3

Summary of therapies targeting p-tau. A Kinase inhibitors such as Tideglusib, lithium, valproate and nilotinib act to prevent hyperphosphorylation. Phosphatase activators such as sodium selenate increases dephosphorylation activity. B Passive p-tau immunotherapy are specific antibodies that target p-tau epitopes for degradation. Active p-tau immunotherapy involves immunization with a p-tau peptide to generate antibodies. Figure was made with Biorender