“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.

Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Which Comes First: The Chicken or the Egg?

“…One is β amyloid (Aβ), which accumulates abnormally in AD brain tissues and forms extracellular plaques known to induce synaptic alterations and neurodegeneration [ 5 , 6 ]. The other is Tau protein, which forms intracellular neurofibrillary tangles that are also responsible for neurodegeneration [ 7 , 8 ].…”

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

“…Amyloid-beta plaque, tau neurofibrillary tangle deposition and neuroinflammation are three key pathological features of AD ( Hyman et al, 2012 ; Guo et al, 2020 ; Chung et al, 2021 ; Xia et al, 2021 ). APP , PSEN1 , and PSEN2 are causative genes for AD ( Reitz et al, 2020 ; Ibanez et al, 2021 ; Seto et al, 2021 ).…”

Targeted proteolytic products of τ and α-synuclein in neurodegeneration

“…Microtubule-associated protein τ is encoded in the MAPT gene and binds to microtubules (MTs), promoting their assembly and stability [5,8]. τ's protein structure is composed of an amino (N)-terminal The 2N/4R τ isoform is 441 amino acids long and is composed of an N-terminal region, a proline-rich region, an MTBD with four MT binding repeats (R1-R4), and a C-terminal region.…”

“…region, a proline-rich region, a microtubule-binding domain (MTBD), and a carboxy (C)-terminal region (Figure 1) [5,8]. In the human central nervous system, τ can be alternatively spliced into six isoforms, based on the presence or absence of exons, 2, 3, and 10 [5,8], and are grouped into 3R or 4R isoforms, which contain three or four MT-associated binding repeats, respectively.…”

“…Prion-like conformational mechanisms have been implicated in the propagation of τ and αSyn protein aggregates associated with the insidious nature of neurodegenerative diseases [1,2,5,6]. Both τ and αSyn can undergo extensive post-translational modifications that may promote their prion-like seeding potency and toxic spread [7][8][9]. Increasing evidence shows that τ and αSyn can lead to the formation of hybrid fibrils and aggregates [10,11].…”