Classified biomarker panel with tau microtubule binding regions identifies pathophysiological changes in Alzheimer’s disease continuum

Secretion of misfolded tau, a microtubule-binding protein enriched in nerve cells, is linked to the progression of tau pathology. However, the molecular mechanisms underlying tau secretion are poorly understood. Recent work by Lee et al. [Biochemical J. (2021) 478: 1471–1484] demonstrated that the transmembrane domains of syntaxin6 and syntaxin8 could be exploited for tau release, setting a stage for testing a novel hypothesis that has profound implications in tauopathies (e.g. Alzheimer's disease, FTDP-17, and CBD/PSP) and other related neurodegenerative diseases. The present commentary highlights the importance and limitations of the study, and discusses opportunities and directions for future investigations.

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A Novel Microtubule-Binding Drug Attenuates and Reverses Protein Aggregation in Animal Models of Alzheimer’s Disease

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2019.00310 ◽

2019 ◽

Vol 12 ◽

Author(s):

Samuel Kakraba ◽

Srinivas Ayyadevara ◽

Narsimha Reddy Penthala ◽

Meenakshisundaram Balasubramaniam ◽

Akshatha Ganne ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Protein Aggregation ◽

Microtubule Binding

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Relationship between microtubule-binding repeats and morphology of neurofibrillary tangle in Alzheimer's disease

Acta Neurologica Scandinavica ◽

10.1111/j.1600-0404.2005.00488.x ◽

2005 ◽

Vol 112 (5) ◽

pp. 327-334 ◽

Cited By ~ 10

Author(s):

T. Kitamura ◽

K. Sugimori ◽

S. Sudo ◽

K. Kobayashi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangle ◽

Microtubule Binding

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Evaluation of a Previously Suggested Plasma Biomarker Panel to Identify Alzheimer's Disease

PLoS ONE ◽

10.1371/journal.pone.0029868 ◽

2012 ◽

Vol 7 (1) ◽

pp. e29868 ◽

Cited By ~ 68

Author(s):

Maria Björkqvist ◽

Mattias Ohlsson ◽

Lennart Minthon ◽

Oskar Hansson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Plasma Biomarker ◽

Biomarker Panel

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C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease

Journal of Cell Science ◽

10.1242/jcs.113.21.3737 ◽

2000 ◽

Vol 113 (21) ◽

pp. 3737-3745 ◽

Cited By ~ 9

Author(s):

A. Abraha ◽

N. Ghoshal ◽

T.C. Gamblin ◽

V. Cryns ◽

R.W. Berry ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amino Acids ◽

Disease Process ◽

Brain Regions ◽

Microtubule Binding ◽

C Terminus ◽

Microtubule Binding Domain ◽

Tau Polymerization

Alzheimer's disease (AD) is, in part, defined by the polymerization of tau into paired helical and straight filaments (PHF/SFs) which together comprise the fibrillar pathology in degenerating brain regions. Much of the tau in these filaments is modified by phosphorylation. Additionally, a subset also appears to be proteolytically truncated, resulting in the removal of its C terminus. Antibodies that recognize tau phosphorylated at S(396/404)or truncated at E(391) do not stain control brains but do stain brain sections very early in the disease process. We modeled these phosphorylation and truncation events by creating pseudo-phosphorylation and deletion mutants derived from a full-length recombinant human tau protein isoform (ht40) that contains N-terminal exons 2 and 3 and all four microtubule-binding repeats. In vitro assembly experiments demonstrate that both modifications greatly enhance the rates of tau filament formation and that truncation increases the mass of polymer formed, as well. Removal of as few as 12 or as many as 121 amino acids from the C terminus of tau greatly increases the rate and extent of tau polymerization. However, deletion of an additional 7 amino acids, (314)DLSKVTS(320), from the third microtubule-binding repeat results in the loss of tau's ability to form filaments in vitro. These results suggest that only part of the microtubule-binding domain (repeats 1, 2 and a small portion of 3) is crucial for tau polymerization. Moreover, the C terminus of tau clearly inhibits the assembly process; this inhibition can be partially reversed by site-specific phosphorylation and completely removed by truncation events at various sites from S(320) to the end of the molecule.

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Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-020-0884-2 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Malcolm Roberts ◽

Ioanna Sevastou ◽

Yoichi Imaizumi ◽

Kavita Mistry ◽

Sonia Talma ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

In Vivo Model ◽

Sequence Motif ◽

Antibody Treatment ◽

Microtubule Binding ◽

High Affinity ◽

The Brain

AbstractTau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer’s disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species (“seeds”) containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro. They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical development.

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