An Overview on the Clinical Development of Tau-Based Therapeutics

Abstract

Tauopathies such as Alzheimer’s disease (AD), frontotemporal lobar degeneration, or progressive supranuclear palsy constitute a group of brain disorders defined by neurodegeneration and the presence of tau aggregates in the affected brains regions. Tau is a microtubule-associated protein that accumulates in the cytosol under pathological conditions, steering the formation of aggregates or inclusions thought to be involved in the degeneration and neuronal death associated with these diseases. Despite a substantial and unmet medical need for novel, more effective disease-modifying therapies for the treatment of AD and tauopathies, the last couple of decades have seen numerous drug development undertakings primarily focused on β-amyloid, with disappointing results to date. On the other hand, tau-focused approaches have not received much attention until recently, notwithstanding that the presence of extensive tau pathology is fundamental for the disease and tau pathology shows a better correlation with impaired cognitive function than with amyloid pathology in AD patients. The last few years have brought us advances in our comprehension of tau biological functions beyond its well-established role as a microtubule-associated protein, unveiling novel physiological tau functions that may also be involved in pathogenesis and thus provide novel targets for therapeutic intervention. This review describes several emerging, encouraging therapeutic approaches aimed at tackling the underlying causes of tau pathology in AD and other tauopathies that have recently reached the clinical development stage.

Copper(II) Coordination Abilities of the Tau Protein's N‐Terminus Peptide Fragments: A Combined Potentiometric, Spectroscopic and Mass Spectrometric Study

“…The biological role of tau protein is associated with its interaction with tubulins to promote their assembly into microtubules and to stabilize the microtubules . Many recent studies suggest that in addition to amyloid‐β, tau protein may also play a significant role in the development of Alzheimer's disease and/or other neurodegenerative disorders . The neuropathological hallmarks of these diseases are related to the accumulation of amyloid‐β into senile plaques and of hyperphosphorylated tau into neurofibrillary tangles .…”

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

“…As described above in the introduction, the GSK‐3β pathological hypothesis has had a significant impact on research for the treatment of AD. In fact, there is now no doubt that potential GSK‐3β‐selective inhibitors, which modulate this enzyme′s activity and consequently prevent the formation of neurofibrillary tangles by hyperphosphorylated tau protein as well as decreased Aβ overproduction, may represent an effective therapeutic approach for the treatment of AD …”

“…[113] Other relevant and noteworthy M1 PAMs illustrate the structural diversity of this compound class. PF-06767832 (20), reportedb yr esearchers at Pfizer, [114] as an M1-selective PAMw ith adequate pharmacokinetics and physicochemical properties. Compound 21,whichcontains a4-alkyloxypyrrolopyrimidinone group, was reportedt ob ea nM 1P AM by Takeda scientists.…”

“…Patients with AD may also have pathological patterns including increased β‐amyloid (Aβ) peptide concentration, with consequent deposition of amyloid plaques, as well as the appearance of neurofibrillary tangles that are made up of abnormally hyperphosphorylated tau protein, another trademark of this disease . Both patterns bring about neuronal degeneration, being associated with the progress of disease symptoms.…”

“…disease. [17][18][19][20] Both patterns bring about neuronal degeneration, being associated with the progress of disease symptoms.T he enzyme glycogen synthase kinase 3-beta (GSK-3b)h as emergeda sa ni mportant biological target for this hypothesis, as it is directly relatedt ot heset wo patterns. [11,21,22] Thus, selective GSK-3b inhibition, which prevents tau hyperphosphorylation and decreases Ab production,m ay be an effective therapeutic approach for the treatment of AD.…”