Tau Propagation as a Diagnostic and Therapeutic Target for Dementia: Potentials and Unanswered Questions

Abstract

A unique clinical course of Alzheimer's disease (AD), beginning with memory deficit as the earliest symptom, is well-correlated with a progressive pattern of intracellular aggregates of tau (neurofibrillary tangles), which spread from the medial temporal lobe to other brain areas in a stereotypical manner. Recent findings from basic research using in vitro and in vivo models demonstrated that pathological forms of extracellular tau can be taken up by cells and induce intracellular tau aggregates. On the basis of these neuropathological observations and experimental findings, the "tau propagation hypothesis" has been proposed, in which the stereotypical spreading of the tau pathology observed in the brain of AD patients can be explained by the interneuron transfer of the pathological form of tau. The concept of tau propagation remains controversial, and many unsolved questions exist; however, it has been attracting attention as a potential therapeutic target for halting AD progression. This article reviews the recent findings regarding the tau propagation hypothesis, including the basic concept and evidence of interneuron tau transfer, potentials as a diagnostic and therapeutic target, and unsolved questions for a better understanding of tau propagation.

Resveratrol targeting tau proteins, amyloid‐beta aggregations, and their adverse effects: An updated review

“…Tau protein is encoded by a single gene known as MAPT that is located on chromosome 17 (Brunello, Merezhko, Uronen, & Huttunen, 2019). This gene is suggested to be expressed on most of the neurons (Takeda, 2019).…”

Age dependent trans-cellular propagation of human tau aggregates inDrosophiladisease models

“…1 C and G respectively. The co-localization coefficient between both the ROI (region of interest), eGFP: tau, was estimated using Leica application suite advanced fluorescence software (LAS AF Lite) [21] and was calculated to be 90.83%, with the remaining percentage corresponding to the non-specific outlier data, as precisely 6 depicted in the scatter plot in Fig. 1 E. The above observations suggest that, although the larval tissues exhibit a notable expression of tau throughout the GMR domain ( Fig.…”

“…The observation that tau progresses throughout the brain via synaptically connected regions led to the hypothesis that tau propagates and spreads via neuronal circuits [5]. The propagation of tau has been distinguished into three major stages with the intracellular tau; (i) being secreted into extracellular space, followed by its (ii) uptake by recipient neurons and finally (iii) formation of novel intracellular aggregates in the recipient cells [6]. Further evidences over the years have strengthened this hypothesis with demonstrations like, injection of brain extracts of mutant P301S mice expressing wild type human tau (exhibit tau pathology) into the hippocampus of transgenic wild type tau-expressing mice (that do not manifest tau pathology) led to development and spread of tau filamentous pathology in it [7].…”

“…It has also been demonstrated that insoluble misfolded human tau is capable of inducing and propagating neurofibrillary pathology in rat model expressing non-mutated human truncated tau protein [8]. Several studies have suggested that tau entities do progress in a "prion like" fashion [5,6,9]. Although, immense amount of work has been contributed to the understanding of seed and spread mechanism of tau pathology via various model systems [8,10,11], yet it is still a field of potential exploration.…”

A Comprehensive, Multi-Modal Strategy to Mitigate Alzheimer’s Disease Risk Factors Improves Aspects of Metabolism and Offsets Cognitive Decline in Individuals with Cognitive Impairment

“…For instance, it has been argued that most clinical trials have been performed on individuals in relatively late stage disease progression, where the pathology may have progressed to an irreversible state [3]. Another line of thought suggests that the primary targets of therapeutic development, amyloid-␤ plaques and tau tangles, may not be a major drivers of disease, or at least that their therapeutic clearance is insufficient to blunt disease progression [4,5]. Instead, amyloid-␤ oligomers may be the primary culprit or, even more concerning, the role of amyloid plaques in disease progression may be overestimated [6].…”