Therapeutic strategies for tau mediated neurodegeneration

Abstract

Based on the amyloid hypothesis, controlling β-amyloid protein (Aβ) accumulation is supposed to suppress downstream pathological events, tau accumulation, neurodegeneration and cognitive decline. However, in recent clinical trials, Aβ removal or reducing Aβ production has shown limited efficacy. Moreover, while active immunisation with Aβ resulted in the clearance of Aβ, it did not prevent tau pathology or neurodegeneration. This prompts the concern that it might be too late to employ Aβ targeting therapies once tau mediated neurodegeneration has occurred. Therefore, it is timely and very important to develop tau directed therapies. The pathomechanisms of tau mediated neurodegeneration are unclear but hyperphosphorylation, oligomerisation, fibrillisation and propagation of tau pathology have been proposed as the likely pathological processes that induce loss of function or gain of toxic function of tau, causing neurodegeneration. Here we review the strategies for tau directed treatments based on recent progress in research on tau and our understanding of the pathomechanisms of tau mediated neurodegeneration.

Keywords: Alzheimer's Disease.

Conflict of interest statement

Competing interests None.

Figures

Figure 1

Chronological relationships among pathology, clinical symptoms and biomarkers. Based on biomarker studies, β-amyloid protein (Aβ) accumulation appears to start ~20 years before the onset of dementia. Amyloid positron emission tomography (PET) or a decrease in Aβ1–42 levels in CSF may indicate Aβ accumulation in the brain, even in preclinical Alzheimer’s disease (AD). Neocortical tau pathology correlates closely with the timing of symptom onset. But, as discussed in the text, these findings need to be reconciled with reports by Braak and colleagues that tau pathology is seen in the brain prior to Aβ pathology, while functional MRI (fMRI) abnormalities may be the earliest biomarker to change in the preclinical phase of AD.– FDG, 2-[18 F]-fluoro-2-deoxy-D-glucose; MCI, mild cognitive impairment.

Figure 2

Schematic presentation of tau mediated neurodegeneration. Phosphorylation and dephosphorylation of tau control the attachment and detachment of tau from microtubules (MT). Hyperphosphorylation of tau induces disassembly of MTs, causing axonal transport insufficiency. Unbound tau self-aggregates into oligomers or aggregates. Tau aggregates in axons or dendrites congest axonal transport. Tau pathology is transmitted synaptically. An interaction between Fyn and tau induces synaptic dysfunction.

Figure 3

Therapeutic targets for possible pathomechanisms in tauopathies. Aβ, β-amyloid protein; MT, microtubules; NFT, neurofibrillary tangle.