Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies

Abstract

Neuronal inclusions comprised of the microtubule-associated protein tau are found in numerous neurodegenerative diseases, commonly known as tauopathies. In Alzheimer's disease - the most prevalent tauopathy - misfolded tau is probably a key pathological agent. The recent failure of amyloid-beta-targeted therapeutics in Phase III clinical trials suggests that it is timely and prudent to consider alternative drug discovery strategies for Alzheimer's disease. Here, we focus on strategies directed at reducing misfolded tau and compensating for the loss of normal tau function.

Figure 1. Tau pathology in AD and related tauopathies

At autopsy, the brains of patients with Alzheimer's disease or related tauopathies show abundant neurofibrillary tangles (NFTs) and neuropil threads that are comprised of pathological tau. These tau deposits can be visualized by treating brain slices with certain silver stains or by immunostaining with antibodies that recognize tau (as shown in A, with darkly-stained NFTs and dense tau neuropil threads that yield a nearly uniform brown staining in a hippocampal section of an Alzheimer's disease brain). A schematic representation of NFTs and neuropil threads within a neuron is shown in B, with an example of tau fibrils that resemble those found in NFTs depicted in the associated inset.

Figure 2. Tau in healthy neurons and in tauopathies

Tau facilitates microtubule (MT) stabilization within cells and it is particularly enriched in neurons. MTs serve as “tracks” that are essential for normal trafficking of cellular cargo along the lengthy axonal projections of neurons, and it is thought that tau function is compromised in Alzheimer's disease and other tauopathies. This probably results both from tau hyperphosphorylation, which reduces the binding of tau to MTs, and through the sequestration of hyperphosphorylated tau into neurofibrillary tangles (NFTs) so that there is less tau to bind MTs. The loss of tau function leads to MT instability and reduced axonal transport, which could contribute to neuropathology.

Figure 3. The Tau gene, known Parkinsonism linked to chromosome 17 (FTDP-17) mutations and sites of hyperphosphorylation

Tau is a mult-exonic gene that undergoes alternative post-transcriptional splicing of exons 2 (orange), 3 (yellow) and 10 (green) to yield six isoforms in the brain. Exons 9-12 encode microtubule (MT)-binding repeat domains and the exclusion or inclusion of exon 10 results in tau with three (3-R) or four (4-R) MT-binding domains, respectively (black bars). Tau mutations that result in FTDP-17 map primarily to exons 9-12 or to the intronic region between exons 10 and 11, with the latter increasing the prevalence of exon 10-containing 4-R tau. There are no reported tau mutations in Alzheimer's disease, but hyperphosphorylated tau inclusions are formed that resemble those seen in FTDP-17. There are ~40 reported sites of tau phosphorylation, and the major hyperphosphorylation sites are shown at the bottom of the figure.

Figure 4. Therapeutic strategies to reduce Tau-mediated neuropathology and neurodegeneration

A number of approaches are being pursued to reduce the consequences of pathological tau in Alzheimer's disease and related tauopathies. It is believed that tau deposition into neurofibrillary tangles (NFTs) results in a loss of normal tau stabilization of microtubules (MTs) and/or the formation of toxic tau multimeric structures. A reduction of tau interaction with MTs might be compensated for by small molecule MT-stabilizing agents. Tau hyperphosphorylation reduces its binding to MTs and enhances its fibrillization, and inhibitors of tau kinases might thus improve both MT function and reduce the formation of pathologic tau multimers. Because tau O-glycosylation and phosphorylation seem to be reciprocally regulated, inhibition of O-GlcNacase might be another approach to decreasing tau hyperphosphorylation. Another potential strategy for increasing the amount of soluble tau available for MT binding and for decreasing potentially toxic aggregates is to inhibit the assembly of tau into larger multimeric structures or dissolve existing aggregates (tau assembly inhibitors). Finally, it may be possible to increase the degradation of misfolded and aggregated tau. Hsp90 inhibitors might increase proteasome-mediated clearance of misfolded and/or hyperphosphorylated tau monomers, whereas enhancers of autophagy have the potential to increase the removal of tau aggregates. For examples of compounds targeting these processes please see table 1.