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

Key Points

  • A number of neurodegenerative diseases of the brain are characterized by inclusions within neurons that are comprised of aggregated fibrils of hyperphosphorylated tau protein. These disorders, which include Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration and certain frontotemporal dementias, are broadly referred to as tauopathies.

  • Tau is normally a soluble protein that stabilizes microtubules within cells and is particularly enriched in neurons, where microtubules serve as the 'tracks' upon which cellular cargo is transported in axonal projections. The formation of insoluble tau aggregates could cause neurodegeneration through the formation of toxic tau species, or through a loss of tau function owing to its hyperphosphorylation and sequestration in inclusions.

  • Tau mutations have been shown to cause frontotemporal lobar degeneration with Parkinsonism linked to chromosome 17 (FTLD17), but tau mutations have not been identified in other tauopathies, including Alzheimer's disease. The causes of tau aggregation in these sporadic tauopathies are not fully understood, although tau hyperphosphorylation might be important, as it decreases tau binding to microtubules and increases tau fibrillization.

  • There is a growing interest in developing therapeutics that target pathological tau, particularly for the treatment of Alzheimer's disease. Most tau-directed drug discovery programmes are in early research stages and are not as advanced as programmes that aim to decrease levels of amyloid-β (Aβ) peptides, which form plaques in the Alzheimer's disease brain.

  • A number of approaches are being pursued for the treatment of tauopathies, including the development of brain-penetrant compounds that can stabilize microtubules and so compensate for tau loss-of-function; reduce tau hyperphosphorylation; inhibit tau assembly into oligomers and fibrils; or enhance tau intracellular degradative pathways.

  • As tau-directed therapies move towards clinical testing in Alzheimer's disease and other tauopathies, they will face many of the difficulties that are presently being encountered in trials of Aβ-targeted drugs for Alzheimer's disease. These include drug safety and the challenge of demonstrating clinical efficacy in a population that is likely to have existing neurodegeneration.

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-β-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.

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Figure 1: Tau pathology in Alzheimer's disease and related tauopathies.
Figure 2: Tau in healthy neurons and in tauopathies.
Figure 3: The tau gene, known FTLD17-associated mutations and sites of hyperphosphorylation.
Figure 4: Compounds directed against potential tauopathy drug targets.
Figure 5
Figure 6: Therapeutic strategies to reduce tau-mediated neuropathology and neurodegeneration.

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Acknowledgements

We thank our colleagues for their contributions to the work summarized here which has been supported by grants from the National Institutes of Health (P01 AG09215, P30 AG10124, P01 AG11542, P01 AG14382, P01 AG14449, P01 AG17586, PO1 AG19724, P01 NS-044,233, UO1 AG24904), and the Marian S. Ware Alzheimer Program. We are indebted to our patients and their families whose commitment to research has made our work possible.

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DATABASES

OMIM

Alzheimer's disease

frontotemporal lobar degeneration

Parkinson's disease

Pick's disease

progressive supranuclear palsy

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Glossary

Dendrite

A branched extension of a neuron that interacts with adjacent cells and transmits electrical impulses.

Fast axonal transport

A mechanism whereby intracellular organelles are transported along microtubules at a rate of 400 mm per day.

Microtubule-stabilizing drug

Typically molecules, such as paclitaxel or epothilones, that were identified from natural products and which bind with high affinity to microtubules, thereby affecting microtubule dynamics. Compounds of this type are used for the treatment of cancer because they affect mitotic spindles and induce cell death in rapidly dividing cells.

Pseudophosphorylation

The substitution of phosphorylated serine and threonine residues in a protein with aspartic acid or glutamic acid residues which, like phosphorylated serine and threonine, carry a negative charge at physiological pH. The effect on the protein is therefore similar to phosphorylation of serine and threonine residues.

Cross-β-fibril

A fibril composed of repeating units enriched in β-sheets that align parallel to the fibril axis with their β-strands perpendicular to this axis.

Macroautophagy

A process whereby a double-membrane structure encapsulates cytosolic material and fuses with lysosomes, resulting in degradation of the sequestered matter.

Lysosomotropic agent

A molecule that enters the lysosome and alters its function, often by increasing the pH of this normally acidic organelle.

Prodromal disease

The earliest phase of a developing condition or disease.

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Brunden, K., Trojanowski, J. & Lee, VY. Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies. Nat Rev Drug Discov 8, 783–793 (2009). https://doi.org/10.1038/nrd2959

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