Tau-targeting therapies for Alzheimer disease

Abstract

Alzheimer disease (AD) is the most common form of dementia. Pathologically, AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, with associated loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles, respectively. In the decades since Aβ and tau were identified, development of therapies for AD has primarily focused on Aβ, but tau has received more attention in recent years, in part because of the failure of various Aβ-targeting treatments in clinical trials. In this article, we review the current status of tau-targeting therapies for AD. Initially, potential anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting therapies in clinical trials are immunotherapies, which have shown promise in numerous preclinical studies. Given that tau pathology correlates better with cognitive impairments than do Aβ lesions, targeting of tau is expected to be more effective than Aβ clearance once the clinical symptoms are evident. With future improvements in diagnostics, these two hallmarks of the disease might be targeted prophylactically.

Figure 1 |. The defining pathological hallmarks of Alzheimer disease.

At the gross anatomical level, the disease is characterized by brain atrophy associated with loss of synapses and neurons. At the microscopic level, deposition of extracellular amyloid-β plaques and intraneuronal neurofibrillary tangles is observed, in association with dystrophic neurites and loss of synapses, as well as microgliosis and astrogliosis.

Figure 2 |. Tau-related therapeutic targets.

Drugs in preclinical or clinical development include active and passive immunotherapies; inhibitors of O-deglycosylation, aggregation, kinases, acetylation, caspases or tau expression; phosphatase activators; microtubule stabilizers; and modulators of autophagy or proteosomal degradation. Ac, acetyl group, Gly, glycosyl group; OGA, O-GlcNAcase; P, phosphate. Figure adapted with permission from ref. , Springer Nature.

Figure 3 |. Proposed modes of action of anti-tau antibodies.

Antibodies can target tau both extracellularly and intracellularly. Pathological tau mostly resides within neurons but in certain individuals and/or tauopathies, it is also evident in other cell types, primarily glia (in particular, astrocytes and oligodendrocytes). A much smaller pool of tau aggregates is found extracellularly, in the form of small aggregates that are not easily detected or as remnants of neurofibrillary tangles following the death of the neuron. Some anti-tau antibodies are not readily taken up into neurons, presumably because of their unfavourable charge and, therefore, they work principally in the extracellular compartment. Within this compartment, antibodies might sequester tau aggregates, interfere with their assembly and promote microglial phagocytosis, with the overall effect of blocking the spread of tau pathology between neurons. Other antibodies are easily detected within neurons, in association with tau, and have been shown to work both intracellularly and extracellularly. Within the cells, these antibodies could bind to tau aggregates within the endosomal–lysosomal system and promote their disassembly, leading to enhanced access of lysosomal enzymes to degrade the aggregates; sequester tau assemblies in the cytosol and prevent their release from the neuron; or promote proteosomal degradation via E3 ubiquitin–protein ligase TRIM21 binding. The most efficacious antibodies are likely to target more than one pathway and/or pool of tau.

Figure 4 |. Current status of clinical trials of drugs that target tau pathology.

At the time of writing, the most active field is tau immunotherapy, with two active vaccines (AADvac1 and ACI-35) and six antibodies (LY3303560, RO 7105705, BMS-986168, C2N-8E12, JNJ-63733657 and UCB0107) in clinical trials, although most of these therapies are still in the early stages of development. Several of the other compounds in trials have complex or incompletely defined mechanisms of action; in this diagram, these compounds are categorized according to their presumed tau-related mode of action. ‘X’ indicates trials that, to our knowledge, have been halted or terminated, as detailed in the main text, although their current status is difficult to determine. PDE4, phosphodiesterase E4.