Tau-targeting therapies for Alzheimer disease
By E. Congdon, E. Sigurdsson. Nature Reviews Neurology, 2018
923 citations recorded by the source corpus.
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.Interest in tau-targeting strategies for Alzheimer disease is increasing, in part because of the failure of various amyloid-β-targeting treatments in clinical trials. Congdon and Sigurdsson review the current status of tau-targeting therapies, including anti-tau drugs and immunotherapies.Key pointsTherapies for Alzheimer disease in clinical trials are gradually shifting from amyloid-β (Aβ)-targeting to tau-targeting approaches.Early 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.Most of the tau-targeting approaches that are currently in clinical trials are immunotherapies.Tau is likely to be a better target than Aβ once cognitive deficits manifest because the tau burden correlates better with clinical impairments than does the Aβ burden.Eventually, with continued improvements in diagnostics, both Aβ and tau are likely to be targeted prophylactically for clearance.
Subfields: Cellular and Molecular Neuroscience, Pharmacology, Physiology
View Paper: https://www.semanticscholar.org/paper/716fddb15717f7605097dd659e8360bee46935ee
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Citations in the corpus
- Role of neuroinflammation in neurodegeneration development (2023, background): “At present, due to the toxicity or lack of efficacy of other anti-tau therapies, most of the tau targeted therapies undergoing clinical trials are immunebased therapies.(531) Sigurdsson’s group was the first to report successful tau targeted therapy based on active and passive immunization against t”
- Cholinesterase inhibitors as Alzheimer's therapeutics (2019, background): “Several drugs under development are in phase iii clinical trials, including methylthioninium, which inhibits τ phosphorylation by activating the τ phosphatases or by inhibiting τ kinases (18,19).”