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.

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

“…Therefore, seeking therapeutic alternatives for AD that target tau proteins has recently captured researchers’ interest. In this context, there are many ongoing investigations targeting the accumulation of tau proteins, among others, is the immunotherapy approach that indicated promising results reported about the clinical trials progress of many antibodies and vaccines for the potential treatment of AD …”

“…In this context, there are many ongoing investigations targeting the accumulation of tau proteins, among others, is the immunotherapy approach that indicated promising results reported about the clinical trials progress of many antibodies and vaccines for the potential treatment of AD. 184,185 In addition, numerous preclinical studies were performed to reduce tau production by targeting tau gene expression via the antisense oligonucleotide-based approach. The latter is currently in phase I clinical trials.…”

Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

“…In later studies, we showed that tau antibodies could have the same effect [5,6], and provided various insights into the possible mechanisms of clearance [7–19]. These studies have been confirmed and extended by various groups showing benefits of immune-targeting the pS396/404 tau epitope [2,4,6–9,12,20–27], and other tau epitopes [20,23–25,27–49], which as mentioned above has resulted in eight clinical trials (for a recent review of these trials see [50]), with several more likely to be initiated in the near future. We have highlighted many of these studies in some details in various reviews over the years as they have been reported so it is not necessary to elaborate further on those particular aspects (see for example [51–53]).…”

Semisynthetic and Enzyme‐Mediated Conjugate Preparations Illuminate the Ubiquitination‐Dependent Aggregation of Tau Protein

“…Intracellular aggregates of the tau protein, with the properties of amyloid fibrils, are the defining feature of a group of neurological disorders known as tauopathies, which include Alzheimer's disease (AD) . Tau pathology has been recognized as a target for the development of disease‐modifying therapies, the success of which requires to acquire a deep knowledge on the multiple molecular factors that contribute to the formation of neurotoxic aggregates …”