In a recent article published within the journal Nature Reviews Neurology, researchers discuss the efficacy of tau-targeting Alzheimer’s disease (AD) therapies and methods that could be implemented to enhance these treatments, especially immunotherapies.

Study: Tau-targeting therapies for Alzheimer disease: Current status and future directions. Image Credit: Gorodenkoff / Shutterstock.com

Background

Since 2018, the prevalence of AD has increased from 5.4 to six.5 million in america. The alarming rise in AD cases amid a growing proportion of aged people worldwide underscores the necessity for effective AD therapies. 

There are two cardinal hallmarks of AD pathology, including the buildup of amyloid-β (Aβ), which is the first component of extracellular plaques, and tau protein, the fundamental constituent of neurofibrillary tangles (NFTs). Previous attempts to develop AD-modifying therapeutics focused on Aβ pathology; nonetheless, most immunotherapies and secretase modifiers targeting Aβ, apart from lecanemab and donanemab, either lacked efficacy or led to antagonistic effects.

The challenges related to Aβ-targeted therapies led researchers to divert their attention to targeting the tau protein which, along with AD, can also be present in other diseases, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick disease, frontotemporal dementia (FTD), and primary-age related tauopathy.

Therapies targeting post-translational modifications

Several post-translational modifications of pathological tau have been targeted through novel therapies, which include hyperphosphorylation, acetylation, truncation, and glycosylation.

Tau phosphorylation

Along with the reduced activity of protein phosphatase 2A (PP2A), tau kinases are believed to contribute to tau hyperphosphorylation observed in AD. These enzymes could be not directly or directly activated by Aβ, which might subsequently contribute to increased phosphorylation of tau and its misfolding.

Several therapies have been developed to specifically goal tau phosphorylation in AD. Memantine, for instance, enhances PP2A activity, whereas sodium selenate reduces tau phosphorylation. Although sodium selenate was effective in preclinical animal models, only modest advantages were observed in AD patients.

Lithium chloride, widely used for treating bipolar disorder, has also been shown to inhibit glycogen synthase kinase 3β (GSK3β), which phosphorylates tau. So far, GSK3β activity has not been significantly affected by lithium chloride treatment; nonetheless, clinical trials are still ongoing.

Tau acetylation

Tau acetylation has also been observed in AD and may result in reduced solubility and degradation of tau protein. Salsalate, which is a small-molecule non-steroidal anti-inflammatory drug (NSAID), has been shown to inhibit tau acetylation in preclinical mouse studies; nonetheless, this agent was not found to achieve success in a phase I clinical trial.

Tau truncation

The truncation of tau proteins has also been observed in AD and other tauopathies; nonetheless, these tau fragments have also been observed in healthy individuals. Minocycline, a caspase inhibitor, has been evaluated in phase II clinical trials; nonetheless, this treatment did not slow cognitive decline in patients with mild AD, with higher doses related to antagonistic effects.

Glycosylation

O-GlcNAcylation, a specialized and protective type of O-glycosylation that reduces phosphorylation and tau aggregation, is reduced during AD. So far, several O-GlycNAcase (OGA) inhibitors have demonstrated clinical safety in adults and are currently being investigated in phase II trials.

Lively tau immunotherapies 

Each energetic and passive immunotherapies have been developed to focus on tau proteins. Lively immunotherapy delivers a tau immunogen and is related to several benefits, including low costs, a polyclonal antibody response, and long-term efficacy. Nevertheless, the endogenous roles of tau protein outside of its contribution to AD can result in antagonistic autoimmune responses, which have been observed in preclinical mouse studies.

AADvac1 is an energetic vaccine that has been developed to specifically goal N-terminally truncated tau fragments. Phase I and II trials of AADvac1 have confirmed the protection and immunogenicity in AD patients, along with cognitive advantages, thus necessitating the necessity for more extensive studies to substantiate its clinical efficacy.

ACI-35 is one other AD vaccine that’s liposome-based and specifically targets p-tau396404. ACI-35 has been found to be each protected and well-tolerated in AD patients; nonetheless, it did not elicit a sufficient immune response, even after booster doses. Since then, ACI-35.030 has been developed to enhance the vaccine’s immunogenicity and binding efficiency to p-tau.

Passive tau immunotherapies

Passive immunotherapy involves targeting specific tau epitopes which might be involved in AD. A further advantage of this approach is that any antagonistic effects could be mitigated through subsequent antibody clearance. Nevertheless, passive immunotherapy is usually dearer and have to be administered more often, thus increasing the chance of secondary infection and other antagonistic effects.  

APNmAb005 is an anti-tau immunoglobulin G (IgG) antibody that preferentially targets tau protein in brain lysates from individuals with AD and mouse models of tauopathy. The security of APNmAb005 is currently being evaluated in a phase I trial conducted in healthy individuals.

Bepranemab is an IgG4 antibody that binds to amino acids 235-250, which is adjoining to the microtubule-binding region throughout the tau protein. Phase I trials have largely confirmed the protection of bepranemab, and phase II trials are currently being conducted to judge the efficacy of this immunotherapy in patients with mild cognitive impairment (MCI) and mild AD.

E2814 is an IgG1 antibody that recognizes the microtubule-binding domain of tau and binds to extracellular tau. In preclinical mouse studies, E2814 has successfully reduced insoluble tau levels, which led to its subsequent investigation in clinical trials which have confirmed its safety in healthy adults. Currently, phase II/III trials are being conducted to find out the efficacy of E2814 together with anti-Aβ treatments.

JNJ-63733657 is one other IgG1 antibody that specifically targets p-tau217. Phase I clinical trials have confirmed the protection of this antibody in healthy patients, in addition to those with prodromal or mild AD. Currently, a phase II study is being conducted in early-stage AD patients to judge the efficacy of JNJ-63733657.