The fight against Alzheimer’s disease (AD) has taken a new direction, with researchers focusing on the development of tau-targeting therapies that show promising efficacy. In a recent article published in the journal Nature Reviews Neurology, scientists discuss the challenges associated with amyloid-β (Aβ)-targeted treatments and the potential of immunotherapies directed at tau protein.
AD, a neurodegenerative disease characterized by memory loss and cognitive decline, has seen a significant increase in prevalence in recent years. In the United States alone, the number of AD cases has risen from 5.4 million to 6.5 million since 2018. This alarming trend highlights the urgent need for effective and innovative AD therapies.
Traditionally, AD research has primarily focused on two main pathological features: the accumulation of Aβ in extracellular plaques and the presence of tau protein in neurofibrillary tangles (NFTs). Previous attempts to develop AD-modifying therapeutics targeted Aβ pathology. However, many of these immunotherapies and secretase modifiers failed to demonstrate efficacy or led to adverse effects, with only lecanemab and donanemab showing promising results.
Given the challenges associated with Aβ-targeted therapies, researchers have shifted their attention to tau protein, which is not only present in AD but also in other neurodegenerative diseases such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick disease, frontotemporal dementia (FTD), and primary-age related tauopathy.
Researchers have explored various strategies to target post-translational modifications of tau protein. These modifications include hyperphosphorylation, acetylation, truncation, and glycosylation.
Tau hyperphosphorylation, observed in AD, is believed to be influenced by the reduced activity of protein phosphatase 2A (PP2A) and the activation of tau kinases. Some therapies have been developed to target tau phosphorylation specifically. For example, memantine enhances PP2A activity, while sodium selenate reduces tau phosphorylation. However, sodium selenate has shown only modest benefits in AD patients after being effective in preclinical models.
Another approach to targeting tau is by inhibiting glycogen synthase kinase 3β (GSK3β), which phosphorylates tau. Lithium chloride, commonly used to treat bipolar disorder, has shown potential as a GSK3β inhibitor. Although clinical trials are ongoing, lithium chloride has not yet significantly affected GSK3β activity.
Tau acetylation, which leads to reduced solubility and degradation of tau protein, is another post-translational modification observed in AD. Salsalate, a non-steroidal anti-inflammatory drug (NSAID), has been shown to inhibit tau acetylation in preclinical studies but was not successful in a phase I clinical trial.
Tau truncation, the process of cleaving tau proteins, has also been observed in AD and other tauopathies, but it is also present in healthy individuals. Minocycline, a caspase inhibitor, has been evaluated in phase II clinical trials but failed to slow cognitive decline in patients with mild AD.
Glycosylation, specifically O-GlcNAcylation, is a protective form of O-glycosylation that reduces tau phosphorylation and aggregation. O-GlycNAcase (OGA) inhibitors have shown clinical safety and are currently being investigated in phase II trials.
Tau targeting can be approached through active immunotherapy and passive immunotherapy.
Active immunotherapy involves delivering a tau immunogen, which stimulates a polyclonal antibody response. One active vaccine, AADvac1, targets N-terminally truncated tau fragments. Phase I and II trials have confirmed the safety, immunogenicity, and cognitive benefits of AADvac1, warranting further studies to establish its clinical efficacy.
Another active vaccine, ACI-35, focuses on p-tau396404 and has shown safety and tolerability in AD patients. However, it failed to elicit a sufficient immune response, leading to the development of ACI-35.030, which is designed to improve immunogenicity and binding efficiency.
Passive immunotherapy involves targeting specific tau epitopes involved in AD. APNmAb005, an anti-tau immunoglobulin G (IgG) antibody, preferentially targets tau protein in brain lysates from AD individuals and mouse models. Safety evaluations are currently underway in a phase I trial involving healthy volunteers.
Bepranemab, an IgG4 antibody, binds to c235-250 near the microtubule-binding region of tau protein. It has undergone phase I trials confirming its safety, and phase II trials are ongoing to evaluate its efficacy in patients with mild cognitive impairment and mild AD.
E2814, an IgG1 antibody, targets the microtubule-binding domain of tau and binds to extracellular tau. Preclinical studies have shown reduced insoluble tau levels, leading to its evaluation in clinical trials confirming safety. Phase II/III trials are now being conducted to assess the efficacy of E2814 in combination with anti-Aβ treatments.
JNJ-63733657, an IgG1 antibody, specifically targets p-tau217. Phase I trials have demonstrated safety in healthy and early-stage AD patients. A phase II study is currently underway to evaluate its efficacy.
In conclusion, redefining the battle against Alzheimer’s disease involves shifting focus to tau-targeting treatments. Various approaches, such as therapies targeting post-translational modifications and active/passive immunotherapies, show promise in modifying the progression of AD. Further research and clinical trials are needed to validate the efficacy and safety of these innovative therapies, with the ultimate goal of improving the lives of individuals affected by this devastating disease.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
