Tau-Targeting Therapies: A New Frontier in the Fight Against Alzheimer's
Learn about the latest advances in tau-targeting therapies for Alzheimer's disease and how they could offer new hope to patients.
DR T S DIDWAL, MD
10/30/20236 min read
Alzheimer's research is shifting its focus from amyloid-beta to tau protein for treating dementia. While Aβ has been the target for decades, therapies haven't been successful. Tau tangles seem to be a better indicator of cognitive decline than Aβ plaques. Early tau-targeting drugs aimed to block tau buildup or stabilize microtubules but caused side effects or weren't effective. The current approach uses immunotherapy to train the immune system to attack tau. According to a review in Nature Reviews Neurology, targeting tau might be more effective than Aβ once symptoms arise. In the future, with better diagnostics, both Aβ and tau might be targeted to prevent Alzheimer's.
Key Findings
Shifting Focus from Amyloid-Beta to Tau
Alzheimer's disease is the most common form of dementia, characterized by protein buildup in the brain leading to memory loss and cognitive decline. Traditionally, research focused on targeting amyloid-beta (Aβ), a protein that forms plaques in the brain. However, recent years have seen a shift towards targeting tau, another protein that forms tangles within brain cells. This shift is due to several reasons:
Aβ Therapies Not Effective Enough: Despite years of research, Aβ-targeting therapies haven't shown significant success in clinical trials.
Tau Pathology Better Correlates with Symptoms: The amount of tau tangles in the brain seems to have a stronger connection to the severity of dementia symptoms compared to Aβ plaques.
Challenges of Early Tau Therapies
The article mentions different approaches explored for targeting tau. Some of these involved:
Inhibiting enzymes (kinases) that contribute to tau tangles
Preventing tau proteins from clumping together (aggregation)
Stabilizing microtubules, structures within cells that tau is essential for
Unfortunately, most of these early attempts were unsuccessful due to:
Toxicity: The medications caused unwanted side effects.
Ineffectiveness: The medications didn't improve patients' conditions.
Rise of Tau-Targeted Immunotherapy
The current focus in tau-targeting therapies is on immunotherapy. These treatments involve training the body's immune system to recognize and remove tau proteins from the brain. This approach has shown promise in preclinical studies, meaning studies conducted in animals or cells before human trials.
Why Target Tau Later in the Disease?
The article suggests that targeting tau might be more effective than targeting Aβ once symptoms appear. This is because the buildup of tau seems to be more closely linked to the degree of cognitive decline experienced by patients.
Future: Targeting Both Aβ and Tau
The article concludes by mentioning the possibility of targeting both Aβ and tau in the future. This would likely involve a combination of therapies and would depend on advancements in diagnostics to identify people at the early stages of the disease before symptoms develop.
In the realm of Alzheimer's disease (AD), where millions suffer, the pursuit of effective treatments has taken a transformative turn. Alzheimer's, the most common cause of dementia among older individuals, is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. These pathological hallmarks result in the loss of synapses and neurons, eventually leading to dementia. The journey to combat this debilitating condition has historically focused on Aβ, but recent developments have shifted the spotlight onto tau protein, a player that holds the potential to rewrite the future of AD research.
The Shift from Aβ to Tau
For many years, the primary emphasis of AD research was placed on Aβ, the key constituent of extracellular plaques commonly found in the brains of AD patients. However, the effectiveness of Aβ-targeting therapies was modest at best, yielding limited success. This necessitated a change in strategy, shifting the focus towards targeting tau pathology.
Tau, a protein that forms neurofibrillary tangles (NFTs) in AD patients' brains, has emerged as a pivotal target. Importantly, tau pathology shows a stronger correlation with the severity of dementia compared to Aβ deposition. The presence of tau pathology in other neurodegenerative conditions, such as progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD), makes it an attractive candidate for therapeutic development.
Key Aspects of Tau Pathology
To delve into the intricacies of tau-targeting therapies, it's essential to understand the key aspects of tau pathology.
Phosphorylated Tau (p-tau): Phosphorylated tau, often referred to as p-tau, plays a pivotal role in tau pathology in AD. The presence of p-tau pre-tangles and neuropil threads can be observed in brain tissue years before the onset of AD symptoms. The spread of tau pathology typically begins in the entorhinal cortex and hippocampus and follows a specific pattern. Various tau species, including monomeric, oligomeric, and aggregated forms, coexist in tauopathies. Different tauopathies exhibit variations in tau isoform composition and multimer morphology.
Post-translational Modifications: In AD, tau undergoes extensive post-translational modifications, including hyperphosphorylation, acetylation, truncation, and glycosylation. Hyperphosphorylation results from increased activity of tau kinases and reduced activity of protein phosphatase 2A (PP2A). Acetylated tau impairs microtubule binding and solubility, while truncation promotes tau assembly and reduces microtubule binding. Glycosylation can have protective or detrimental effects, with O-GlcNAcylation promoting microtubule binding and reducing aggregation.
Tau Aggregation: Tau aggregates come in various forms, including small soluble aggregates, paired helical filaments (PHFs), straight filaments, and twisted ribbons. Oligomeric tau is considered the primary pathogenic species, leading to acute toxicity and multiple impairments, including synaptic dysfunction, mitochondrial dysfunction, and synaptic function. Larger NFT aggregates, while initially protective, result in changes in gene expression, synapse loss, and energy deficits.
Cytoskeletal Dysfunction: Neurons bearing NFTs in AD exhibit reduced tubulin expression, altered microtubule structure, and increased tubulin acetylation. This disruption in the microtubule network offers a potential target for therapeutic intervention.
Protein Degradation Pathway Impairment: AD and other tauopathies are associated with defects in various protein degradation pathways, such as macroautophagy, endosomal microautophagy, and chaperone-mediated autophagy. These impairments further hinder the clearance of tau aggregates.
Strategies for Targeting Tau Pathology
The quest to conquer tau pathology in AD has led to the development of various strategies, each holding the promise of a breakthrough:
Reducing Tau Expression: Tau antisense oligonucleotides (ASOs) target human MAPT mRNA to reduce tau expression. Clinical trials have shown promising results, with significant reductions in tau levels in cerebrospinal fluid and the brain. However, more extensive studies are needed to determine if these reductions translate into clinical benefits.
Targeting Tau Protein Modifications:
Phosphatase Modifiers: Drugs like memantine, which enhance PP2A activity, have shown potential in reducing tau hyperphosphorylation. Research is ongoing to assess their efficacy further.
Kinase Inhibitors: Lithium chloride, which inhibits glycogen synthase kinase 3β (GSK3β), an enzyme responsible for phosphorylating tau, is under investigation. Preliminary studies have been conducted, but more data is needed to evaluate its effectiveness.
Acetylation Inhibitors: Salsalate, an anti-inflammatory drug that inhibits tau acetylation, has demonstrated promising results in preclinical studies. Clinical trials are ongoing to assess its potential for slowing tau pathology in patients with AD and related conditions.
Deglycosylation Inhibitors: Research on deglycosylation inhibitors, particularly O-GlcNAcylation modifiers, is still in its early stages. These compounds show promise in promoting tau's microtubule binding and preventing phosphorylation.
Tau Aggregation Inhibitors: Various small-molecule inhibitors have been developed to prevent or reverse tau aggregation, potentially reducing the spread of pathology. These inhibitors are currently in preclinical and clinical development.
Microtubule Stabilizers: Microtubule-stabilizing agents, such as TPI-287 and NAP, aim to compensate for the loss of normal microtubule-stabilizing function in the presence of pathological tau. Clinical trials are underway to assess their potential in AD and tauopathies.
Protein Clearance Enhancers: Modulators of autophagy and proteasomal degradation have been explored to enhance the clearance of pathological tau. These approaches hold promise in removing tau aggregates from neurons.
The Future of Tau-Targeting Therapies
The development of tau-targeting therapies marks a significant shift in the AD research landscape. While challenges and uncertainties persist, ongoing clinical trials and the emergence of new therapeutic candidates provide hope for more effective treatments in the future. Immunotherapies, particularly antibody-based therapies, are at the forefront of these efforts, with several candidates currently in clinical trials.
In conclusion, Alzheimer's disease remains a formidable public health challenge, affecting an ever-growing number of individuals worldwide. The pursuit of tau-targeting therapies represents a promising strategy in the quest for effective treatments. While many questions remain unanswered, ongoing research and clinical trials offer hope for better outcomes and an improved quality of life for those living with AD and related conditions.
Progress in the field of tau-targeting therapies has been challenging, but the intricate nature of tau makes it a formidable target. It is time for tau-targeting therapies to receive the support they deserve, parallel to their Aβ-targeting counterparts. Ongoing research and exploration of the pathological mechanisms of AD and tauopathies will guide the optimization of existing candidates and the identification of new intervention targets.
Reference Article
Congdon, E.E., Sigurdsson, E.M. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 14, 399–415 (2018). https://doi.org/10.1038/s41582-018-0013-z
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