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Brain health: Immune enzyme linked to toxic tau buildup in Alzheimer’s disease

Alzheimer’s disease is one of the world’s biggest health problems. Yet, despite the fact millions of people globally are diagnosed with the disease each year, it remains a challenge to treat. This is largely because the underlying causes are still not fully understood.

However, a new study in mice brings us one step closer to understanding what triggers the disease. The researchers have uncovered a specific enzyme that may be behind one of the key features of Alzheimer’s.

One of the key features of Alzheimer’s disease is an accumulation of a harmful protein called tau. In a healthy brain, tau primarily helps to support and stabilise brain cells (neurons). This maintains the structure of these cells, and assists in transporting key substances throughout the neuron so it can function optimally.

But in people with Alzheimer’s disease, tau appears to behave abnormally in the brain. Instead of performing its normal function, tau builds up inside neurons and forms twisted clumps, called neurofibrillary tangles.

These tangles can disrupt communication between neurons. Communication between neurons is fundamental for our memory, thinking and behaviour, so any disruption can lead to damage in those areas of the brain.

While scientists have known for decades that tau is involved in the disease, they’re still trying to understand exactly why healthy tau misfolds to form these toxic, sticky tangles. This latest study, published in Nature Neuroscience, offers promising new insights into how tau turns toxic in mice. Toxic tau

To mimic Alzheimer’s disease, the team of US-based scientists used mice that had been genetically altered to have a build-up of tau in their brains. They found that a specific enzyme may be responsible for turning healthy tau into the toxic tau that accumulates in the brain.

An enzyme is a protein that usually plays a helpful role in the body – making reactions happen faster and more efficiently. But this study found that the enzyme tyrosine kinase 2 (TYK2), which plays a central role in the immune system, adds a special tag to tau. This tag then appears to make it difficult for the brain to properly clear away unwanted tau. In both mouse models and human cell cultures, the enzyme caused tau to build up and become toxic.

Using genetic tools, the scientists then blocked TYK2 in the mice with Alzheimer’s. This resulted in a reduction in the overall amount of tau in the brain – including the amount of harmful, disease-causing tau with the added tag.

The neurons also showed signs of recovery. This suggests that blocking TYK2 could be a way to reduce the toxic tau buildup, and the damage it causes in diseases like Alzheimer’s. This could also open new avenues for drug development that could tackle toxic tau in ways that haven’t been explored yet.

The finding that lowering or blocking TYK2 could treat Alzheimer’s is encouraging, as TYK2 inhibitor drugs have already been tested in humans for a range of different conditions – such as the autoimmune diseases psoriatic arthritis and inflammatory bowel disease.

However, studies are needed to check if TYK2 inhibitors are able to pass the blood-brain barrier. As tau is inside brain cells, it’s tough to remove. If these drugs can’t reach the brain, they won’t be able to lower tau levels in humans and make a difference in Alzheimer’s disease. Alzheimer’s treatments

There’s a desperate need for new treatment options for Alzheimer’s disease. While two therapies, donanemab and lecanemab, have recently been approved in the UK, they’re too expensive for widespread use on the NHS and come with serious side-effects. Many argue that their drawbacks outweigh their benefits.

These treatments focus on removing amyloid plaques, another protein linked to Alzheimer’s. But targeting tau, the protein at the heart of this new research, could be a game changer in the search for a more effective treatment.

It should, however, be noted that this research is in its early stages and is still very pre-clinical. Despite mice models being extremely valuable for understanding disease mechanisms, their results don’t always translate directly to humans. More research is needed to see if this technique has the same effect on tau levels in the human brain, whether there are any harmful side-effects – and if blocking TYK2 to clear toxic tau actually improves symptoms of Alzheimer’s, such as memory loss.

Targeting TYK2 to reduce toxic tau in the brain shows promise as a potential new approach to treating Alzheimer’s. The next steps will be to explore if the same is true in humans.

The New and Novel Complex Brain-Based Therapy and Jazz

In August 1991, former World Boxing Champion John Famechon sustained severe incapacitating brain injuries. In December of 1993, he began a new and novel complex multi-movement therapy and rehabilitation program, which eventually helped him regain a condition close to his pre-accident state. “The New and Novel Complex Brain Therapy?”

The question to ask and answer was: What was meant by the descriptor “a new and novel therapy?” Which eventually evolved to be described as complex brain-based multi-movement therapy (CBBMMT) and then complex multi-movement therapy (CMMT).

In terms of application, it was my contention that my new and novel therapy had three elements. First, the focus of the therapy was the brain; and it was the application and action of movement that was the only way to access and influence the brain to change, which would then hopefully lead to physical changes taking place.

Second, the aim was to apply as much complexity as possible when visibly feasible. My rationale for this (personal philosophical principle) was that this approach would bring about neurological, neurobiological, and neuromuscular transmission firing, leading to neurological and neuromuscular connections. The hope was that this would lead to neurological and neuromuscular changes, leading to movement returning to limbs that previously were unable to move.

Third, the idea and ongoing hope was to achieve maximum brain and body benefits. That would eventually lead to becoming self-initiated complex brain and body movement. I had no idea if this would happen, but it always made sense to me. My studies in “Play Theory” influenced my thinking about this. Play Theory research declared that play was imperative because when play took place, thinking and movement occurred. This play-based process then changed the brain and continued to develop and advance the fine and gross muscles of the body. This also led to the development and ongoing enhancement of movement and physical skill potential.

The Complex New and Novel Brain-Based Multi-Movement Therapy and Jazz

As I progressed with applying my new and novel complex brain-based multi-movement therapy, its application, and the intuitive movement format I was applying (as time progressed and as I began to see the physical and movement changes taking place, all of this began to remind me of jazz. That idea came to mind because (to my understanding of jazz), that jazz music had, at its essence, the application of instrumental musical intuition. This meant that nothing was planned. The music that came into existence (occurred in the intuitive moment), in accordance with what each musician was hearing and playing.

Jazz is usually improvised (i.e., invented as it is played). However, the musician had to be highly skilled to be able to play the musical instrument in question. This skill level could only be achieved through hard work and unrelenting practice (Alterhaug, 2004; Benson, 2006; Torrance and Schumann, 2019; Zack, 2000).

Jazz is characterised by a strong but flexible rhythmic understructure with solo and ensemble improvisations on basic tunes and chord patterns and, more recently, a highly sophisticated harmonic idiom (Alterhaug, 2004; Benson, 2006; Torrance and Schumann, 2019; Zack, 2000).

Jazz music is (as noted), played by highly skilled and talented musicians in various increasingly complex styles. It is generally marked by intricate, propulsive rhythms, polyphonic ensemble playing, improvisatory, virtuosic solos, melodic freedom, and a harmonic idiom ranging from simple rhythms to complicated atonality (Alterhaug, 2004; Benson, 2006; Torrance and Schumann, 2019; Zack, 2000).

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Plasma Proteomics and social relationships

A new study published in Nature Human Behaviour unveils the intricate biological links between social isolation, loneliness, and a plethora of health outcomes, including cardiovascular disease, diabetes, and mortality. By leveraging data from 42,062 participants in the UK Biobank, the researchers have deciphered plasma proteomic signatures that provide a molecular-level understanding of how social relationships, or the lack thereof, influence human health.

Social connections are fundamental to human survival and well-being, yet modern societies face an increasing prevalence of social isolation and loneliness. These two constructs, while related, represent distinct facets of social disconnection: the former being an objective state of limited social interactions and the latter a subjective feeling of being alone. Both have been empirically linked to increased morbidity and mortality, with effects comparable to traditional risk factors like smoking and obesity. However, the biological mechanisms mediating these associations have remained elusive – until now.

This comprehensive study utilized high-throughput plasma proteomics to explore the proteomic profiles associated with social isolation and loneliness. The findings illuminate shared and distinct molecular pathways, particularly those involving inflammation, antiviral responses, and complement systems, that underlie the health impacts of social disconnection. Furthermore, the study extends beyond correlation, employing Mendelian randomization (MR) to infer causality, thereby identifying five key proteins—GFRA1, ADM, FABP4, TNFRSF10A, and ASGR1—as central mediators in the relationship between loneliness and adverse health outcomes.

Proteins, as the functional products of gene expression, are critical to understanding disease mechanisms and represent prime targets for therapeutic interventions. In this study, 776 proteins were initially associated with social isolation and 519 with loneliness, with 175 and 26 proteins, respectively, maintaining significance after rigorous statistical adjustments. Growth differentiation factor 15 (GDF15), an inflammatory marker, emerged as the most strongly associated protein with social isolation, while proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of cholesterol metabolism, was most significantly linked to loneliness. Importantly, over 50% of these proteins were prospectively linked to major diseases and mortality over a 14-year follow-up.

The interplay between these proteins and health was further dissected using protein-protein interaction (PPI) networks and pathway enrichment analyses. Hub proteins such as interleukin 6 (IL6) and intercellular adhesion molecule-1 (ICAM1) were identified, underscoring the pivotal role of immune and inflammatory pathways in the biological impact of social disconnection. Notably, proteins linked to social isolation exhibited enrichment in complement activation and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways, while loneliness was associated with metabolic and antiviral processes.

Building on these findings, the study employed MR analysis to infer causal relationships. Loneliness was causally linked to changes in the abundance of five proteins, with ADM and ASGR1 showing strong evidence of colocalization, indicating a shared genetic basis for loneliness and these protein levels. ADM, a protein involved in neuroendocrine stress responses and inflammation, exhibited robust associations with systemic biomarkers such as C-reactive protein (CRP) and brain regions implicated in interoception and emotional processing. These findings highlight ADM’s central role in translating the experience of loneliness into physiological changes that predispose individuals to disease.

The study also explored the mediating role of these proteins in the relationship between loneliness and health outcomes. ADM was identified as a key mediator, explaining up to 16.3% of the excess mortality risk associated with loneliness. The findings suggest that loneliness exerts its health effects not only through behavioral pathways, such as reduced physical activity or unhealthy diets, but also through direct biological mechanisms involving specific proteins and pathways.

To validate these findings, the researchers conducted extensive sensitivity analyses, including stratified analyses by sex, age, and ethnicity, as well as replication in a representative subset of the UK Biobank. The robustness of the results was further supported by cross-validation, colocalization analyses, and mediation modeling. While the study is limited by the observational nature of the data and the inability to measure protein levels in specific tissues, the authors argue that the plasma proteome provides a valuable window into systemic physiological processes.

This research represents a significant leap forward in understanding the biological basis of social relationships and their impact on health. By identifying specific proteins and pathways involved in the effects of social isolation and loneliness, the study opens new avenues for targeted interventions. Potential strategies could include developing drugs that modulate the activity of these proteins, designing biomarkers for early detection of at-risk individuals, or implementing public health policies aimed at reducing social disconnection.

The study underscores the critical importance of social relationships for human health and survival. The proteomic signatures of social isolation and loneliness reveal a complex interplay between biological, psychological, and social factors, offering a comprehensive framework for addressing the health consequences of social disconnection. As societies grapple with the challenges of an increasingly disconnected world, these findings provide a compelling case for prioritizing social relationships as a public health imperative.

Subject of Research: Plasma proteomics and social relationships

Article Title: Plasma proteomic signatures of social isolation and loneliness associated with morbidity and mortality

News Publication Date: 03 January 2025

Article Doi References: 10.1038/s41562-025-00987-5 Image Credits: Not specified

Keywords: Social isolation, Loneliness, Plasma proteomics, Morbidity, Mortality, Inflammation, Mendelian randomization, Public health, Cardiovascular disease, ADM protein