Tauopathies are a group of neurodegenerative diseases characterized by pathological changes in tau proteins. Among these diseases, Alzheimer’s disease (AD) is perhaps the most well-known. A defining feature of tauopathies is the presence of intracellular neurofibrillary tangles (NFTs), which are primarily composed of hyperphosphorylated aggregates of tau protein. These tangles play a significant role in the progression of neurodegeneration and are closely linked to cognitive decline observed in affected individuals.
Recent research has made significant strides in understanding the mechanisms underlying tauopathies. A groundbreaking study published in the journal Science and conducted by a team of researchers at the University of Pennsylvania has shed light on a novel protein known as TRIM11. This triple motif protein has been identified as playing a crucial role in safeguarding soluble tau monomers from misfolding and irregular aggregation through a variety of mechanisms. Importantly, the study revealed that patients with Alzheimer’s disease exhibit markedly reduced levels of TRIM11 in their brains, suggesting a potential link between TRIM11 deficiency and tau pathology.
The application of TRIM11-targeted therapy has demonstrated remarkable effectiveness in combating tau pathology and neuroinflammation. In experiments conducted across three distinct mouse models—including the widely used 3xTg-AD mouse model, which simulates various aspects of Alzheimer’s disease—treatment with TRIM11 resulted in significant improvements in both cognitive and motor performance. These findings indicate that TRIM11 may represent a promising therapeutic target for the treatment of tauopathies, offering new hope for individuals affected by these debilitating conditions.
The preservation of proteins’ normal structure and physiological function is governed by a built-in protein quality control (PQC) system found within all organisms. This intricate system includes several components: degradation pathways that recycle faulty proteins, molecular chaperones that help prevent protein misfolding and aggregation, and depolymerization enzymes that break down pre-existing protein deposits. The failure of this system can lead to the accumulation of misfolded proteins, contributing to various neurodegenerative diseases, including tauopathies.
Triple motif proteins (TRIMs) constitute a class of proteins characterized by their unique cyclic structural domain, B-box motif, and coiled helix structure. These proteins are found exclusively in multicellular organisms, with over 70 TRIM proteins having been identified to date. Emerging evidence suggests that TRIM proteins play a significant role in the mechanisms of PQC, making them essential players in cellular health and disease.
In this recent study, the researchers focused on TRIM11 in an effort to unlock the key to regulating tau proteins. Their analytical approach involved two core strategies. Firstly, they systematically evaluated nearly all known human TRIM proteins to assess their ability to eliminate tau aggregates from cultured cells. Secondly, they conducted a comparative analysis of TRIM proteins in brain tissue samples obtained from Alzheimer’s disease patients with varying levels of tau pathology and compared these to samples from healthy control subjects.
The specific tau protein under investigation was tau P301L, a mutant tau protein associated with familial tauopathies. Out of the 75 TRIM proteins analyzed, TRIM10, TRIM11, and TRIM55 exhibited exceptional outcomes, effectively degrading nearly all tau P301L aggregates. Remarkably, knocking down TRIM10, TRIM11, or TRIM55 using CRISPR technology led to an 80–130% increase in tau protein aggregation levels, highlighting their critical roles in maintaining tau homeostasis.
Among the investigated TRIM proteins, TRIM11 stood out as having the most substantial impact on tau regulation. Further research included a detailed comparison of mRNA and protein levels of TRIM10, TRIM11, and TRIM55 in brain tissue samples from 23 sporadic AD patients and 14 age- and sex-matched controls without known neurodegenerative diseases. While the mRNA levels of all three proteins remained similar across both groups, TRIM11 protein levels were significantly reduced in the brains of AD patients, witnessing a decline of approximately 55%. Concurrently, immunofluorescence analysis confirmed a decrease in neuron count in the affected brains. The fact that transcriptional levels of TRIM11 were unchanged suggests the presence of a post-transcriptional regulatory mechanism.
Delving deeper into the mechanisms at play, the researchers identified three primary ways in which TRIM11 orchestrates the regulation of tau levels. Firstly, TRIM11 can bind to tau proteins—particularly those that are mutant or hyperphosphorylated—and facilitate their ubiquitination, which culminates in proteasome-mediated degradation. Secondly, TRIM11 functions as a molecular chaperone for tau proteins, preventing their misfolding and aggregation. Lastly, TRIM11 possesses the ability to degrade tau proteins directly and dissolve existing tau protein deposits, showcasing its multifaceted role in combating aberrant tau accumulation.
To investigate the effects of TRIM11 further, the research team conducted experiments using two specific mouse models. The first was PS19 mice, a tauopathy model featuring the common tau mutant P301L, which gradually accumulates tau deposits. In these mice, injections of pre-formed tau protofibrils were used to intensify disease symptoms. The second model, 3xTg-AD mice, expresses tau P301L along with APP and PSEN1 mutations.
Targeted injections of TRIM11 into the hippocampus of 2.5-month-old PS19 mice via AAV9 vectors demonstrated a remarkable 55% reduction in tau lesions within the brains of treated mice by the age of 10 months. Cognitive testing indicated preserved long-term memory, and the treated mice exhibited enhanced motor skills compared to untreated controls. Similar outcomes were observed in the other mouse models used in the study.
In addition, the researchers administered TRIM11 via cerebrospinal fluid to 3xTg-AD mice. This treatment resulted in a 35% reduction in hippocampal tau protein and a 50–70% reduction in neurofibrillary tangles. The treated mice displayed improved motor and cognitive performance compared to their controls, reinforcing the potential therapeutic benefits of TRIM11.
Given that abnormalities in tau proteins are believed to be more pivotal than amyloid beta (Aβ) in the progression of Alzheimer’s disease, targeting tau proteins has emerged as a potent therapeutic avenue. The discovery of TRIM11’s critical role in regulating tau proteins holds immense promise for advancing treatment strategies for Alzheimer’s disease and other tauopathies. As research continues to unfold, TRIM11 may pave the way for innovative therapeutic approaches aimed at mitigating the devastating effects of these neurodegenerative disorders.
