CT-KIBRA-mediated Synaptic Repair as a Therapeutic Strategy for Cognitive Restoration in Tauopathies

Significance 

Tauopathies are neurodegenerative diseases characterized by the abnormal accumulation of tau protein in the brain. Tau is a microtubule-associated protein primarily involved in stabilizing microtubules in neuronal cells. Microtubules are essential components of the cell’s cytoskeleton, playing a critical role in nutrient transport, cell signaling, and neuronal plasticity. In healthy individuals, tau helps maintain the stability of these structures, but in tauopathies, tau proteins become abnormally phosphorylated and accumulate into insoluble aggregates known as neurofibrillary tangles leading to cell death and brain dysfunction. The tauopathies encompass a wide range of disorders, each with its own set of clinical features, though they share the common pathology of tau protein aggregation. These include Alzheimer’s disease (AD) which is the most common tauopathy, where tau pathology coexists with amyloid-beta plaque formation. Neurofibrillary tangles primarily accumulate in the hippocampus and cortical regions, leading to memory loss, cognitive decline, and behavioral changes. Another taupathy disease frontotemporal dementia which is characterized by degeneration in the frontal and temporal lobes of the brain, affecting behavior, language, and movement. Certain subtypes of FTD, such as Pick’s disease, are associated with tau protein accumulation. The precise mechanism by which tau pathology leads to neurodegeneration is not fully understood, but it is believed that the abnormal tau disrupts cellular functions by impairing microtubule stability, interfering with axonal transport, and promoting inflammation and cell death. Currently, there is no cure for tauopathies, and treatment focuses on managing symptoms. Research is ongoing to develop therapies that can reduce tau pathology or prevent tau aggregation. For instance, tau immunotherapies, which aim to clear aggregated tau or prevent its formation using antibodies, are under investigation. Other approaches include targeting tau phosphorylation, enhancing tau clearance mechanisms, and stabilizing microtubules. Understanding tauopathies is critical for developing effective treatments for these debilitating disorders. As research progresses, it is hoped that new insights into tau biology will lead to breakthroughs in preventing and treating these conditions. To address these challenges, a new study published in the Journal of Clinical Investigation and led by Professor Tara  Tracy from the Buck Institute for Research on Aging in California and conducted by Grant Kauwe, Kristeen  Pareja-Navarro, Lei Yao, Jackson  Chen, Ivy Wong, Rowan Saloner, Helen Cifuentes, Alissa L. Nana, Samah Shah, Yaqiao Li, David Le, Salvatore Spina, Lea Grinberg, William Seeley, Joel Kramer, Todd Sacktor, Birgit Schilling, Li Gan, and Kaitlin Casaletto, the authors investigated the impact of pathogenic tau on synaptic plasticity and memory in AD and related tauopathies, highlighting a potential therapeutic approach.

A novel focus of this research is on KIdney/BRAin (KIBRA), a postsynaptic protein linked to memory and AD risk. KIBRA levels are significantly reduced in AD brains, correlating with cognitive impairment and abnormal tau modifications. Intriguingly, elevated KIBRA levels in cerebrospinal fluid are associated with cognitive decline and tau pathology, suggesting its potential as a biomarker for synaptic dysfunction in tauopathy. The team introduced the concept of synaptic repair via the C-terminus of the KIBRA protein (CT-KIBRA), demonstrating its ability to restore synaptic plasticity and memory in mouse models of tauopathy without altering pathogenic tau levels or preventing tau-induced synapse loss. Mechanistically, CT-KIBRA enhances synaptic function through stabilization of protein kinase Mζ (PKMζ), crucial for maintaining LTP and memory despite tau-mediated pathology. This identifies KIBRA as not only a biomarker but also a foundation for synapse repair mechanisms to counteract cognitive impairment in tauopathy. Further investigations revealed associations between KIBRA levels in human brain and CSF with tau pathology and cognitive impairment, underscoring its relevance across different tauopathies. The study’s innovative approach using a truncated version of KIBRA (CT-KIBRA) to counteract synaptic plasticity and memory impairments in transgenic mouse models of tauopathy, without modifying tau pathology directly, provides a promising therapeutic strategy.

CT-KIBRA’s efficacy in reversing synaptic dysfunction and memory loss, despite the presence of tau pathology, suggests a mechanism that enhances synaptic resilience to tau toxicity. The stabilization of PKMζ by CT-KIBRA, facilitating the maintenance of synaptic plasticity and memory, underscores a targeted approach for cognitive restoration in tauopathies. The new work enhances our understanding of the molecular underpinnings of tau-induced cognitive decline and opens avenues for developing therapies aimed at synaptic repair and cognitive function restoration in neurodegenerative diseases marked by tau pathology. Moreover, the research provided critical insights into how pathological tau disrupts synaptic plasticity, a fundamental process underlying memory formation and learning. By establishing a link between pathogenic tau, the reduction of KIBRA protein levels in the brain, and synaptic dysfunction, the study deepens our understanding of the molecular mechanisms leading to cognitive impairments in tauopathies. Moreover, the discovery that changes in KIBRA levels in the cerebrospinal fluid correlate with cognitive impairment and pathological tau levels in disease highlights its potential as a biomarker for diagnosing and monitoring the progression of tauopathies. Furthermore, identifying KIBRA’s role in modulating synaptic signaling and strength positions it as a promising therapeutic target for restoring cognitive functions in neurodegenerative diseases. Furthermore, the study introduces a novel therapeutic approach using the CT-KIBRA to reverse synaptic dysfunction and memory loss in tauopathy models. This strategy focuses on enhancing synaptic resilience and function without directly altering tau pathology, suggesting a potential treatment pathway that could be complementary to therapies targeting tau and other pathological aggregates directly. By demonstrating that CT-KIBRA can restore synaptic plasticity and cognitive functions in mouse models through the stabilization of protein kinase Mζ (PKMζ), the research lays the groundwork for developing synapse repair mechanisms as a therapeutic avenue. This approach could benefit a wide range of neurodegenerative diseases characterized by synaptic dysfunction and cognitive decline. Additionally, the authors’ findings have implications beyond Alzheimer’s disease, encompassing a spectrum of tauopathies. The ability of CT-KIBRA to improve cognitive functions in models of tauopathy, regardless of the specific tau pathology, suggests a universal strategy that could be applied across different diseases marked by tau accumulation and synaptic impairment. Overall, the study by Professor Tara Tracy and her colleagues demonstrated a link between KIBRA, synaptic dysfunction, and cognitive decline in tauopathies, and proposed a novel and promising therapeutic strategy focused on synaptic repair. The potential to apply the authors’ findings across a range of neurodegenerative conditions will be a step forward in the search for effective treatments for these challenging diseases.

CT-KIBRA-mediated Synaptic Repair as a Therapeutic Strategy for Cognitive Restoration in Tauopathies - Medicine Innovates

About the author

Tara Tracy, PhD
Assistant Professor
Buck Institute for Research on Aging

Synapses are specialized structures that are critical for the transmission of information between neurons in the brain. Fine-tuning of the electrochemical activity at synapses underlies cognitive processes. In Alzheimer’s disease, memory loss coincides with synapse deterioration. The Tracy lab is investigating the molecular events that lead to synapse dysfunction and cognitive decline in Alzheimer’s disease and frontotemporal dementia. We think that synapses are particularly vulnerable to toxicity early in the progression of dementia before neurons begin to die. Tau, a microtubule-associated protein, accumulates in the brain and becomes toxic to neurons in Alzheimer’s disease and frontotemporal dementia. We are exploring how tau-mediated toxicity contributes to the emergence of synapse pathophysiology in these diseases. We are using mouse models and human induced pluripotent stem cell (iPSC)–derived neurons to dissect the mechanisms that trigger synapse and neuronal dysfunction during pathogenesis. Our long-term goal is to establish a foundation for new treatment strategies to restore synapse function and cognition at the early stages of disease progression before neurons are lost.

Reference 

Kauwe G, Pareja-Navarro KA, Yao L, Chen JH, Wong I, Saloner R, Cifuentes H, Nana AL, Shah S, Li Y, Le D, Spina S, Grinberg LT, Seeley WW, Kramer JH, Sacktor TC, Schilling B, Gan L, Casaletto KB, Tracy TE. KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss. J Clin Invest. 2024 Feb 1;134(3):e169064. doi: 10.1172/JCI169064.

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