Catalyst Grant Projects

Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by progressive motor deficits such as tremor, muscle stiffness, and slowness of movement, and affects 6 million worldwide. Despite ongoing efforts to discover the mechanisms underlying this disease, PD remains an incurable disorder.

Normal aging and neurodegenerative disease are typically characterized by accumulation of waste products inside the brain and in particular by aggregation of various types of proteins like Amyloid-beta outside of cells or the proteins Tau, alpha-synuclein, and TDP-43 inside cells.

The ketogenic diet, fasting, and ketone supplements switch the body's fuel source from carbs to fats, a state known as ketosis. This switch can be good for your brain, helping to keep it healthy and resilient to damage. In ketosis, your liver makes a special fat-derived fuel called beta-hydroxybutyrate, or BHB for short.

Brain resilience, the ability to withstand adverse outcomes despite significant risk factors, is crucial in late-onset Alzheimer’s disease (AD), where the Apolipoprotein E4 (APOE4) gene is a major risk factor. Carrying APOE4 increases AD risk up to 15-fold compared to the ApoE3 allele.

Current treatments for neurodegenerative disorders (proteinopathies) offer limited efficacy and typically target specific genetic forms. The goal of this research project is to discover targets shared across proteinopathies and advance the development of early diagnostic/prognostic tools and disease-modifying pan-proteinopathy approaches.

Recent data suggest that increased circulation of cerebrospinal fluid (CSF) to clear the brain and spinal cord of waste is associated with improved outcomes in aging and recovery from brain injury, suggesting that inducing CSF clearing could enhance brain resilience. However, a therapeutic modality for directly inducing CSF clearing has not been available.

Myelin, traditionally thought of as the brain's electrical insulator, has emerged as an active and dynamic regulator of brain functions including neuroprotection, learning, and memory. Myelin dysfunction and loss is increasingly found to be central to brain aging and neurodegenerative diseases including Alzheimer's.

It has been appreciated for decades years that cognitive decline and dementia are frequently accompanied by changes that cause proteins within brain cells to clump abnormally into structures called neurofibrillary tangles. Resilient brains are better able to resist this process but the underlying mechanisms for why individuals’ brains are more or less resilient are not fully understood.

Memories are stored at synapses and circuits, which tragically are pruned and deconstructed in Alzheimer's disease (AD). Genetic mutations including APP generate high levels of soluble oligomeric beta amyloid (oAbeta42), leading to insoluble beta amyloid plaques - hallmarks of late-stage disease. Clinical trials have designed "plaque-busting" drugs assuming that plaques cause disease.

This team aims to use the power of artificial intelligence to make new findings about brain aging, with the goal of boosting brain repair and resilience. They are particularly interested in spatial changes in the brain during aging. Their goal is to understand how aging renders the brain susceptible to injuries that accentuate neurodegenerative diseases.

This team will explore the idea that neurotoxic protein aggregates seen in neurodegenerative disorders act at the synaptic connections between cells, and that resilience against these disorders may come from natural synapse-supporting factors that could be transformed into new forms of therapy.

This team aims to define a network of genes that contribute to stress resistance in neurons and identify how it could be activated to enhance brain resilience and protect against neurodegenerative disease.

Using new animal models such as the African killifish, this team aims to develop approaches to predict individual brain aging trajectories early in life based on behaviors that can be modulated to promote healthy memory, executive function and processing speed as well as counter dementia.

This team aims to be the first to study the cellular and molecular impact of traumatic brain injury by studying genetic material in human cerebrospinal fluid. This will help clinicians and researchers ID markers of brain resilience after injury, and ultimately improve treatment for severe TBI.

This team plans to map how age-related dysfunction of cellular waste disposal in lysosomes could lead to neurodegenerative diseases, potentially laying the foundation for a map of organelle function in the brain.

This team plans to study whether changes in neurons in the midbrain that regulate sleep, wakefulness, and immunity could contribute to aging and neurodegeneration. If successful, this information could rescue deficits in sleep and restore a normal immune profile.

This team proposes the first comprehensive study of how mitochondrial DNA is related to cognitive function and susceptibility to dementia in a diverse population of over 11,000 adults. The outcomes of this study will provide insight into possible racial disparities in brain health.

This team will study the brains of individuals who lived past ninety with their cognitive function intact, using advanced tissue imaging and computer science to understand mechanisms of resilience that could slow neurodegeneration and preserve brain health.

This team aims to better understand how Parkinson's disease attacks the brain's basic motor programs and to spawn novel therapies against the disease using gene-editing technology.

This team aims to discover whether the brain’s endocannabinoid system is dysregulated during aging, triggering inflammation via molecules called prostaglandins. If so, a drug that decouples these systems might restore a youthful brain state and rescue cognitive function.