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.