Autoimmune Mechanisms of Metabolic Dysfunction in the Central Nervous System

PROJECT SUMMARY Up to 25% of individuals in the United States have low serum vitamin B12 levels, leading to hematologic impairment (megaloblastic anemia) and/or neurologic deficits (loss of coordination, memory loss, psychosis). Comorbid B12 deficiency is associated with worse neurologic outcomes in patients with Alzheimer’s disease (AD) and Parkinson’s disease. Therefore, improvements in the diagnosis and treatment of B12 deficiency, either as a primary disease or a comorbid condition, have the potential to substantially improve brain health at a population level. I recently discovered an autoimmune cause of B12 deficiency restricted to the central nervous system (CNS), termed autoimmune B12 central deficiency (ABCD). Using unbiased antigen discovery technology, I identified autoantibodies targeting the transcobalamin receptor (CD320) which inhibit cellular uptake of B12, an essential cofactor for hematopoiesis and myelination. Anti-CD320 is highly predictive (96% specificity) of low B12 in the CSF despite normal B12 in the blood and remarkably prevalent (~10%) in patients with dementia. However, the mechanism by which anti-CD320 impairs B12 transport across the blood-brain barrier (BBB), its effect on neurologic function, and its comorbid contribution to neurodegeneration remain unknown. In Aim 1 of this proposal, I will elucidate the mechanism of action of anti-CD320 at atomic resolution. In Aim 2, I will determine the effects of anti-CD320 on myelination and neurologic function. Finally, in Aim 3, I will measure the prevalence and penetrance of anti-CD320 in AD. A mechanistic understanding of ABCD may lead to substantial improvements in brain health, ameliorate the burden of unexplained neurologic disease, and identify a modifiable contributor to cognitive dysfunction in patients with comorbid neurodegenerative disorders like AD. With the support of my mentors and advisors at the University of California San Francisco, this K08 proposal will allow me to fill training gaps and acquire new technical, communication, and management skills necessary for my transition to an independent investigator role at the interface of autoimmune neurology and neurodegeneration.