Theses Doctoral

Innate and Adaptive Immune Dynamics in Alzheimer’s and Parkinson’s Disease

Chatila, Zena

Myeloid cells of the innate immune system have been strongly implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Similarly, several lines of evidence call on the adaptive immune system as a critical driver of disease, particularly in PD. The immune dynamics in both of these diseases are complex, and span across not only the innate and adaptive immune systems, but also across the periphery local action in the central nervous system (CNS). This thesis aims to address critical gaps in our knowledge regarding molecular and functional alterations of immune cells in AD and PD. We apply tools including single nucleus RNA – and ATAC – sequencing as well as protein – level and functional studies to advance our understanding of molecular pathways involved in the innate and adaptive immune dysfunction in these diseases, including both immune cells in the CNS as well as in the periphery.

Chapter 1 provides an overview of the evidence implicating myeloid cell dysfunction in AD and PD, including microglia as well as peripheral myeloid cells such as monocytes. It also describes the features of immune dysregulation in both diseases, and evidence implicating the adaptive immune system in PD.

Chapter 2 aims to address our currently limited understanding of microglial molecular phenotypes and diversity in PD, by characterizing microglial transcriptomic and chromatin signatures in disease. We demonstrate microglial subpopulation-specific effects, including the focal depletion of a microglial population in the substantia nigra in PD, which open novel avenues for targeted neuroimmune interventions in PD.

Chapter 3 aims to identify interactions regulating the infiltration and retention of peripheral immune cells into the CNS in PD; a process which is implicated in the progression of this disease, but the mechanisms of which are not fully understood. We characterized transcriptomic signatures of infiltrating lymphocytes and blood brain barrier cells, and found increased T cell infiltration in PD as well as fibroblast and endothelial populations associated with disease. We further identified transcriptional shifts suggestive of a proinflammatory and profibrotic milieu in disease, in which chemokines and extracellular matrix elements produced by fibroblasts may influence T cell trafficking and retention in the substantia nigra in PD. Chapter 4 aims to address the gap in our knowledge of how myeloid dysfunction in the periphery contributes to AD.

While genetics implicate all myeloid cells in AD and PD, contributions of peripheral myeloid cells, such as monocytes, have been largely overlooked in place of microglia, which are resident in the CNS. We evaluate the convergence of the AD genetic risk loci on functional outcomes in monocytes, in the context of Aβ as an immune stimulus. We identified functional convergence of the CD33 and SPI1 AD risk variants in the context of Aβ stress, including reduced phagocytosis and loss of surface TREM2 expression, demonstrating an interaction between genetics and environment to reduce myeloid cell fitness. Finally, Chapter 5 concludes with a summary of key findings from this work, and discusses future directions for modulating innate and adaptive immune populations, both in the CNS and in the periphery, as therapeutic approaches for these neurodegenerative diseases.


This item is currently under embargo. It will be available starting 2026-02-22.

More About This Work

Academic Units
Neurobiology and Behavior
Thesis Advisors
Bradshaw, Elizabeth
Ph.D., Columbia University
Published Here
February 28, 2024