Cell states and neuronal vulnerabilities in neurodegenerative diseases

Abstract

Neurodegenerative diseases are pathologically characterized by the induction of gliotic states and the loss of specific neurons in the human brain. A precise ascertainment of cellular states altered and those types of neurons that are lost has not been made in Alzheimer’s and Parkinson’s disease, the two most common forms of brain degeneration. We employed new single-cell genomic technologies to better understand the cellular alterations that occur in both these diseases. In Parkinson’s disease, we developed a method to enrich midbrain dopaminergic neuronal nuclei from postmortem human samples. Using this strategy, we profiled thousands of these neurons to identify the diversity of these different types in the midbrain. Strikingly, we found one population, confined to the ventral tier of the pars compacta, was uniquely susceptible to Parkinson’s-associated cell loss. This same population was enriched for common variant heritable risk of the disease, suggesting cell-autonomous mechanisms underlie the genetics of PD. To better understand the cellular alterations in Alzheimer’s disease before death, we profiled individuals with suspected idiopathic normal pressure hydrocephalus (iNPH) with comorbid AD pathology. We identified two microglia populations, one increased and one decreased in abundance respectively, and confirmed these alterations in postmortem AD datasets. We further identified a single interneuron subpopulation residing in the uppermost layer of the neocortex as lost especially in the earliest stages of AD pathology. Finally, we find oligodendrocytes are an unrecognized contributor to beta-amyloid pathology. Measurement of beta-amyloid from stem cell-derived human oligodendrocytes confirmed that these cells are a significant producer of this important peptide. This body of work offers compelling evidence towards identifying the specific cellular state changes in association with two common brain diseases, offering new and testable hypotheses for future biological investigations into their pathogenesis.