Abdulraouf Abdulraouf (United States of America)
Broad Institute Stanley Center for Psychiatric ResearchAuthor Of 1 Presentation
EARLY ALZHEIMER’S DISEASE PATHOLOGY IN HUMAN CORTEX IS ASSOCIATED WITH A TRANSIENT PHASE OF DISTINCT CELL STATES
Abstract
Aims
How specific cell types change during the initial stages of the Alzheimer’s disease (AD) pathogenic process has been challenging to study within human brain tissue. Here, we aim to assess the degree and types of molecular changes associated with early stage amyloid beta pathology.
Methods
We leveraged a rare cohort of surgical biopsies of the frontal cortex, isolated from patients presenting with normal pressure hydrocephalus (NPH), to characterize cell-type-specific changes in tissue with low levels of amyloid beta plaque burden using high-throughput single-nucleus RNA-seq (snRNA-seq). In total, we sampled 892,828 profiles from 52 biopsies. Using robust computational methods, we additionally integrated these data with 27 published studies of postmortem AD and other neurological diseases, for a total of 2.4 million profiles, to nominate consistent changes across our cohorts.
Results
In neurons, we identified a prominent and selective loss of layer 1 inhibitory neuron populations expressing NDNF along with a concurrent, transient increase in metabolic activity and excitability in upper layer pyramidal neurons. Within microglia, we characterized expanded states overexpressing neuroinflammatory-related processes (including autophagy and TGF-beta signaling), which increased in magnitude with higher AD pathological burden. Finally, in both oligodendrocytes and neurons, we nominated a transient early rise in amyloid beta production, and validated the intrinsic amyloid production capacity in both cell types using stem cell-derived cultures.
Conclusions
Collectively, we have identified four components of a unique, transient response to early amyloid pathology, which we collectively refer to as the Early Cortical Amyloid Response (ECAR). Our insights define a distinct, largely transient phase in AD pathogenesis, in which neural circuit hyperactivity, selective interneuron loss, specific microglial state alterations and amyloid beta production by neurons and oligodendrocytes are prominent features.