Single-Cell RNA-sequencing of neural precursor cells from an Alzheimer's mouse model, wild-type mice, and Alzheimer's mice rescued with Usp16 haploinsufficiency

Alzheimer’s disease (AD) is a progressive neurodegenerative disease
observed with aging that represents the most common form of
dementia. To date, therapies targeting end-stage disease plaques, tangles,
or inflammation have limited efficacy. Therefore, we set out to identify
an earlier targetable phenotype. Utilizing a mouse model of AD we
found that cell intrinsic neural precursor cell (NPC)
dysfunction precedes widespread inflammation and amyloid plaque
pathology, making it one of the earlier defects
in the evolution of the disease. We demonstrate that reversing
impaired NPC self-renewal via genetic reduction of USP16, a
histone modifier and critical physiological antagonist of the
Polycomb Repressor Complex 1, can prevent downstream cognitive
defects and decrease astrogliosis in vivo. To delineate potential
self-renewal pathways that might contribute to the defect and rescue of
Tg-SwDI NPCs and Tg-SwDI/Usp16+/- NPCs, respectively, we
performed single-cell RNA-seq and gene set enrichment analysis (GSEA) on
lineage depleted primary FACS-sorted CD31-CD45-Ter119-CD24- NPCs
from Tg-SwDI, WT, and Tg-SwDI/Usp16+/- mice at 3-4 months and 1
year of age. Using the GSEA Hallmark gene sets,
we found only three gene sets that were enriched in Tg-SwDI mice over WT
mice and rescued in the Tg-SwDI/Usp16+/- mice at both ages: TGF-ß
pathway, oxidative phosphorylation, and Myc Targets. The TGF-ß pathway
consistently had the highest normalized enrichment score in pairwise
comparisons between Tg-SwDI vs WT and Tg-SwDI vs Tg-SwDI/Usp16+/- of the
three rescued pathways. These data suggest that USP16 may regulate neural
precursor cell function in part through the BMP pathway.