Alzheimers Disease risk modifier genes do not impact tau aggregate uptake, seeding or maintenance in cell models

Abstract

Alzheimers disease (AD) afflicts millions of people worldwide, and is caused by accumulated amyloid beta and tau pathology. Progression of tau pathology in AD may utilize prion mechanisms of propagation in which pathological tau aggregates released from one cell are taken up by neighboring or connected cells and act as templates for their own replication, a process termed \"seeding.\" In cultured cells we have modeled various aspects of pathological tau propagation, including uptake of aggregates, induced (naked) seeding by exogenous aggregates, seeding caused by Lipofectamine-mediated delivery to the cell interior, and chronic maintenance of aggregates in cells through mother-to-daughter transmission. The factors that regulate these processes are not well understood, and we hypothesized that AD risk modifier genes might play a role. We identified 22 genes strongly linked to AD via meta-analysis of genome-wide association studies (GWAS). We used CRISPR/Cas-9 to individually knock out each in gene in HEK293T cells, and verified disruption using genomic sequencing. We then tested the effect of gene knockout in tau aggregate uptake, naked and Lipofectamine-mediated seeding, and aggregate maintenance in cultured cell lines. GWAS gene knockouts had no effect on these models of tau pathology. With obvious caveats due to the model systems used, these results imply that these 22 AD risk modifier genes do not directly modulate tau uptake, seeding, or aggregate maintenance.