Alzheimer's disease risk modifier genes do not affect tau aggregate uptake, seeding or maintenance in cell models

Sourav Kolay, Marc I. Diamond

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's 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’. We have used HEK293T cells to model various aspects of pathological tau propagation, including uptake of tau aggregates, induced seeding by exogenous aggregates, seeding caused by Lipofectamine-mediated delivery to the cell interior, and stable maintenance of aggregates in dividing cells. 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 study (GWAS). We used CRISPR/Cas9 to individually knock out each 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 these cultured cell lines. GWAS gene knockouts had no effect in these models of tau pathology. With obvious caveats due to the model systems used, these results imply that the 22 AD risk modifier genes are unlikely to directly modulate tau uptake, seeding, or aggregate maintenance in a cell-autonomous fashion.

Original languageEnglish (US)
Pages (from-to)1912-1920
Number of pages9
JournalFEBS Open Bio
Volume10
Issue number9
DOIs
StatePublished - Sep 1 2020

Keywords

  • Alzheimer's disease
  • Alzheimer's risk factors
  • GWAS
  • Tau prion mechanism
  • Tau propagation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Alzheimer's disease risk modifier genes do not affect tau aggregate uptake, seeding or maintenance in cell models'. Together they form a unique fingerprint.

Cite this