More than making amyloid-β: Defining the roles for Presenilins in microglial function. — The Association Specialists
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More than making amyloid-β: Defining the roles for Presenilins in microglial function. (21753)

Melissa Eccles 1 2 , Amy Woodfield 1 , Ayeisha Milligan Armstrong 1 , Mark Agostino 1 3 , David Groth 1 , Giuseppe Verdile 1 4
  1. Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia
  2. Centre for Genetics and Experimental Medicine, University of Edinburgh, Edinburgh, Scotland
  3. Curtin Institute for Computation, Curtin University, Bentley, Western Australia, Australia
  4. School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia

Background: Presenilins, of which there are two homologues, Presenilin 1 (PS1) and presenilin 2 (PS2), are the catalytic components of the γ -secretase enzyme, most well-known for its essential role in generating amyloid-beta (Aβ) associated with Alzheimer’s disease (AD). The enzyme is also essential in signalling pathways within microglia and murine studies suggest that presenilins have a role in microglia activity. However, whether there are specific PS1/PS2 roles or associated pathways in microglia remain to be determined.

Objective: To investigate microglia activity and function in human microglia lacking PS1 or PS2.

Methods: PS1/PS2 CRISPR knockout human microglia (HMC3) cells were generated and underwent functional assays that included, expression analysis, morphology, phagocytosis, inflammatory response, and transcriptomics. Computational homology modelling was used to identify potential binding preferences of relevant γ-secretase substrates.

Results: Cells retaining PS2 have increased Aβ phagocytosis, and a specific cytokine response to lipopolysaccharide treatment. However, cells retaining PS1 have a specific cytokine response to Aβ treatment. Transcriptome analysis of these microglial cells revealed distinct transcription profiles between cells with either a PS1+/PS2+, PS1 only or PS2 only genotype, further indicating the functional distinction between PS1 and PS2. Modelling revealed that PS1- and PS2-γ-secretase typically demonstrate specific substrate binding preferences.

Conclusion: In addition to Aβ production, presenilins have essential roles in microglial function and activity. We provide novel evidence that PS1 and PS2 have differential roles in specific microglia functions. These differential roles should be considered when therapeutically targeting γ-secretase in AD.