Autosomal Dominant Alzheimer’s Disease Mutations in Human Microglia Are Not Sufficient to Trigger Amyloid Pathology in WT Mice but Might Affect Pathology in 5XFAD Mice

Author:

Romero-Molina Carmen1,Neuner Sarah M.1,Ryszawiec Marcelina1,Pébay Alice2, ,Marcora Edoardo1,Goate Alison1

Affiliation:

1. Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA

2. Department of Anatomy and Physiology, Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC 3010, Australia

Abstract

Several genetic variants that affect microglia function have been identified as risk factors for Alzheimer’s Disease (AD), supporting the importance of this cell type in disease progression. However, the effect of autosomal dominant mutations in the amyloid precursor protein (APP) or the presenilin (PSEN1/2) genes has not been addressed in microglia in vivo. We xenotransplanted human microglia derived from non-carriers and carriers of autosomal dominant AD (ADAD)-causing mutations in the brain of hCSF1 WT or 5XFAD mice. We observed that ADAD mutations in microglia are not sufficient to trigger amyloid pathology in WT mice. In 5XFAD mice, we observed a non-statistically significant increase in amyloid plaque volume and number of dystrophic neurites, coupled with a reduction in plaque-associated microglia in the brain of mice xenotransplanted with ADAD human microglia compared to mice xenotransplanted with non-ADAD microglia. In addition, we observed a non-statistically significant impairment in working and contextual memory in 5XFAD mice xenotransplanted with ADAD microglia compared to those xenotransplanted with non-ADAD-carrier microglia. We conclude that, although not sufficient to initiate amyloid pathology in the healthy brain, mutations in APP and PSEN1 in human microglia might cause mild changes in pathological and cognitive outcomes in 5XFAD mice in a manner consistent with increased AD risk.

Funder

JPB Foundation

Dominantly Inherited Alzheimer Network

National Institute on Aging

NHMRC Senior Research Fellowship

Yulgilbar Alzheimer’s Research Program

Publisher

MDPI AG

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