Familial Alzheimer’s Disease Neurons Bearing Mutations in PSEN1 Display Increased Calcium Responses to AMPA as an Early Calcium Dysregulation Phenotype

Author:

Targa Dias Anastacio Helena1ORCID,Matosin Natalie2ORCID,Ooi Lezanne1ORCID

Affiliation:

1. Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia

2. School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia

Abstract

Familial Alzheimer’s disease (FAD) can be caused by mutations in PSEN1 that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca2+) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD; however, it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess the early calcium and glutamate phenotypes of FAD by measuring the Ca2+ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA, and kainate compared to isogenic control and healthy lines. The data show that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca2+ responses to glutamate and AMPA, but not NMDA or kainate. Together, this suggests that PSEN1 mutations alter Ca2+ and glutamate signaling as an early phenotype of FAD.

Funder

National Health and Medical Research Council

Publisher

MDPI AG

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