Victoria Fernandez (United States of America)
Washington University in St. Louis
Hope center for Neurology Disorders
Dr. Fernandez has broad expertise and extensive experience in the field of genetics that started with her study of population genetics and phylogenetic analyses in non-model organisms. She now investigates the genetics of neurodegenerative diseases in humans. As a postdoctoral researcher, she dove into the genetics of Alzheimer’s disease (AD) by analyzing whole-exome sequence data from early onset AD (EOAD) individuals as well as families highly affected by the disease, either late onset AD (LOAD) or autosomal dominant AD (ADAD) families. Now, as an assistant professor she investigates -omic technologies to identify common, altered pathways among the three main AD etiologies (ADAD, EOAD, and LOAD). In addition, she uses iPSC and 3D models to interrogate novel findings and their potential as therapeutic targets in the context of Alzheimer’s disease.

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 Conference Calendar

EXAMINING THE ROLE OF AGFG2 IN AΒ METABOLISM FOR ALZHEIMER DISEASE

Session Name
0760 - DISEASE MECHANISMS, INFLAMMATION. MICROGLIA, ASTROCYTES, AMYLOIDS (ID 128)
Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 113
Lecture Time
02:45 PM - 03:00 PM
Presenter

Abstract

Aims

There are three main clinical presentations in Alzheimer disease (AD) with diversity in phenotype, onset and progression of clinical symptoms: autosomal dominant (ADAD), early onset (EOAD) and late onset (LOAD); yet, they share the common AD pathology: deposition of Aβ and ptau protein aggregates in the brain. This work aims to identify and characterize common disrupted pathways across AD etiologies.

Methods

We examined bulk transcriptomic data from brain donors to the DIAN (ADAD, N=19) and Knight-ADRC (EOAD, N=13; LOAD, N=55; controls (CO), N=16). Through differential gene expression (DGE) analyses, we identified common signals across AD etiologies. We used three independent datasets to replicate our findings and followed our top gene using functional assays that include iPSC and N2A cells.

Results

DGE analysis in our discovery dataset identified AGFG2, a gene under the AD GWAs signal for NYAP1, to have higher expression ((p=7×10-4) in ADAD, EOAD or LOAD compared to CO. This effect was replicated in Mount Sinai (p=8.63×10-3), Mayo (p=5.88×10-12) and ROSMAP (p=3.96×10-05). We have overexpressed human AGFG2 on N2a APP695wt and observed, via ELISA, an increase in extracellular Aβ40 and Aβ42. Using brain single cell nuclei data, we identified that astrocytes are the main cell type expressing AGFG2. We have cultured human iPSC-derived astrocytes and knockdown this gene using siRNA.

Conclusions

AGFG2 is a gene primarily expressed in astrocytes and we have observed that higher AGFG2 leads to higher extracellular Aβ40 and Aβ42. Upcoming experiments will use iPSC-derived astrocytes to further identify the relationship between AGFG2 and Aβ.

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