Language
English
Publication Date
7-3-2024
Journal
Neuron
DOI
10.1016/j.neuron.2024.04.009
PMID
38692279
PMCID
PMC11223975
PubMedCentral® Posted Date
7-3-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Genome-wide association studies (GWASs) have uncovered over 75 genomic loci associated with risk for late-onset Alzheimer's disease (LOAD), but identification of the underlying causal genes remains challenging. Studies of induced pluripotent stem cell (iPSC)-derived neurons from LOAD patients have demonstrated the existence of neuronal cell-intrinsic functional defects. Here, we searched for genetic contributions to neuronal dysfunction in LOAD using an integrative systems approach that incorporated multi-evidence-based gene mapping and network-analysis-based prioritization. A systematic perturbation screening of candidate risk genes in Caenorhabditis elegans (C. elegans) revealed that neuronal knockdown of the LOAD risk gene orthologs vha-10 (ATP6V1G2), cmd-1 (CALM3), amph-1 (BIN1), ephx-1 (NGEF), and pho-5 (ACP2) alters short-/intermediate-term memory function, the cognitive domain affected earliest during LOAD progression. These results highlight the impact of LOAD risk genes on evolutionarily conserved memory function, as mediated through neuronal endosomal dysfunction, and identify new targets for further mechanistic interrogation.
Keywords
Alzheimer Disease, Caenorhabditis elegans, Animals, Humans, Genome-Wide Association Study, Systems Biology, Memory, Induced Pluripotent Stem Cells, Neurons, Genetic Predisposition to Disease, Caenorhabditis elegans Proteins
Published Open-Access
yes
Recommended Citation
Hudgins, Adam D; Zhou, Shiyi; Arey, Rachel N; et al., "A Systems Biology-Based Identification and in Vivo Functional Screening of Alzheimer’s Disease Risk Genes Reveal Modulators of Memory Function" (2024). Faculty, Staff and Students Publications. 7970.
https://digitalcommons.library.tmc.edu/baylor_docs/7970