Year: 2018
Type: article
Abstract: The Alzheimer's Disease (AD) patient population consists almost entirely (∼98%) of the late-onset form of AD (LOAD); however, most mouse models currently used to develop therapies for AD are based on familial AD (fAD) mutations in APP, PSEN1 or PSEN2. This may contribute to failures moving potential therapies from preclinical models into the clinic. The Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) Center was created to develop, characterize, and distribute more precise preclinical models for LOAD. Because the APOE4 variant and variants at the Trem2 locus are the strongest genetic risk factors for LOAD, we first created a homozygous model expressing humanized APOE4 and the R47H allele of the Trem2 gene. Additional genetic variants were prioritized in loci previously identified by GWAS using data from the IGAP, ADNI, and ADSP projects. These variants have been engineered into the APOE4/Trem2*R47H model to increase the risk of developing AD-like phenotypes. We have created models including SNPs corresponding to risk variants in ABCA7 and MTHFR, and knockouts of mouse Il1rap and Ceacam1. We have also created a humanized APP model by altering the three amino acids that differ between human and mouse Aβ42. In addition, we have created APOE3 and APOE2 variants to serve as controls. We will present validation data including transcriptomics, pathology, and functional assays on the APOE4/Trem2 model; all new models are currently being aged for phenotypic studies, and results will be compared to those from fAD models as well as to clinical data. We have created novel mouse models that express combinations of genetic variants identified in human LOAD patient populations. Our strategy closely integrates human and mouse data, with the aim that these new LOAD models will show a high degree of clinical translatability for preclinical testing of new therapeutic targets. All new models will be made available for both academic and for-profit use from The Jackson Laboratory (www.jax.org/alzheimers ), and all validation data will be shared via the AMP-AD knowledge portal (www.synapse.org/alzheimers ). We seek input and collaborations from the basic research and pharma/biotech communities. For more information see www.model-ad.org.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2897843213