Moderator of 1 Session
Presenter of 1 Presentation
LOAD2: A NOVEL MOUSE MODEL FOR INVESTIGATING INTERACTIONS BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS FOR LATE-ONSET ALZHEIMER'S DISEASE
Abstract
Aims
MODEL-AD (Model Organism Development and Evaluation for Late-onset AD) is developing and characterizing novel mouse models that aim to better phenocopy human LOAD for preclinical testing.
Methods
APOE4 and Trem2*R47H were incorporated into C57BL/6J (B6) mice to produce LOAD1. A humanized amyloid-beta (Aβ) allele was added to LOAD1 mice to form the LOAD2 strain. Female and male LOAD1 and LOAD2 mice on control diet (CD) or high fat diet (HFD) are being assessed for behavior, cognition, in vivo imaging of brain perfusion and metabolism, fluid biomarkers, neuropathology, transcriptomics, metabolomics, proteomics, dendritic spine density and long-term potentiation (LTP) from 4-24 months of age (mos).
Results
Compared to other groups, at 12 mos, LOAD2 mice on HFD showed elevated levels of insoluble Aβ42. LOAD2 mice on HFD also showed reduced density of cortical neurons. These brain changes correlated with elevated levels of TNFa and IL10 in the plasma and neurofilament light chain in cerebral spinal fluid. At 24 mos, accumulation of human APP was observed in cortical neurons of LOAD2 mice on CD suggesting that Aβ processing and clearance may be perturbed. Both LTP and dendritic spine density were reduced from 4 mos in LOAD2 mice on CD similar to previous reports for APOE4 mice. However, these changes were not correlated with deficits in hippocampal spatial working memory.
Conclusions
The combination of aging, genetic risk (APOE4, Trem2*R47H, humanized Aβ) with HFD as an environmental risk induced age-dependent LOAD-relevant phenotypes making LOAD2 mice a useful tool for mechanistic studies and therapeutic testing.