# Disease Model Development and Phenotyping Project

> **NIH NIH U54** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $5,384,155

## Abstract

PROJECT SUMMARY DISEASE MODEL DEVELOPMENT AND PHENOTYPING (DMP) PROJECT
In the initial funding period, the DMP created and evaluated more than forty new models incorporating 33 LOAD-
relevant alleles. This included a set of platform strains that incorporated humanized APOE4, Trem2*R47H and
humanized Aβ sequence. Platform strains were evaluated from 4 to 24 months through the IU/JAX/PITT MODEL-
AD phenotyping pipeline that included PET/CT, multi-omics (transcriptomics, proteomics and metabolomics),
neuropathology, and fluid biomarker analysis. The first platform strain, LOAD1 (double homozygous for APOE4
and Trem2*R47H) showed primarily age-dependent affects and few genotype-specific effects. For our second
platform strain, LOAD2 (triple homozygous for APOE4, Trem2*R47H and hAβ), we included a high fat/high sugar
diet (HFD) group as an environmental risk factor. Compared to control mice, at 12 months, HFD-fed LOAD2
mice showed elevated levels of insoluble Aβ42, loss of neurons in the subiculum, reduced long-term potentiation
(LTP), and reduced spine densities in the hippocampus. In addition to the platform models, 24 putative genetic
risk variants identified by the Bioinformatics and Data Management core (BDMC) were introduced into LOAD1
or LOAD2 by CRISPR/Cas9 and evaluated by comparing brain transcriptomes to Accelerated Medicines
Partnerships in AD (AMP-AD) data. The putative risk variants were located in both previously identified (e.g.,
Abca7, CR1, Plcg2, Mthfr and Epha1) as well as novel AD risk genes. Through this work, Abca7*A1527G,
Plcg2*M28L and Mthfr*677C>T were prioritized for full characterization through our phenotyping pipeline.
Collectively, these data support our overarching hypothesis that combinations of LOAD-relevant genetic and/or
environmental risk factors, in the absence of familial AD (fAD) mutations, will induce hallmark AD pathologies in
mice and therefore create improved mouse models for preclinical testing. In the renewal we will continue to
evaluate novel LOAD models, with an increased focus on identifying models for the preclinical testing core (PTC).
To achieve this, our phenotyping pipeline has been enhanced and incorporates a combined cross-sectional and
longitudinal design, extensive biomarker analysis, MRI, additional PET ligands (e.g., for neuroinflammation and
synapse loss), digital spatial profiling, and synaptic and cognitive assessment. We will first complete
characterization of three prioritized LOAD strains as well as characterize a novel platform model LOAD3 (triple
homozygous for APOE4, hAβ and a humanized MAPT allele) with and without HFD (Aim 1).
Hyperphosphorylation and aggregation of TAU is a hallmark pathology for LOAD and absent in our current
strains. Therefore, we will next evaluate four MAPT variants (N279K, P301L, R406W and S320F) that are
predicted to increase susceptibility to TAU pathology (Aim 2). Finally, no single LOAD model is expected to
represent the heterogeneity of human LOAD and we ...

## Key facts

- **NIH application ID:** 10916534
- **Project number:** 5U54AG054345-09
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Gareth R Howell
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $5,384,155
- **Award type:** 5
- **Project period:** 2016-09-30 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916534

## Citation

> US National Institutes of Health, RePORTER application 10916534, Disease Model Development and Phenotyping Project (5U54AG054345-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10916534. Licensed CC0.

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