Characterization of the knock-in AppSAA mouse model as a powerful tool for Alzheimer’s disease preclinical research

Product:

Mouse Panel 120

Topic:

Neurology

Disease Area:

Alzheimer's Disease

Sample Type:

Plasma-Mouse

Abstract

BACKGROUND Preclinical Alzheimer’s disease (AD) research requires models with age-dependent, physiologically relevant amyloid pathology, unlike overexpression in transgenic lines. We characterized the humanized App^SAA knock-in model to define translationally relevant therapeutic windows.

METHODS Homozygous App^SAA and control mice were evaluated from 4 to 19 months using whole-brain 3D plaque imaging, cerebral amyloid angiopathy (CAA) quantification, multiplex neuropathology, brain transcriptomics, and plasma biomarkers. Hippocampal synaptic analysis and context-dependent memory was performed at 12 months.

RESULTS Plaques, CAA, plaque-associated neuroinflammation, and dystrophic neurites accumulated with age. By 12 months, brain transcriptomes aligned with human AMP-AD co-expression modules, and plasma pTau-217, GFAP, and SNAP25 rose with age. App^SAA mice retained associative memory but showed memory interference and CA1 dendritic-spine loss that was exacerbated in proximity to plaques.

CONCLUSIONS App^SAA mice recapitulate age-dependent, human-relevant AD phenotypes with defined therapeutic windows for preclinical research. The model is available without restriction from The Jackson Laboratory.

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Authors and Affiliations

Lucy J. Sloan¹, Dylan T. Garceau¹, Nick J. Ryan¹, Justice Pomeroy-Tuck¹, Ritesh Chidambaram², Tim Ragan², Ravi S. Pandey³, Erik B. Bloss¹, Gregory W. Carter¹˒³, Adrian L. Oblak⁴, and Michael Sasner¹*

¹ The Jackson Laboratory, Bar Harbor, ME, 04609, USA
² TissueVision, Newton, MA, 02458, USA
³ The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
⁴ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

* Corresponding author: Michael Sasner

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition. He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.