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Basic Science and Pathogenesis.

Michael Sasner1, Dylan Garceau1, Nick Ryan1

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The APPSAA mouse model exhibits Alzheimer's disease (AD) phenotypes like amyloid plaques and neuroinflammation. This model is valuable for preclinical research, offering insights into early AD progression and potential therapeutic targets.

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Area of Science:

  • Neuroscience
  • Pathology
  • Genetics

Background:

  • The APPSAA mouse model was developed for accessible Alzheimer's disease (AD) preclinical research.
  • It avoids licensing restrictions and artifacts associated with transgenic overexpression models.

Purpose of the Study:

  • To characterize clinically relevant phenotypes of the APPSAA mouse throughout aging.
  • To establish the APPSAA mouse as a translational research model for preclinical testing.

Main Methods:

  • In vivo amyloid plaque labeling (Methoxy-X04) and 3D whole-brain imaging (TissueCyte STP+).
  • Iterative immunolabeling (IBEX) for neuroinflammation and vascular responses.
  • Transcriptomics, metabolomics, lipidomics, and spatial transcriptomics (10X Genomics Xenium).
  • Cognitive assays using touchscreen chambers.

Main Results:

  • Amyloid plaques detected from 4 months, accumulating up to 12 months; vascular amyloid observed after 15 months.
  • Brain transcriptomics correlated with AD pathways, particularly immune modules.
  • Microglial and astrocyte-driven neuroinflammation localized near plaques.
  • Seizures, mild learning impairments, and dendritic spine loss observed by 12 months.

Conclusions:

  • The APPSAA model is translationally relevant for studying early amyloidosis and microglial activation.
  • It is available without legal restrictions, unlike some overexpression models.
  • Key assays and age/disease stages for preclinical testing are demonstrated.