Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer’s disease

Whitesell, Jennifer D.; Buckley, Alex R.; Knox, Joseph E.; Kuan, Leonard; Graddis, Nile; Pelos, Andrew; Mukora, Alice; Wakeman, Wayne; Bohn, Phillip; Ho, Anh; Hirokawa, Karla E.; Harris, Julie A.

doi:10.1002/cne.24555

Cited by 99Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer’s disease

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Whitesell, Jennifer D., Buckley, Alex R., Knox, Joseph E., Kuan, Leonard, Graddis, Nile, Pelos, Andrew, Mukora, Alice, Wakeman, Wayne +4 more·2019·Journal of Comparative Neurology

DOI 10.1002/cne.24555PMC PMC8026112

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Abstract

A variety of Alzheimer's disease (AD) mouse models overexpress mutant forms of human amyloid precursor protein (APP), producing high levels of amyloid β (Aβ) and forming plaques. However, the degree to which these models mimic spatiotemporal patterns of Aβ deposition in brains of AD patients is unknown. Here, we mapped the spatial distribution of Aβ plaques across age in three APP‐overexpression mouse lines (APP/PS1, Tg2576, and hAPP‐J20) using in vivo labeling with methoxy‐X04, high throughput whole brain imaging, and an automated informatics pipeline. Images were acquired with high resolution serial two‐photon tomography and labeled plaques were detected using custom‐built segmentation algorithms. Image series were registered to the Allen Mouse Brain Common Coordinate Framework, a 3D reference atlas, enabling automated brain‐wide quantification of plaque density, number, and location. In both APP/PS1 and Tg2576 mice, plaques were identified first in isocortex, followed by olfactory, hippocampal, and cortical subplate areas. In hAPP‐J20 mice, plaque density was highest in hippocampal areas, followed by isocortex, with little to no involvement of olfactory or cortical subplate areas. Within the major brain divisions, distinct regions were identified with high (or low) plaque accumulation; for example, the lateral visual area within the isocortex of APP/PS1 mice had relatively higher plaque density compared with other cortical areas, while in hAPP‐J20 mice, plaques were densest in the ventral retrosplenial cortex. In summary, we show how whole brain imaging of amyloid pathology in mice reveals the extent to which a given model recapitulates the regional Aβ deposition patterns described in AD.

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By registering whole brain images of p-tau deposition in PS19 mice into the annotated Allen CCFv3, we identified seven regions which consistently exhibited pathology at 6mo and all later ages.
“By registering whole brain images of p-tau deposition in PS19 mice into the annotated Allen CCFv3, similar to recent studies (Whitesell et al., 2019; Cornblath et al., 2021), we identified seven regions which consistently exhibited pathology at 6mo and all later ages.”
From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Whitesell et al., 2019

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Harris JA, Mihalas S, Hirokawa KE, Whitesell JD, Knox J, Bernard A, … Zeng H (2018). The organization of intracortical connections by layer and cell class in the mouse brain. BioRxiv. Retrieved from http://biorxiv.org/content/early/2018/04/18/292961.abstract
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Selective Regional Loss of Cortical Synapses Lacking Presynaptic Mitochondria in the 5xFAD Mouse Model
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Transcranial in vivo detection of amyloid-beta at single plaque resolution with large-field multifocal illumination fluorescence microscopyPreprint
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Three-dimensional quantitative analysis of amyloid plaques in the whole brain with high voxel resolution
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Endogenous pathology in tauopathy mice progresses via brain networksPreprint
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Excessive local host-graft connectivity in aging and amyloid-loaded brain
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Transferrin receptor-binding blood-brain barrier shuttle enhances brain delivery and plaque-clearing efficacy of a therapeutic anti-Aβ antibody
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Proteomics of spatially identified tissues in whole organsPreprint
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Spontaneous pathology in PS19 tauopathy mice progresses via brain networks
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Genetically modified mice for research on human diseases: A triumph for Biotechnology or a work in progress?
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Exploring Iron Deposition Patterns Using Light and Electron Microscopy in the Mouse Brain Across Aging and Alzheimer's Disease Pathology Conditions
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Two novel mouse models of slow-wave-sleep enhancement in aging and Alzheimer’s disease
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Fibrillar Aβ causes profound microglial metabolic perturbations in a novel APP knock-in mouse modelPreprint
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Quantification of AMPA receptor subunits and RNA editing-related proteins in the J20 mouse model of Alzheimer’s disease by capillary western blotting
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Multi-omics reveals changes in astrocyte fatty acid metabolism during early stages of Alzheimer's disease
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Variation in Group Composition Alters an Early-Stage Social Phenotype in hAPP-Transgenic J20 Mice
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Differential disruptions in population coding along the dorsal-ventral axis of CA1 in the APP/PS1 mouse model of Aβ pathology
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Inhibiting the transient receptor potential melastatin 2 channel in microglia: current evidence and therapeutic potential in neurological disorders
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Translating brain anatomy and disease from mouse to human in latent gene expression space
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P4‐225: WHOLE BRAIN IMAGING REVEALS DISTINCT SPATIAL PATTERNS OF AMYLOID BETA DEPOSITION AND ATROPHY IN MOUSE MODELS OF ALZHEIMER'S DISEASE
Whitesell, J. D., Buckley, A. R., Graddis, N., Kuan, L., Knox, J. E., Naeemi, M., Bohn, P., Mukora, A., Hirokawa, K. E., & Harris, J. A. (2018) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2018.07.046
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A novel whole‐brain imaging pipeline for high resolution spatial and temporal measurements of amyloid‐beta plaque dynamics in pre‐clinical Alzheimer’s Disease animal models
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Analysis of differential plaque depositions in the brains of Tg2576 and Tg-APPswe/PS1dE9 transgenic mouse models of Alzheimer disease
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Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer’s disease
Tsui, K. C., Roy, J., Chau, S. C., Wong, K.-H., Shi, L., Poon, C. H., Wang, Y., Strekalova, T. V., Aquili, L., Chang, R. C., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.964336 · Cited by 44 · see citing works
A novel whole‐brain imaging pipeline for amyloid‐beta plaque integrated with downstream iterative immunolabeling in pre‐clinical Alzheimer’s Disease animal models
Sasner, M., Garceau, D. T., Elk, K. J., Kamelin, P., Yew, E. Y. S., Chidambaram, R., & Ragan, T. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.090850

Authors: Whitesell, J. D., Buckley, A. R., Knox, J. E., Kuan, L., Graddis, N., Pelos, A., Mukora, A., Wakeman, W., Bohn, P., Ho, A., Hirokawa, K. E., & Harris, J. A.
Affiliations: Allen Institute for Brain Science (US)
Washington University in St. Louis (US)
Corresponding author: Harris, Julie A.
ORCID: Whitesell, Jennifer D.
Buckley, Alex R.
Knox, Joseph E.
Mukora, Alice
Wakeman, Wayne
Bohn, Phillip
Ho, Anh
Hirokawa, Karla E.
Harris, Julie A.
Venue: Journal of Comparative Neurology
Publisher: Wiley
Published: 2018-12-04
Volume: 527
Issue: 13
Pages: 2122-2145
ISSN: 0021-9967 (ISSN-L)
1096-9861
DOI: 10.1002/cne.24555
PMC: PMC8026112
OpenAlex: W2949152232
Cited by: 99
References: 71
Citations by year: 2026: 10 · 2025: 12 · 2024: 7 · 2023: 10 · 2022: 17 · 2021: 24 · 2020: 5 · 2019: 14
FWCI: 7.39
Type: journal article
Language: en
Open access: green
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: The Journal of Comparative Neurology (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Aging (R01AG047589)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: Alzheimer's disease, amyloid plaques, amyloid precursor protein overexpression, APP/PS1 mice, Tg2576 mice, plaque density, whole-brain imaging, brain atlas registration, plaque segmentation, hippocampus, neocortex, olfactory bulb, mouse models of Alzheimer's disease
MeSH terms: Alzheimer Disease, Animals, Brain, Disease Models, Animal, Image Processing, Computer-Assisted, Mice, Transgenic, Amyloid beta-Peptides, Mice, Neuroimaging

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Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer’s disease

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