Bidirectional Relationship between Functional Connectivity and Amyloid-β Deposition in Mouse Brain
Open accessAbstract
Brain region-specific deposition of extracellular amyloid plaques principally composed of aggregated amyloid-β (Aβ) peptide is a pathological signature of Alzheimer's disease (AD). Recent human neuroimaging data suggest that resting-state functional connectivity strength is reduced in patients with AD, cognitively normal elderly harboring elevated amyloid burden, and in advanced aging. Interestingly, there exists a striking spatial correlation between functional connectivity strength in cognitively normal adults and the location of Aβ plaque deposition in AD. However, technical limitations have heretofore precluded examination of the relationship between functional connectivity, Aβ deposition, and normal aging in mouse models. Using a novel functional connectivity optical intrinsic signal (fcOIS) imaging technique, we demonstrate that Aβ deposition is associated with significantly reduced bilateral functional connectivity in multiple brain regions of older APP/PS1 transgenic mice. The amount of Aβ deposition in each brain region was associated with the degree of local, age-related bilateral functional connectivity decline. Normal aging was associated with reduced bilateral functional connectivity specifically in retrosplenial cortex. Furthermore, we found that the magnitude of regional bilateral functional correlation in young APP/PS1 mice before Aβ plaque formation was proportional to the amount of region-specific plaque deposition seen later in older APP/PS1 mice. Together, these findings suggest that Aβ deposition and normal aging are associated with region-specific disruption of functional connectivity and that the magnitude of local bilateral functional connectivity predicts regional vulnerability to subsequent Aβ deposition in mouse brain.
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Bilateral functional connectivity in the HJ6.3 group appeared more globally restored and resembled that of healthy wild-type mice.
“Compared with PBS-treated mice, bilateral functional connectivity in the HJ6.3 group appeared to be more globally restored and to resemble that of healthy, wild-type mice (Fig. 7C), as described previously (White et al., 2011;Bero et al., 2012).”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Bero et al., 2012
The Results sections on functional connectivity disruption and local Aβ deposition report bilateral connectivity measurements in wild-type and APP/PS1 mice, providing a basis for the wild-type comparison. They do not report HJ6.3 or PBS treatment, so this paper does not support the claimed restoration in the HJ6.3 group. (LLM, conf=0.86)
Experimental — accuracy not yet measuredValidation data for non-commercial antibodies (anti-Fcrls, anti-Apoe, anti-Abeta, anti-Itgb8) were published in cited works.
“Validation data for non-commercial antibodies: anti-Fcrls mab was published by Butovsky et al. 2014 (PMID: 24316888). Validation data for anti-Apoe mab was published by Kim et al. 2012 (PMID: 23129750), anti-Abeta mab was published by Bero et al. 2012 (PMID: 22457485), and anti-Itgb8 mAb was published by Dodagatta-Marri et al., 2021 (PMID: 34233193).”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as Bero et al. 2012
The Materials and methods section (Aβ plaque deposition; page unavailable) identifies HJ3.4 as an in-house anti-Aβ monoclonal antibody, and the Results report its use to stain and quantify Aβ plaques. These passages support the antibody’s identification and use, but do not present antibody-specific validation data, such as specificity controls. The other antibodies in the citing sentence are attributed to other works, not to Bero et al. (LLM, conf=0.82)
Experimental — accuracy not yet measuredFunctional connectivity deficits in ArcAβ mice appeared already robustly reduced in the early phase of life, whereas functional connectivity appeared increased in young APP/PS1 mice compared with wild-type.
“Their results differ from ours as FC deficits in ArcA mice appeared already robustly reduced in the early phase of life, whereas it appeared increased in young APP/PS1 compared with wild-type”
From Early Alterations in Functional Connectivity and White Matter Structure in a Transgenic Mouse Model of Cerebral Amyloidosis (2014) · cites this paper as Bero et al., 2012
The Results section (page unavailable) reports higher connectivity values for young APP/PS1 than young wild-type mice in several regions, including motor and retrosplenial cortex. It does not report a direct statistical comparison between those groups, and the pattern is not consistent across all regions. This paper studies APP/PS1 mice, not the ArcAβ finding in the preceding clause. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe discrepancy in regional functional connectivity impairments between mice and humans might be related to a link between neuronal activity and Aβ release affecting FC strength and amyloid deposition in later life.
“The discrepancy in regional FC impairments between mice and human might be related to a link between neuronal activity and A release affecting FC strength and amyloid deposition in later life (Bero et al., 2011(Bero et al., , 2012)).”
From Early Alterations in Functional Connectivity and White Matter Structure in a Transgenic Mouse Model of Cerebral Amyloidosis (2014) · cites this paper as Bero et al., 2012
The Discussion (page unavailable) links neuronal activity with interstitial Aβ levels and suggests an association among neural activity, functional connectivity, and later amyloid deposition in mice. It also notes a mouse–human difference in regional connectivity changes, but does not propose the neuronal-activity/Aβ link as an explanation for that discrepancy or establish Aβ release as the mechanism. (LLM, conf=0.84)
Experimental — accuracy not yet measuredfcOIS is a sensitive imaging modality capable of measuring functional connectivity between brain regions in healthy mice.
“We have shown previously that fcOIS is a sensitive imaging modality capable of measuring functional connectivity between brain regions in healthy mice (White et al., 2011;Bero et al., 2012)”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Bero et al., 2012
There is functional disruption in APP/PS1 mice after Aβ deposition.
“and that there is functional disruption in APP/PS1 mice after A deposition (White et al., 2011;Bero et al., 2012).”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Bero et al., 2012
Previous studies of APP/PS1 and ArcBeta transgenic mice have demonstrated deficits in the functional connectivity of multiple brain regions that is associated with amyloid deposition.
“Previous studies of APP/PS1 and ArcBeta transgenic mice have demonstrated deficits in the functional connectivity of multiple brain regions that is associated with amyloid deposition (Bero et al., 2012; Grandjean et al., 2014; Shah et al., 2013).”
From Functional and structural connectome properties in the 5XFAD transgenic mouse model of Alzheimer’s disease (2018) · cites this paper as Bero et al., 2012
Amyloid deposition around the vasculature affects neurovascular coupling and potentially masks functional connectivity measured by hemodynamic readouts such as BOLD fMRI and intrinsic optical imaging.
“which inherently affects the neurovascular coupling and potentially masks FC measured on the basis of hemodynamic readouts, such as BOLD fMRI (Nicolakakis and Hamel, 2011) and intrinsic optical imaging (Bero et al., 2012).”
From Early Alterations in Functional Connectivity and White Matter Structure in a Transgenic Mouse Model of Cerebral Amyloidosis (2014) · cites this paper as Bero et al., 2012
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“Previous studies of APP/PS1 and ArcBeta transgenic mice have demonstrated deficits in the functional connectivity of multiple brain regions that is associated with amyloid deposition (Bero et al., 2012; Grandjean et al., 2014; Shah et al., 2013).”
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“…and compromised WM indices have shown in TgF344 rats (Anckaerts et al., 2019), 5XFAD mice (Kesler et al., 2018), APP/PS1 mice (Shah et al., 2013, Bero et al., 2012), ArcAβ mice (Grandjean et al., 2014, Grandjean et al., 2016), aging apoE4 and apoE-KO mice (Zerbi et al., 2014) and PSAPP mice…”
Background
- Authors
- Bero, A. W., Bauer, A. Q., Stewart, F. R., White, B. R., Cirrito, J. R., Raichle, M. E., Culver, J. P., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-03-28
- Volume
- 32
- Issue
- 13
- Pages
- 4334-4340
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3326343
- OpenAlex
- W2156997013
- Cited by
- 181
- References
- 8
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 4 · 2023: 12 · 2022: 16 · 2021: 8 · 2020: 15 · 2019: 10 · 2018: 14 · 2017: 18 · 2016: 12 · 2015: 11 · 2014: 24 · 2013: 18 · 2012: 4
- FWCI
- 9.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- Ellison Medical Foundation
- Cure Alzheimer's Fund
- National Institutes of Health
- National Institute on Aging (AG033452, F31AG033452)
- National Institute on Drug Abuse (T90DA022871)
- National Institute of Neurological Disorders and Stroke (P30NS057105, P01NS074969)
- National Institute of Biomedical Imaging and Bioengineering (R01EB008085, R01EB009233)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta deposition, resting-state functional connectivity, Alzheimer's disease, APP/PS1 mice, normal brain aging, retrosplenial cortex, amyloid plaques, mouse models of Alzheimer's disease
- MeSH terms
- Aging, Amyloidosis, Animals, Brain, Disease Models, Animal, Male, Mice, Inbred Strains, Mice, Transgenic, Neural Pathways, Amyloid beta-Peptides, Mice, Plaque, Amyloid, Functional Neuroimaging
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