Soluble brain homogenates from diverse human and mouse sources preferentially seed diffuse Aβ plaque pathology when injected into newborn mouse hosts

Authors

  • Brenda D. Moore Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Yona Levites Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Guilian Xu Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Hailey Hampton Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Munir F. Adamo Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Cara L. Croft Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Hunter S. Futch Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Corey Moran Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Susan Fromholt Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Christopher Janus Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Stefan Prokop Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Department of Pathology, University of Florida, Gainesville, FL 32610, USA; Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL 32610, USA
  • Dennis Dickson Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
  • Jada Lewis Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Benoit I. Giasson Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
  • Todd E. Golde Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Department of Neurology, College of Medicine, University of Florida, Gainesville FL 32610, USA
  • David R. Borchelt Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA

DOI:

https://doi.org/10.17879/freeneuropathology-2022-3766

Keywords:

Amyloid-β, Tau, α-Synuclein, Seeding, Alzheimer’s disease, Lewy body dementia

Abstract

Background: Seeding of pathology related to Alzheimer’s disease (AD) and Lewy body disease (LBD) by tissue homogenates or purified protein aggregates in various model systems has revealed prion-like properties of these disorders. Typically, these homogenates are injected into adult mice stereotaxically. Injection of brain lysates into newborn mice represents an alternative approach of delivering seeds that could direct the evolution of amyloid-β (Aβ) pathology co-mixed with either tau or α-synuclein (αSyn) pathology in susceptible mouse models.

Methods: Homogenates of human pre-frontal cortex were injected into the lateral ventricles of newborn (P0) mice expressing a mutant humanized amyloid precursor protein (APP), human P301L tau, human wild type αSyn, or combinations thereof. The homogenates were prepared from AD and AD/LBD cases displaying variable degrees of Aβ pathology and co-existing tau and αSyn deposits. Behavioral assessments of APP transgenic mice injected with AD brain lysates were conducted. For comparison, homogenates of aged APP transgenic mice that preferentially exhibit diffuse or cored deposits were similarly injected into the brains of newborn APP mice.

Results: We observed that lysates from the brains with AD (Aβ+, tau+), AD/LBD (Aβ+, tau+, αSyn+), or Pathological Aging (Aβ+, tau-, αSyn-) efficiently seeded diffuse Aβ deposits. Moderate seeding of cerebral amyloid angiopathy (CAA) was also observed. No animal of any genotype developed discernable tau or αSyn pathology. Performance in fear-conditioning cognitive tasks was not significantly altered in APP transgenic animals injected with AD brain lysates compared to nontransgenic controls. Homogenates prepared from aged APP transgenic mice with diffuse Aβ deposits induced similar deposits in APP host mice; whereas homogenates from APP mice with cored deposits induced similar cored deposits, albeit at a lower level.

Conclusions: These findings are consistent with the idea that diffuse Aβ pathology, which is a common feature of human AD, AD/LBD, and PA brains, may arise from a distinct strain of misfolded Aβ that is highly transmissible to newborn transgenic APP mice. Seeding of tau or αSyn comorbidities was inefficient in the models we used, indicating that additional methodological refinement will be needed to efficiently seed AD or AD/LBD mixed pathologies by injecting newborn mice.

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Published

2022-03-23

How to Cite

Moore, B. D., Levites, Y., Xu, G., Hampton, H., Adamo, M. F., Croft, C. L., Futch, H. S., Moran, C., Fromholt, S., Janus, C., Prokop, S., Dickson, D., Lewis, J., Giasson, B. I., Golde, T. E., & Borchelt, D. R. (2022). Soluble brain homogenates from diverse human and mouse sources preferentially seed diffuse Aβ plaque pathology when injected into newborn mouse hosts. Free Neuropathology, 3, 9. https://doi.org/10.17879/freeneuropathology-2022-3766
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Issue

Vol. 3 (2022)

Section

Original Papers

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Copyright (c) 2022 Brenda D. Moore, Yona Levites, Guilian Xu, Hailey Hampton, Munir F. Adamo, Cara L. Croft, Hunter S. Futch, Corey Moran, Susan Fromholt, Christopher Janus, Stefan Prokop, Dennis Dickson, Jada Lewis, Benoit I. Giasson, Todd E. Golde, David R. Borchelt

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