CaltechAUTHORS
  A Caltech Library Service

Decoupling the Effects of the Amyloid Precursor Protein From Amyloid-β Plaques on Axonal Transport Dynamics in the Living Brain

Medina, Christopher S. and Uselman, Taylor W. and Barto, Daniel R. and Cháves, Frances and Jacobs, Russell E. and Bearer, Elaine L. (2019) Decoupling the Effects of the Amyloid Precursor Protein From Amyloid-β Plaques on Axonal Transport Dynamics in the Living Brain. Frontiers in Cellular Neuroscience, 13 . Art. No. 501. ISSN 1662-5102. PMCID PMC6901799. https://resolver.caltech.edu/CaltechAUTHORS:20191223-160903062

[img] PDF - Published Version
Creative Commons Attribution.

4Mb
[img] Archive (ZIP) - Supplemental Material
Creative Commons Attribution.

11Mb

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20191223-160903062

Abstract

Amyloid precursor protein (APP) is the precursor to Aβ plaques. The cytoplasmic domain of APP mediates attachment of vesicles to molecular motors for axonal transport. In APP-KO mice, transport of Mn²⁺ is decreased. In old transgenic mice expressing mutated human (APP^(SwInd)) linked to Familial Alzheimer’s Disease, with both expression of APP^(SwInd) and plaques, the rate and destination of Mn²⁺ axonal transport is altered, as detected by time-lapse manganese-enhanced magnetic resonance imaging (MEMRI) of the brain in living mice. To determine the relative contribution of expression of APP^(SwInd) versus plaque on transport dynamics, we developed a Tet-off system to decouple expression of APP^(SwInd) from plaque, and then studied hippocampal to forebrain transport by MEMRI. Three groups of mice were compared to wild-type (WT): Mice with plaque and APP^(SwInd) expression; mice with plaque but suppression of APP^(SwInd) expression; and mice with APP^(SwInd) suppressed from mating until 2 weeks before imaging with no plaque. MR images were captured before at successive time points after stereotactic injection of Mn²⁺ (3–5 nL) into CA3 of the hippocampus. Mice were returned to their home cage between imaging sessions so that transport would occur in the awake freely moving animal. Images of multiple mice from the three groups (suppressed or expressed) together with C57/B6J WT were aligned and processed with our automated computational pipeline, and voxel-wise statistical parametric mapping (SPM) performed. At the conclusion of MR imaging, brains were harvested for biochemistry or histopathology. Paired T-tests within-group between time points (p = 0.01 FDR corrected) support the impression that both plaque alone and APP^(SwInd) expression alone alter transport rates and destination of Mn²⁺ accumulation. Expression of APP^(SwInd) in the absence of plaque or detectable Aβ also resulted in transport defects as well as pathology of hippocampus and medial septum, suggesting two sources of pathology occur in familial Alzheimer’s disease, from toxic mutant protein as well as plaque. Alternatively mice with plaque without APP^(SwInd) expression resemble the human condition of sporadic Alzheimer’s, and had better transport. Thus, these mice with APP^(SwInd) expression suppressed after plaque formation will be most useful in preclinical trials.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.3389/fncel.2019.00501DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901799PubMed CentralArticle
https://www.frontiersin.org/articles/10.3389/fncel.2019.00501/full#supplementary-materialPublisherSupplementary Material
ORCID:
AuthorORCID
Jacobs, Russell E.0000-0002-1382-8486
Additional Information:© 2019 Medina, Uselman, Barto, Cháves, Jacobs and Bearer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Received: 02 August 2019; Accepted: 22 October 2019; Published: 03 December 2019. We thank Xiaowei Zhang, Kathleen Kilpatrick, Aaron Gonzales, Crina Floruta, Joe Gallagher, and Sharon Wu Lin for technical support, and Neurosciences Associates for their serial sectioning and histologic staining of our mouse brains. We are grateful to the Beckman Institute at Caltech for support of the 11.7 T Bruker MR scanner, the Biological Imaging Center at Caltech, Harry Gray for helpful discussions, and Ralph Adolphs, Marianne Bronner, and the Division of Biology and Biological Engineering at Caltech for sponsoring EB as a Visiting Associate. Data Availability Statement: The datasets generated for this study are available on request to the corresponding author. Ethics Statement: The animal study was reviewed and approved by the Institutional Animal Care and Use Committees (IACUC) of the California Institute of Technology and of the University of New Mexico. Author Contributions: EB designed the experiments, performed the microscopy and biochemistry, and co-wrote the manuscript. CM did the analysis and drafted the manuscript. TU performed the SPM and ROI analysis, and edited the manuscript. DB helped with the 3D rendering and guided TU in the use of Amira. FC performed the stereology and statistical analysis. RJ performed the MR imaging and edited the manuscript. This work was supported by NINDS RO1 NS062184, NS046810 (EB), NIMH R01 MH096093 (EB), the Harvey Family Endowment, and Postdoctoral research fund IRACDA NIH 5K12GM088021 (DB). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funders:
Funding AgencyGrant Number
NIHRO1 NS062184
NIHNS046810
NIHR01 MH096093
Harvey Family EndowmentUNSPECIFIED
NIH Postdoctoral Fellowship5K12GM088021
Caltech Division of Biology and Biological EngineeringUNSPECIFIED
Subject Keywords:transgenic mice for Alzheimer’s disease investigation, amyloid precursor protein (APP), fast microtubule-based axonal transport, CA3 of the hippocampus, dentate gyrus and septal nuclei, manganese-enhanced magnetic resonance imaging (MEMRI), cholinergic neurons, Swedish and Indiana mutation (APPSwInd)
PubMed Central ID:PMC6901799
Record Number:CaltechAUTHORS:20191223-160903062
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191223-160903062
Official Citation:Medina CS, Uselman TW, Barto DR, Cháves F, Jacobs RE and Bearer EL (2019) Decoupling the Effects of the Amyloid Precursor Protein From Amyloid-β Plaques on Axonal Transport Dynamics in the Living Brain. Front. Cell. Neurosci. 13:501. doi: 10.3389/fncel.2019.00501
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100428
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:24 Dec 2019 00:26
Last Modified:24 Dec 2019 00:26

Repository Staff Only: item control page