1. Neuroscience

Amyloid and tau accumulate across distinct spatial networks and are differentially associated with brain connectivity

  1. Joana B Pereira  Is a corresponding author
  2. Rik Ossenkoppele
  3. Sebastian Palmqvist
  4. Tor Olof Strandberg
  5. Ruben Smith
  6. Eric Westman
  7. Oskar Hansson  Is a corresponding author
  1. Karolinska Institute, Sweden
  2. VU University Medical Center, Netherlands
  3. Lund University, Sweden
https://doi.org/10.7554/eLife.50830
Share this article
Cite this article
  1. Joana B Pereira
  2. Rik Ossenkoppele
  3. Sebastian Palmqvist
  4. Tor Olof Strandberg
  5. Ruben Smith
  6. Eric Westman
  7. Oskar Hansson
(2019)
Amyloid and tau accumulate across distinct spatial networks and are differentially associated with brain connectivity
eLife 8:e50830.
https://doi.org/10.7554/eLife.50830
  2. Download BibTeX
  3. Download .RIS

Abstract

The abnormal accumulation of amyloid-β and tau targets specific spatial networks in Alzheimer's disease. However, the relationship between these networks across different disease stages and their association with brain connectivity has not been explored. In this study, we applied a joint independent component analysis to 18F- Flutemetamol (amyloid-β) and 18F-Flortaucipir (tau) PET images to identify amyloid-β and tau networks across different stages of Alzheimer's disease. We then assessed whether these patterns were associated with resting-state functional networks and white matter tracts. Our analyses revealed nine patterns that were linked across tau and amyloid-β data. The amyloid-b and tau patterns showed a fair to moderate overlap with distinct functional networks but only tau was associated with white matter integrity loss and multiple cognitive functions. These findings show that amyloid-b and tau have different spatial affinities, which can be used to understand how they accumulate in the brain and potentially damage the brain's connections.

Data availability

Source data files have been provided for Figures 4 and 5. The source data for the rest of the analyses performed in this study can be requested from Prof. Oskar Hansson (Oskar.Hansson@med.lu.se), after signing a material transfer agreement from Lund University that ensures that the data will only be used for the sole purpose of replicating procedures and results presented in the article and as long as data transfer is in agreement with EU legislation on the general data protection regulation and decisions by the Ethical Review Board of Sweden and Region Skåne.

Article and author information

Author details

  1. Joana B Pereira

    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden
    For correspondence
    joana.pereira@ki.se
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4604-2711

  2. Rik Ossenkoppele

    Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.

  3. Sebastian Palmqvist

    Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
    Competing interests
    No competing interests declared.

  4. Tor Olof Strandberg

    Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
    Competing interests
    No competing interests declared.

  5. Ruben Smith

    Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
    Competing interests
    No competing interests declared.

  6. Eric Westman

    Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden
    Competing interests
    No competing interests declared.

  7. Oskar Hansson

    Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
    For correspondence
    oskar.hansson@med.lu.se
    Competing interests
    Oskar Hansson, has acquired research support (for the institution) from Roche, GE Healthcare, Biogen, AVID Radiopharmaceuticals, Fujirebio, and Euroimmun. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen, Roche, and Fujirebio.

Funding

European Research Council, Swedish Research Council, Swedish Brain Foundation, Startneuro, Swedish Alzheimer Foundation, Knut and Alice Wallenberg foundation, Strategic Research Area Multipark

  • Oskar Hansson

Swedish Research Council, Alzheimerfonden, Swedish Brain Research

  • Joana B Pereira

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Muireann Irish, University of Sydney, Australia

Ethics

Human subjects: This study received ethical approval from the Regional Ethical Review Board of Lund University (Dnr 2008-695, 2008-290, 2010-156), the Swedish Medicines and Products Agency (Dnr 151:2012/4552, 5.1-2014-62949), and the Radiation Safety Committee of Skåne University Hospital in Sweden. All participants provided informed consent before being included in the study.

Version history

  1. Received: August 4, 2019
  2. Accepted: December 6, 2019
  3. Accepted Manuscript published: December 9, 2019 (version 1)
  4. Version of Record published: December 31, 2019 (version 2)

Copyright

© 2019, Pereira et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,422
    views
  • 564
    downloads
  • 60
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Joana B Pereira
  2. Rik Ossenkoppele
  3. Sebastian Palmqvist
  4. Tor Olof Strandberg
  5. Ruben Smith
  6. Eric Westman
  7. Oskar Hansson
(2019)
Amyloid and tau accumulate across distinct spatial networks and are differentially associated with brain connectivity
eLife 8:e50830.
https://doi.org/10.7554/eLife.50830

Share this article

https://doi.org/10.7554/eLife.50830

Categories and tags

Research organism

Further reading

    1. Biochemistry and Chemical Biology
    2. Neuroscience

    Alzheimer’s disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling

    Katarzyna Marta Zoltowska, Utpal Das ... Lucía Chávez-Gutiérrez
    Research Article

    Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17–42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.

    1. Computational and Systems Biology
    2. Neuroscience

    Myelin dystrophy impairs signal transmission and working memory in a multiscale model of the aging prefrontal cortex

    Sara Ibañez, Nilapratim Sengupta ... Christina M Weaver
    Research Article

    Normal aging leads to myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are positively correlated with degree of cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First, we built a multicompartment pyramidal neuron model fit to monkey dlPFC empirical data, with an axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions. This model was used to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination. Next, we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from ultrastructure up to behavior during normal aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.

    1. Neuroscience

    Prediction error determines how memories are organized in the brain

    Nicholas GW Kennedy, Jessica C Lee ... Nathan M Holmes
    Research Article

    How is new information organized in memory? According to latent state theories, this is determined by the level of surprise, or prediction error, generated by the new information: a small prediction error leads to the updating of existing memory, large prediction error leads to encoding of a new memory. We tested this idea using a protocol in which rats were first conditioned to fear a stimulus paired with shock. The stimulus was then gradually extinguished by progressively reducing the shock intensity until the stimulus was presented alone. Consistent with latent state theories, this gradual extinction protocol (small prediction errors) was better than standard extinction (large prediction errors) in producing long-term suppression of fear responses, and the benefit of gradual extinction was due to updating of the conditioning memory with information about extinction. Thus, prediction error determines how new information is organized in memory, and latent state theories adequately describe the ways in which this occurs.