Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline

  1. Stephanie L Leal  Is a corresponding author
  2. Susan M Landau
  3. Rachel K Bell
  4. William J Jagust  Is a corresponding author
  1. University of California, Berkeley, United States

Abstract

The amyloid hypothesis suggests that beta-amyloid (Aβ) deposition leads to alterations in neural function and ultimately to cognitive decline in Alzheimer's disease. However, factors that underlie Aβ deposition are incompletely understood. One proposed model suggests that synaptic activity leads to increased Aβ deposition. More specifically, hyperactivity in the hippocampus may be detrimental and could be one factor that drives Aβ deposition. To test this model, we examined the relationship between hippocampal activity during a memory task using fMRI and subsequent longitudinal change in Aβ using PIB-PET imaging in cognitively normal older adults. We found that greater hippocampal activation at baseline was associated with increased Aβ accumulation. Furthermore, increasing Aβ accumulation mediated the influence of hippocampal activation on declining memory performance, demonstrating a crucial role of Aβ in linking hippocampal activation and memory. These findings support a model linking increased hippocampal activation to subsequent Aβ deposition and cognitive decline.

Article and author information

Author details

  1. Stephanie L Leal

    Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
    For correspondence
    stephanieleal@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8082-8291
  2. Susan M Landau

    Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Rachel K Bell

    Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. William J Jagust

    Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
    For correspondence
    jagust@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institute on Aging (AG054116)

  • Stephanie L Leal

National Institute on Aging (AG034570)

  • William J Jagust

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

Ethics

Human subjects: Informed consent was obtained from all research participants and approved by the Institutional Review Boards of Lawrence Berkeley National Labs and UC Berkeley.

Reviewing Editor

  1. Alison Goate, Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Received: November 5, 2016
  2. Accepted: February 6, 2017
  3. Accepted Manuscript published: February 8, 2017 (version 1)
  4. Version of Record published: February 24, 2017 (version 2)

Copyright

© 2017, Leal 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

  • 3,122
    Page views
  • 612
    Downloads
  • 62
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

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. Stephanie L Leal
  2. Susan M Landau
  3. Rachel K Bell
  4. William J Jagust
(2017)
Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline
eLife 6:e22978.
https://doi.org/10.7554/eLife.22978

Further reading

    1. Neuroscience
    Angela R Wild et al.
    Tools and Resources Updated

    Protein S-palmitoylation is a reversible post-translational lipid modification that plays a critical role in neuronal development and plasticity, while dysregulated S-palmitoylation underlies a number of severe neurological disorders. Dynamic S-palmitoylation is regulated by a large family of ZDHHC palmitoylating enzymes, their accessory proteins, and a small number of known de-palmitoylating enzymes. Here, we curated and analyzed expression data for the proteins that regulate S-palmitoylation from publicly available RNAseq datasets, providing a comprehensive overview of their distribution in the mouse nervous system. We developed a web-tool that enables interactive visualization of the expression patterns for these proteins in the nervous system (http://brainpalmseq.med.ubc.ca/), and explored this resource to find region and cell-type specific expression patterns that give insight into the function of palmitoylating and de-palmitoylating enzymes in the brain and neurological disorders. We found coordinated expression of ZDHHC enzymes with their accessory proteins, de-palmitoylating enzymes and other brain-expressed genes that included an enrichment of S-palmitoylation substrates. Finally, we utilized ZDHHC expression patterns to predict and validate palmitoylating enzyme-substrate interactions.

    1. Neuroscience
    Orie T Shafer et al.
    Research Article Updated

    The circadian clock orchestrates daily changes in physiology and behavior to ensure internal temporal order and optimal timing across the day. In animals, a central brain clock coordinates circadian rhythms throughout the body and is characterized by a remarkable robustness that depends on synaptic connections between constituent neurons. The clock neuron network of Drosophila, which shares network motifs with clock networks in the mammalian brain yet is built of many fewer neurons, offers a powerful model for understanding the network properties of circadian timekeeping. Here, we report an assessment of synaptic connectivity within a clock network, focusing on the critical lateral neuron (LN) clock neuron classes within the Janelia hemibrain dataset. Our results reveal that previously identified anatomical and functional subclasses of LNs represent distinct connectomic types. Moreover, we identify a small number of non-clock cell subtypes representing highly synaptically coupled nodes within the clock neuron network. This suggests that neurons lacking molecular timekeeping likely play integral roles within the circadian timekeeping network. To our knowledge, this represents the first comprehensive connectomic analysis of a circadian neuronal network.