1. Neuroscience
Download icon

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
Research Article
  • Cited 56
  • Views 3,019
  • Annotations
Cite this article as: eLife 2017;6:e22978 doi: 10.7554/eLife.22978

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

  • 3,019
    Page views
  • 596
    Downloads
  • 56
    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)

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

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

Further reading

    1. Neuroscience
    Qing-Tao Meng et al.
    Research Article Updated

    Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by Npr1. However, BNP also binds to its cognate receptor, NPRC encoded by Npr3 with equal potency. Moreover, natriuretic peptides (NP) signal through the Gi-couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here, we report that Npr3 expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via Gq-couped PLCβ-Ca2+ signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca2+ responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice.

    1. Cell Biology
    2. Neuroscience
    Sergio Velasco-Aviles et al.
    Research Article

    The class IIa histone deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express Hdac4, 5 and 7 but not Hdac9. Here we show that a transcription factor regulated genetic compensatory mechanism within this family of proteins, blocks negative regulators of myelination ensuring peripheral nerve developmental myelination and remyelination after injury. Thus, when Hdac4 and 5 are knocked-out from Schwann cells in mice, a JUN-dependent mechanism induces the compensatory overexpression of Hdac7 permitting, although with a delay, the formation of the myelin sheath. When Hdac4,5 and 7 are simultaneously removed, the Myocyte-specific enhancer-factor d (MEF2D) binds to the promoter and induces the de novo expression of Hdac9, and although several melanocytic lineage genes are misexpressed and Remak bundle structure is disrupted, myelination proceeds after a long delay. Thus, our data unveil a finely tuned compensatory mechanism within the class IIa Hdac family, coordinated by distinct transcription factors, that guarantees the ability of Schwann cells to myelinate during development and remyelinate after nerve injury.