Functional Connectivity Predicts Aβ Deposition in Mice

In the human brain, functional connectivity is intimately linked with amyloid-β pathology. Brain areas that communicate during the long hours the brain spends at rest—the default-mode network—become the most burdened by Aβ plaques, and connectivity is, in turn, disrupted with amyloid load. Functional imaging in mice now shows a similar trend. David Holtzman and colleagues from Washington University, St. Louis, Missouri, report that communication between connected areas takes a nosedive in aged AD mouse models, and areas that show the strongest connectivity in young transgenic mice accumulate the most amyloid plaques later on. These findings are published in the March 28 Journal of Neuroscience.

"The finding will give human imaging researchers more confidence in this AD mouse model studied here," said William Seeley, University of California, San Francisco, who was not involved in the work. Researchers may soon use this and other animal models to investigate more than just amyloid deposition, he added. "Having a controllable model system enables one to map out the sequence of pathological events: When, for example, does functional connectivity begin to change in the natural history of amyloid aggregation?" (Seeley will discuss the brain networks' role in the spread of misfolded proteins on 10 April 2012 in an Alzforum Webinar; see the Alzforum homepage to read the spotlight for the Webinar.)

In humans, weakening of the default-mode network (DMN) correlates with plaque deposition early in the course of Alzheimer's disease (ARF related news story on Greicius et al., 2004). The DMN also suffers more amyloid plaque than other brain areas (see ARF related news story). Aβ released by high levels of synaptic activity may be to blame for the DMN's high plaque load (see ARF related news story). Last year, Holtzman's lab reported that, in transgenic mice, greater synaptic activity in certain brain areas (analogous to the DMN in humans) early in life predicts more plaque accumulation in those areas when the animals age (see ARF related news story). The group wondered if connectivity would be disrupted in these areas in older animals as well. In the current study, Holtzman's team used a newly developed technique to test if resting functional connectivity declines in aged and plaque-laden mice.

Joint first authors Adam Bero (now at MIT) and Adam Bauer looked at brain function in both three- and 11.5-month-old APP/PS1 mice. Age-matched wild-type mice served as controls. The researchers chose functional connectivity optical intrinsic signal imaging, or fcOIS, to measure brain activity. Reflecting visible light off the brains of anesthetized mice (through their naturally translucent skulls) reveals local concentrations of hemoglobin. This allows researchers to measure oxygen being delivered to and consumed by active neurons (see White et al., 2011). The researchers focused fcOIS on right and left frontal, motor, somatosensory, cingulate, retrosplenial, and visual cortices. They mapped oxygen use over time, measuring how activity in each area tracked with its contralateral cortex to determine connectivity. After fcOIS was complete, the researchers located areas of Aβ plaque deposition by removing mouse brains and staining slices with the anti-Aβ antibody, HJ3.4.

According to maps of the older transgenic mice, connectivity (relative to the young transgenic mice) weakened between frontal, motor, cingulate, and retrosplenial hemispheres, but not the visual and somatosensory cortices. "There was a significant and strong decline in connectivity that paralleled the amount of amyloid deposition," Holtzman told Alzforum. In older wild-type mice, similar reductions only showed up in the retrosplenial cortex (the human equivalent of the posterior cingulate cortex), suggesting to the authors that normal aging comes with a slight decline in functional connectivity, which is exacerbated by Aβ deposition. The more plaque deposited, the greater the decline in functional connectivity. The most drastic effects showed up in the retrosplenial cortex.

In addition, the strength of the functional connectivity in the young transgenic mice predicted where Aβ would deposit later. In the younger mice, frontal, motor, cingulate, and retrosplenial cortices were strongly correlated with contralateral counterparts, and lateron Aβ plaques deposited heavily in these regions, more so than in the visual and somatosensory cortices. "The amount of connectivity in a brain region strongly predicts how much plaque is going to develop there," said Holtzman. This parallels previous findings in humans (see ARF related news story). "The implication is that fcOIS will be important for translating animal to human studies," he said. In addition to looking at functional connectivity in other models of neurodegeneration, the group next plans to determine whether ApoE genotype might play a role in this measure.

As in any study with anesthetized animals, some caution is warranted in interpreting the functional results, because anesthesia could produce slight functional changes in these mice, said Alexander Drzezga, Technische Universität München, Germany. Nevertheless, combined with amyloid imaging in mice with PIB, which his lab just demonstrated (see ARF related news story), this functional technique could one day help researchers get more out of mouse model studies. "Having an option to look at these kinds of pathological parameters in a longitudinal way is a perfect approach to establish causal interactions between pathologies," said Drzezga. "You could never do this in cross-sectional studies."—Gwyneth Dickey Zakaib

Comments

  1. This is another very interesting paper from David Holtzman's lab, continuing a very interesting theme that suggests neural function (or dysfunction, in this case) affects Aβ deposition. Previous work (a nice paper by in Nature Neuroscience last year, Bero et al., 2011) showed that neural activity was related to subsequent development of plaques in transgenic animals. This paper breaks new ground by applying a method this lab developed that uses optical imaging to measure functional connectivity. It's motivated by studies in humans with fMRI that show disruption of functional connectivity in normal older people with Aβ deposition. In this case, through the use of transgenic animals, the authors were able to demonstrate regional loss of connectivity in young animals, prior to Aβ deposition.

    This is quite a novel finding, and extends the theme that the lab has been working on relating neural activity to Aβ to include measures of functional connectivity. The functional connectivity measures in this paper are especially interesting because of their relevance to similar human functional connectivity data.

    References:

    Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci. 2011 Jun;14(6):750-6. Epub 2011 May 1 PubMed.

    View all comments by William Jagust

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References

News Citations

  1. Network Diagnostics: "Default-Mode" Brain Areas Identify Early AD
  2. Cortical Hubs Found Capped With Amyloid
  3. Paper Alert: Synaptic Activity Increases Aβ Release
  4. Do Overactive Brain Networks Broadcast Alzheimer’s Pathology?
  5. Animals for PET: Amyloid Imaging in Mice

Paper Citations

  1. Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4637-42. PubMed.
  2. White BR, Bauer AQ, Snyder AZ, Schlaggar BL, Lee JM, Culver JP. Imaging of functional connectivity in the mouse brain. PLoS One. 2011;6(1):e16322. PubMed.

Other Citations

  1. Alzforum homepage

External Citations

  1. APP/PS1 mice

Further Reading

Papers

  1. Kramer G, van der Flier WM, de Langen C, Blankenstein MA, Scheltens P, Stam CJ. EEG functional connectivity and ApoE genotype in Alzheimer's disease and controls. Clin Neurophysiol. 2008 Dec;119(12):2727-32. PubMed.
  2. Drzezga A, Becker JA, Sreenivasan A, Talukdar T, Van Dijk K, Sullivan C, Schultz AP, Sepulcre J, Buckner RL, Sperling RA. Relation between hypometabolism, impaired functional connectivity and ß-amyloid load in pre-dementia stages of Alzheimer’s disease. Human Amyloid Imaging 2010 Meeting Abstracts. 2010 April 9;
  3. Hedden T, Van Dijk KR, Becker JA, Mehta A, Sperling RA, Johnson KA, Buckner RL. Disruption of functional connectivity in clinically normal older adults harboring amyloid burden. J Neurosci. 2009 Oct 7;29(40):12686-94. PubMed.
  4. Mormino EC, Smiljic A, Hayenga AO, Onami SH, Greicius MD, Rabinovici GD, Janabi M, Baker SL, Yen IV, Madison CM, Miller BL, Jagust WJ. Relationships between beta-amyloid and functional connectivity in different components of the default mode network in aging. Cereb Cortex. 2011 Oct;21(10):2399-407. PubMed.

Primary Papers

  1. Bero AW, Bauer AQ, Stewart FR, White BR, Cirrito JR, Raichle ME, Culver JP, Holtzman DM. Bidirectional relationship between functional connectivity and amyloid-β deposition in mouse brain. J Neurosci. 2012 Mar 28;32(13):4334-40. PubMed.

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