Synaptic Plasticity Falters Early in AD Mice

Scientists believe that Abeta weakens synapses early in the course of Alzheimer’s disease–but how early? In the June 6 Journal of Neuroscience, researchers led by Brad Hyman at Massachusetts General Hospital, Charlestown, report that AD mice as young as one month already show measurable defects in synaptic plasticity. To demonstrate this, Hyman and colleagues used ocular dominance in the visual cortex, a well-studied paradigm of plasticity. The researchers found abnormalities in the transgenic mice when they occluded vision in one eye during the critical period of visual development. In normal mice, this leads neurons connected to the good eye to step up their synaptic activity; the open eye may also annex more territory in the visual cortex in the absence of competition from the other eye. However in the AD mice, neurons failed to increase their activity or make new synaptic contacts.

"This paper pushes the detection of synaptic changes very early," said Ahmad Salehi at Stanford University Medical Center, Palo Alto, California. He was not involved in the research. "What we learn is you have to challenge [neurons] to see [early deficits]. You will not be able to see them just by comparing transgenic versus nontransgenic."

In recent years numerous studies have shown that soluble, oligomeric forms of Abeta damage synapses, crippling their ability to change in response to experience (see, e.g., ARF related news story; ARF news story; ARF news story ; and ARF related news story). Adding Abeta to hippocampal cultures blocks long-term potentiation, the primary form of synaptic plasticity (Lambert et al., 1998; Chen et al., 2002; Walsh et al., 2002). Hyman and colleagues wondered how early such deficits might be detectable in vivo.

To study this, first author Christopher William tested ocular dominance plasticity using two different mouse models that express human APP with the Swedish mutation, APP/PS1 and Tg 2576. These animals do not show cognitive deficits until three months of age, while the critical period for visual development occurs in the fourth and fifth weeks of life. William and colleagues first verified, using immunoprecipitations and immunohistochemistry, that APP and Abeta were present in the brains of one-month-old transgenics. Then the authors employed two different methods—gene induction and optical intrinsic signal imaging—to look at activity in the visual cortex.

The first method involves exposing the animals to 30 minutes of light after 15 hours in darkness, while covering one eye. In response, neurons in the visual cortex that are driven by the open eye pump up transcription of the Arc gene, which is involved in synaptic plasticity. By sacrificing the mice and looking at brain sections, researchers can see the pattern of functional connections at cellular resolution based on Arc mRNA expression. The authors found that transgenic APP mice and their nontransgenic littermates responded equally well to visual stimuli when both eyes were open and showed normal functional organization of the visual cortex. After either four or 10 days of monocular vision, however, it was a different story. While the area driven by the open eye expanded noticeably in nontransgenic animals, it failed to do so in either line of AD mice.

To measure the magnitude of the visual response, the authors turned to intrinsic signal imaging in awake mice. In this method, animals view moving patterns on a LCD monitor while researchers assess small changes in autofluorescence (reflecting metabolic activity) in neurons of the visual cortex through a cranial window. The authors covered one eye for four days, then opened it for testing. Neurons in control mice showed the expected activity changes, with those connected to the deprived eye less active than before visual occlusion, indicating that long-term depression had occurred. In contrast, activity in neurons connected to the nondeprived eye slightly strengthened. AD mice responded abnormally; although neurons connected to the deprived eye weakened, so did those connected to the normal eye, suggesting that ocular dominance plasticity failed. Together with the Arc induction data, the results make the case for an early synaptic plasticity defect in AD mice, the authors conclude.

Salehi noted that this system could provide a new tool for testing therapeutic interventions. “The method looks quite quantitative. You could easily see the effects of drugs,” he suggested.

What do the data imply for human disease? People with Down’s syndrome carry an extra copy of the gene for APP, leading to life-long elevated levels of the protein. These synaptic plasticity defects could be relevant to developmental abnormalities in this condition, the authors suggest. However, Salehi pointed out that AD mice overexpress APP at much higher levels than are present in Down’s syndrome brains. For AD, the data dovetail with other findings in the field that suggest that synaptic deficits occur a decade or more before dementia begins. “This tells you that small alterations in synaptic function occur much earlier than what we observe in terms of structural changes,” Salehi noted. The ocular dominance data may provide a glimpse into early AD pathology, suggested Thomas Arendt at Universität Leipzig, Germany, writing to Alzforum, “The present study adds an important piece of evidence to the concept that a failure of synaptic reorganization is of utmost critical importance in the AD pathomechanism.” (See full comment below.)—Madolyn Bowman Rogers

Comments

  1. The current paper from Brad Hyman´s group very nicely shows that transgenic mice overexpressing FAD-mutated APP have reduced ocular dominance plasticity in the visual cortex. The data are very convincing as the study is carefully performed on two independent transgenic lines, applying two complementary methods assessing synaptic reorganisation after visual deprivation. Confounding effects of transgene expression on the basic spatial extent and laminar distribution of the visual cortex response to light or the overall responsiveness of the visual cortex have been ruled out, indicating that baseline functional organization of visual responses most unlikely account for the observed effects.

    In line with recent evidence that NMDA signalling, a mechanism required for synaptic plasticity, can be affected by Aβ (e.g. Hsieh et al. Neuron 2006;52:831), it is very tempting to assume a causative role for Aβ in disrupting synaptic plasticity. Still, other explanations might be possible, and it would be interesting to compare those strains analysed in the present study with transgenic mice expressing human wild-type APP at a comparable level. This also might shed light on previous discrepant findings reporting decreased (Wegenast-Braun et al. 2009) or increased (Grinevich et al. 2009; Perez-Cruz et al. 2011) Arc expression in different APP mouse strains. Accordingly, a recent study by Seeger et al. (Neurobiol.Dis. 2009;35:258) has shown a synaptotrophic effect for transgenic wild-type APP, which is lost when FAD-mutated APP is overexpressed instead.

    Irrespectively of the precise molecular mechanisms that account for the observed changes, the present study adds an important piece of evidence to the concept (e.g. Arendt; Neuroscience 2001;102:723) that a failure of synaptic reorganisation is of utmost importance in the AD pathomechanism. Realizing that Aβ and perhaps other fragments of APP might have an intrinsic role in making and reshaping our brain, the size of the challenge to interfere with these mechanisms with a therapeutic intention immediately becomes clear.

    References:

    Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron. 2006 Dec 7;52(5):831-43. PubMed.

    Wegenast-Braun BM, Fulgencio Maisch A, Eicke D, Radde R, Herzig MC, Staufenbiel M, Jucker M, Calhoun ME. Independent effects of intra- and extracellular Abeta on learning-related gene expression. Am J Pathol. 2009 Jul;175(1):271-82. PubMed.

    Grinevich V, Kolleker A, Eliava M, Takada N, Takuma H, Fukazawa Y, Shigemoto R, Kuhl D, Waters J, Seeburg PH, Osten P. Fluorescent Arc/Arg3.1 indicator mice: a versatile tool to study brain activity changes in vitro and in vivo. J Neurosci Methods. 2009 Oct 30;184(1):25-36. Epub 2009 Jul 21 PubMed.

    Perez-Cruz C, Nolte MW, van Gaalen MM, Rustay NR, Termont A, Tanghe A, Kirchhoff F, Ebert U. Reduced spine density in specific regions of CA1 pyramidal neurons in two transgenic mouse models of Alzheimer's disease. J Neurosci. 2011 Mar 9;31(10):3926-34. PubMed.

    Seeger G, Gärtner U, Ueberham U, Rohn S, Arendt T. FAD-mutation of APP is associated with a loss of its synaptotrophic activity. Neurobiol Dis. 2009 Aug;35(2):258-63. PubMed.

    Arendt T. Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization. Neuroscience. 2001;102(4):723-65. PubMed.

    View all comments by Thomas Arendt

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References

News Citations

  1. AMPA Receptors: Going, Going, Gone in Aβ-exposed Synapses, PSD95 Knockouts
  2. Aβ Oligomers and NMDA Receptors—One Target, Two Toxicities
  3. Neuronal Glutamate Fuels Aβ-induced LTD
  4. Spine Shrinkers: Aβ Oligomers Caught in the Act

Paper Citations

  1. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53. PubMed.
  2. Chen QS, Wei WZ, Shimahara T, Xie CW. Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus. Neurobiol Learn Mem. 2002 May;77(3):354-71. PubMed.
  3. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002 Apr 4;416(6880):535-9. PubMed.

Other Citations

  1. Tg 2576

External Citations

  1. APP/PS1

Further Reading

Papers

  1. Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, Vandersteen A, Segers-Nolten I, Van Der Werf K, Subramaniam V, Braeken D, Callewaert G, Bartic C, D'Hooge R, Martins IC, Rousseau F, Schymkowitz J, De Strooper B. Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio. EMBO J. 2010 Oct 6;29(19):3408-20. PubMed.
  2. Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006 Mar 16;440(7082):352-7. PubMed. RETRACTED

Primary Papers

  1. William CM, Andermann ML, Goldey GJ, Roumis DK, Reid RC, Shatz CJ, Albers MW, Frosch MP, Hyman BT. Synaptic plasticity defect following visual deprivation in Alzheimer’s disease model transgenic mice. J Neurosci. 2012 June 6;32(23):8004-11.

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