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...  Read more

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.

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.

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.

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.

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. Epub 2009 May 18.

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

View all comments by Thomas Arendt

• The nature of toxic Aβ intermediates can be more accurately controlled by injecting Aβ preparations that are characterized before and after chronic injection, as we did in our paper (Fig. 1 and Fig. 2D).
• Since the intrahippocampal injections are done in awake, freely moving mice, there are no confounding interference effects between any anesthetic agents and the Aβ solution on intracellular pathways.
• To take into account aging—the most robust risk factor associated with AD—the effects of soluble Aβ1-42 oligomers were determined during the process of aging in 12-month-old mice. Chronic Aβ1-42 injections can also be done in younger and older mice to see their effects at different ages.
• The collateral injection of soluble Aβ1-42 oligomers and vehicles permitted the control of any alteration within the same mouse.
• Since Aβ accumulates in a time-dependent manner, the number of injections and the dose of Aβ can be adjusted to obtain more or less severe readouts of Aβ...  Read more
  

• The nature of toxic Aβ intermediates can be more accurately controlled by injecting Aβ preparations that are characterized before and after chronic injection, as we did in our paper (Fig. 1 and Fig. 2D).
• Since the intrahippocampal injections are done in awake, freely moving mice, there are no confounding interference effects between any anesthetic agents and the Aβ solution on intracellular pathways.
• To take into account aging—the most robust risk factor associated with AD—the effects of soluble Aβ1-42 oligomers were determined during the process of aging in 12-month-old mice. Chronic Aβ1-42 injections can also be done in younger and older mice to see their effects at different ages.
• The collateral injection of soluble Aβ1-42 oligomers and vehicles permitted the control of any alteration within the same mouse.
• Since Aβ accumulates in a time-dependent manner, the number of injections and the dose of Aβ can be adjusted to obtain more or less severe readouts of Aβ pathogenicity.
• Because cell death occurs in the proximity of the Aβ injection site, neuronal loss can be induced in various and very localized brain regions.
• The toxic effect of Aβ oligomers on molecular and cellular pathways can also be determined before and after neuronal loss within a reasonably short timeframe.
• Since Aβ species were cleared gradually after injection, the long-term effects of Aβ oligomers after their removal can be analyzed both at the molecular and behavioral levels.
• This new animal model can be used for preclinical validation of agents designed to prevent Aβ neurodegeneration, as shown in our paper using transthyretin (TTR).

As discussed in the manuscript, TTR monomers have previously been shown to bind more extensively to Aβ monomers, impeding the further growth of Aβ aggregates (Du and Murphy, 2010). On the other hand, TTR tetramers interact more with Aβ aggregates than with Aβ monomers, and have been observed disrupting fibril formation (Du and Murphy, 2010). Thus, one could argue that the neuroprotective effect of TTR is mainly caused by the prevention of fibril/protofibril-induced toxicity. Although we cannot completely exclude the possibility that part of the neuroprotective effect of TTR is attributed to this mechanism, we think that the major mechanism for the TTR-mediated protection against Aβ toxicity is the sequestration of discrete toxic species and the arrest of Aβ monomer growth into multimers, since we observed that solutions containing an elevated concentration of small Aβ species were more toxic than Aβ1-42 preparation containing larger oligomers (Fig. 5).

In summary, our novel animal model recapitulated many key neuropathological hallmarks of AD in a time-dependent manner, such as Aβ accumulation, marked neuronal loss, abnormal tau phosphorylation, and memory dysfunction. This in-vivo approach can prove useful in determining the toxicity of Aβ preparations as a function of their temporal profile.

Since current methods of oligomer characterization are very limited and provide only semi-quantitative information, it is difficult to compare different oligomeric preparations in terms of concentration, conformation, and their potential relevance to the disease. In terms of oligomer identification and characterization, "in-vitro" and "ex-vivo" Aβ preparations have their own advantages and pitfalls (for more details, see our critical review, Benilova et al., 2012). In our study, we used recombinant human Aβ42 that was previously assessed under denaturing and non-denaturing conditions using Western blot, transmission electron microscopy (TEM), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FT-IR), electrospray-ionization mass spectrometry (ESI-MS), and nuclear magnetic resonance spectroscopy (NMR) (Kuperstein et al., 2010; Broersen et al., 2011). In future studies, it will be interesting to determine if Aβ preparations isolated directly from AD brains can induce similar effects using this model.

References:
Benilova I, Karran E, De Strooper B (2012) The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes. Nat Neurosci. 15(3):349-357. Abstract

Broersen K, Jonckheere W, Rozenski J, Vandersteen A, Pauwels K, Pastore A, Rousseau F, Schymkowitz J (2011) A standardized and biocompatible preparation of aggregate-free amyloid β peptide for biophysical and biological studies of Alzheimer's disease. Protein Eng Des Sel. 24:743-750. Abstract

Du J, Murphy RM (2010) Characterization of the interaction of β-amyloid with transthyretin monomers and tetramers. Biochemistry. 49:8276-8289. Abstract

Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, Vandersteen A, Segers-Nolten I, Van Der WK, Subramaniam V, Braeken D, Callewaert G, Bartic C, D'Hooge R, Martins IC, Rousseau F, Schymkowitz J, De Strooper B (2010) Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio. EMBO J. 29:3408-3420. Abstract

View all comments by Jonathan Brouillette