. AMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice. Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3410-5. PubMed.


Please login to recommend the paper.


  1. This paper is very interesting. The authors show decreased
    synaptic AMPARs leading to disrupted plasticity and episodic-like memory in
    a double knock-in model of AD. This work, in the context of other studies in
    vitro and in vivo showing amyloid-related synaptic changes including NMDAR
    internalization and dendritic spine loss and changes in plasticity, strongly
    suggests that amyloid-associated synaptotoxicity contributes to cognitive
    decline in AD.

  2. This study is very interesting. The authors explore how cognitive deficits arise in Alzheimer disease using a knock-in mouse model where, without overexpression of transgenes, there is accumulation of β amyloid with aging. The authors perform extensive electrophysiological characterization of these mice at three different stages, pre-plaque (young), few plaques (middle-age) and robust deposition (old). While normal at young age, basal synaptic transmission and long-term plasticity was impaired after middle age, before major plaque load.

    Mechanistically, the authors find by quantitative immuno-EM that although there was no reduction in the number of AMPA-containing spines, there was a small reduction in the amount of AMPA gold particles in old 2xKI mice. I was a bit surprised by this small difference given that the differences in AMPA currents were dramatic. I suspect that this is due to EM not being an optimal method for quantitative analysis.

    In summary, the authors provide convincing data confirming that changes in AMPA receptors may be an early feature of Aβ-induced synaptic dysfunction. In the discussion, the authors suggest that their results are discrepant from those of Kamenetz et al. (2003) and Snyder et al. (2005) because these studies found NMDA receptor changes. Chang et al. suggest that this discrepancy may be because these two studies addressed “acute” alterations, that is, minutes to hours after either addition of Aβ or transfection with APP constructs. However, in Snyder et al. we did, in fact, observe surface NMDA receptor (NR1) reductions in neurons of Tg2576 mice that progressively accumulate Aβ42 over days in culture (see Takahashi, 2004).

    The authors may also want to read our published work on early reductions in GluR1 AMPA receptor subunits in cultured neurons derived from APP mutant Tg2576 mice (Almeida et al., 2005). In this study we found that, early on, spine density was reduced and, later on, that is, in older cultures, the alterations were more pronounced and also included presynaptic changes. These correlate with increased accumulation and oligomerization of Aβ42 in these neurons. We also observed that alterations in synaptic AMPA receptors were more pronounced than those of NMDA receptors in Tg2576 neurons. Our data support this present study by Chang et al., since it suggests that it is possible that AMPA receptors are affected earlier, and NMDA receptors later, due to the progressive accumulation of Aβ. Therefore I disagree with the authors’ affirmation that one cannot make conclusions from cultured neurons. Neurons in culture are a limited model but so are mouse models; together they all may help us to better understand AD pathogenesis.


    . APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. PubMed.

    . Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005 Aug;8(8):1051-8. PubMed.

    . Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci. 2004 Apr 7;24(14):3592-9. PubMed.

    . Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis. 2005 Nov;20(2):187-98. PubMed.

Make a Comment

To make a comment you must login or register.

This paper appears in the following:


  1. Hyperactive Neurons and Amyloid, Side by Side
  2. Synaptic Function in Aging and AD