Ting JT, Kelley BG, Lambert TJ, Cook DG, Sullivan JM.
Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms.
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):353-8.
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This paper confirms recent studies that demonstrate a decrease in AMPA
receptor activity as a consequence of exposure to Aβ peptides, but
it is more than just confirmatory. The earlier studies employed
exogenous Aβ at relatively high concentrations, experiments that
are always open to question. This new work suggests that endogenous
Aβ is the likely agent responsible for the decrease in synaptic
transmission. Their use of a mutant APP incapable of generating Aβ
is a new approach that has great potential for further studies.
Ting et al. provide an interesting and well-done analysis of how endogenous Abeta may depress synaptic transmission, namely by depressing AMPA receptor-mediated EPSCs. Also, the authors find subtle presynaptic deficits in synaptic vesicle cycling with unknown consequences for synaptic communication. The key here is the possibility that cellularly derived Abeta may be causing these effects, thereby bypassing problems related to Abeta concentration or Abeta conformation typically associated with exogenously applied Abeta. It will eventually be useful to know the specific types of Abeta that are responsible for this phenomenon.
Several groups have demonstrated that synaptic activity can regulate release of Abeta from neurons (Kamenetz et al., 2003, Cirrito et al., 2005 ). Is activity-dependent release of Abeta necessary for this phenomenon, or is Abeta release via other mechanisms sufficient to mediate the effect on AMPA receptors? These questions ultimately address whether Abeta may act as a negative feedback signal for synaptic transmission.
APP with a mutation at the BACE cleavage site was a very clever tool to use in these studies. As the authors note, while this vector suggests that Abeta could be a key mediator of the effects seen here, other APP cleavage products are also affected and therefore cannot be excluded.
Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R.
APP processing and synaptic function.
Neuron. 2003 Mar 27;37(6):925-37.
Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM.
Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.
Neuron. 2005 Dec 22;48(6):913-22.
Our PNAS study identifies deficits in synaptic transmission when APP is overexpressed in neurons. We use Semliki Forest virus to rapidly upregulate APP in autaptic (isolated microisland) cultures of hippocampal neurons, and record synaptic responses 12 to 24 hours after infection. Our finding that AMPA receptor-mediated responses are reduced in neurons overexpressing APP is consistent with a number of recent studies reporting APP- or Aβ-mediated internalization of AMPA receptors (e.g., Almeida et al., 2005; Roselli et al., 2005; Hsieh et al., 2006).
One notable difference between our study and that of Hsieh et al. is that we do not observe a decrease in NMDA receptor-mediated synaptic responses. I believe we fortuitously caught our synapses at a point predicted but not seen by Hsieh et al.—that is, after AMPA receptor removal but prior to spine retraction—by recording a few hours earlier after infection than Hsieh et al. We also identified a presynaptic deficit in synaptic vesicle recycling that has implications for neurotransmission in response to extended trains of action potentials.
Almeida CG, Tampellini D, Takahashi RH, Greengard P, Lin MT, Snyder EM, Gouras GK.
Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses.
Neurobiol Dis. 2005 Nov;20(2):187-98.
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.
Roselli F, Tirard M, Lu J, Hutzler P, Lamberti P, Livrea P, Morabito M, Almeida OF.
Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses.
J Neurosci. 2005 Nov 30;25(48):11061-70.