Béïque JC, Lin DT, Kang MG, Aizawa H, Takamiya K, Huganir RL.
Synapse-specific regulation of AMPA receptor function by PSD-95.
Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19535-40.
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Hsieh and colleagues provide exciting results on a major question in AD
research: how β amyloid induces synaptic dysfunction.
In well-controlled experiments, they show that the mechanisms of Aβ
effects on synapses parallel those involved in LTD. They confirm that Aβ
causes internalization of AMPA receptors, suggesting that this is required
for subsequent alterations in NMDA receptors. Importantly, an endocytosis-defective GluR2 construct prevents the physiological alterations induced by Aβ.
This work strengthens the idea that Aβ has a role in synaptic biology, although
the molecular mechanisms whereby Aβ causes internalization of AMPA
receptors and promotes pathology at synapses in AD remain unclear.
Our findings reported in Neuron indicate that removal of synaptic AMPAR by Aβ leads to loss of spines and loss of NMDA responses. In other cases, removal of synaptic AMPAR does not lead to loss of NMDA responses (e.g., Shi et al., 2001; expression of GluR2 c-tail leads to selective decrease in AMPAR responses). In the Beique et al. paper, which is a very nice study, they find that in PSD95 knockout animals, there are some large spines with no AMPAR responses. So I would conclude that removal of AMPAR from synapses can lead to spine loss, but it appears to be dependent on how those receptors are lost. There may be AMPAR-associated molecules, which normally stabilize spines, that are also removed by Aβ but can persist in PSD95 KO animals.
The study by Malinow and colleagues provides compelling evidence for a direct link between the synaptic deficits associated with Aβ production and known cellular pathways for physiological synaptic plasticity. This work is important, as it points to several well-established molecular mechanisms of glutamate receptor trafficking as potential early mediators of amyloid-induced synaptic dysfunction.
The study by Huganir and colleagues sheds new light on the fundamental molecular events regulating synaptic transmission and excitatory synapses in the brain. The authors generated mutant mice lacking a critical protein component of excitatory synapses, the scaffold molecule PSD-95. In brain slices from these animals, synaptic transmission was impaired, but plasticity was actually increased. These findings are important because they pinpoint the functional defects in synaptic transmission produced when synapses lack PSD-95. Together with the results of Malinow and colleagues, one can begin to envision an unraveling of the molecular mechanisms underlying synaptic failure in Alzheimer disease and other disorders of memory and cognition.
This is a landmark paper on how Aβ peptides might induce synaptic depression by reducing the number of AMPA receptors at postsynaptic sites of hippocampal neurons. The authors propose that Aβ peptides, either generated endogenously from APP, or added exogenously, induce endocytosis mechanisms that are thought to underlie long-term depression. Two questions, which I imagine the authors are now poised to answer, are (i) the identity of the active Aβ peptide (is it a monomer dimer, oligomer, or Aβ*?) and (ii) how it acts on the postsynaptic membrane. My guess is that the active Aβs must be either monomers or dimers, since the effect is seen when Aβs are generated from endogenous APP, and there is no reason to expect large amounts of Aβ to be generated at concentrations needed to oligomerize. Synthetic Aβ peptides added to the medium of the hippocampal slices need not act only on the external surface of the membrane, since they were added at concentrations (micromolar) high enough to enter and cross the lipid bilayer, giving them access to the cytoplasmic surface. If present at high enough concentration, they might affect in some way the functioning of the cytoskeletal network which must play a role in the endocytosis process.
Alternatively, they could partition within the lipid bilayer, as was proposed earlier (1). If a fraction of the Aβ peptide pool remained within the lipid bilayer, their hydrophobic domains, which contain GxxxG/A sequences, could conceivably interact with comparable domains in the TARP proteins, all of which have two hydrophobic and putative transmembrane segments that are similar but not identical to the Aβ domains. A comparison between Aβ and one of the T-M domains is shown below:
Interactions between Aβ peptides and T-M segments of TARP proteins could affect the AMPA receptor trafficking mechanisms proposed earlier (2), and this would be an alternative way in which Aβ peptides might reduce the AMPA receptor population. A test of this idea would be to express Aβ alone in hippocampal neurons with a vector that incorporates an appropriate signal sequence along with the Aβ segment and some anchoring sequence at its C-terminus.
The classical view of amyloid action in the pathogenesis of Alzheimer disease centers around the neurotoxic properties of aggregated peptides. Recent studies have, however, been challenging this as the exclusive mechanism, suggesting direct modulatory functions for Aβ; compelling evidence that supports this view is now provided by the paper by Hsieh et al., who offer some novel mechanistic insights. They use a clever combination of imaging (with synaptopHluorin tagged receptors) and electrophysiological (electrophysiological tagging of AMPA receptors) techniques. The authors show that application of synthetic Aβ or the overexpression of C99 causes endocytosis of GluR1 and Glur2 receptors from synapses. Furthermore, Hsieh et al. show the involvement of p38/MAPK and calcineurin in GluR2 endocytosis, and detect an increase in the phosphorylation of the cytoplasmic tail of GluR2 after Aβ treatment. Based on these findings, Hsieh et al. suggest that Aβ induces GluR2 endocytosis through a pathway that may be shared with LTD induction. In fact, they also show that Aβ can mimic and partly occlude mGluR1-induced LTD. Finally, Hsieh et al. bridge the difficult gap between electrophysiological and morphological plasticity and show that Aβ treatment, as well as C99 overexpression, leads to synaptic spine loss, an effect that can be mimicked by expressing AMPAR, which bears mutations that result in enhanced endocytosis; in doing the reverse experiment, they demonstrate that the same mutated AMPAR attenuates Aβ-induced spine loss. On the basis of previous data from this same group (Kamenetz et al., 2003) as well as from Cirrito et al. (2005), it is now suggested that Aβ cleavage is dependent upon synaptic activity which, together with the data from Hsieh et al., strongly backs the view of Aβ as modulator of synaptic activity. In summary, the studies by Hsieh et al. indicate that Aβ might operate in a negative feedback loop to homeostatically regulate synaptic strength.
Hsieh et al. conducted carefully executed experiments addressing the mechanisms underlying Aβ-induced depression of glutamatergic synaptic transmission. Their work provides convincing evidence that Aβ causes internalization of AMPA receptors which results in synaptic dysfunction and dendritic spine loss. These results further support the link between Aβ and glutamate receptor function during pathological onset in AD.
We wish to learn more about how AMPA receptor internalization leads to the loss of functional NMDA receptors. Specifically, the mechanisms by which loss of AMPA receptors leads to the loss of NMDA receptors remain unclear. There is undoubtedly a correlation between the two events because of their anatomical location and functional relation; however, there are several steps in the process that have yet to be revealed.