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. PubMed.
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Comments
University of California, San Diego
These are very interesting studies. There has been growing evidence that some of the primary targets of AD and APP are synapses. These studies support this view. Furthermore, there has been recent interest in the relation between APP processing and synaptic transmission and in the trafficking of postsynaptic receptors. These studies provide important molecular evidence that such processes are key targets of Aβ. The molecular details of how APP derivatives affect synapses will be an important area of research, since judicious modulation of these processes may open therapeutic avenues to the treatment of AD.
View all comments by Roberto MalinowThese papers provide intriguing evidence for a link among β-amyloid, excitatory synaptic transmission, and altered membrane trafficking. It has been known for some time that early stages of Alzheimer disease (AD) are associated with learning impairments and cognitive decline before the prototypical pathological hallmarks of plaques and tangles. These learning impairments have been linked to altered transmission at excitatory synapses, and in particular learning-related forms of plasticity such as long-term potentiation and long-term depression in the hippocampus. Now, Greengard, Gouras, and colleagues reveal that β-amyloid—the toxic peptide which accumulates in AD—exerts an unexpected influence over the abundance of both primary types of neurotransmitter at excitatory synapses: the AMPA- and NMDA-type glutamate receptors. These findings emphasize the critical need for an understanding of the cell biology of postsynaptic receptor trafficking under healthy physiological conditions and how such cellular processes go awry in the early stages of AD.
View all comments by Michael EhlersI would be interested in how the community thinks this study ties in with the prescription of memantine (an NMDA-receptor antagonist) for moderate to severe Alzheimer disease. If NMDA receptor deficits contribute significantly to Alzheimer disease, would not this treatment be expected to have a detrimental rather than a beneficial effect?
View all comments by Adam KlineThese two papers from the Greengard and Gouras labs identify specific pre- and postsynaptic defects in cultured neurons induced by exposure to the β-amyloid peptide (Aβ). It is well-established that synaptic loss likely occurs early in the Alzheimer pathological cascade, and rodent studies have demonstrated a specific depression in long-term potentiation associated with Aβ1-42. These two new studies, therefore, provide mechanistic insights into neuronal alterations potentially associated with AD memory loss. The Snyder et al. study demonstrates a specific loss of surface NMDA glutamate receptors in cortical neurons exposed to Aβ. Importantly, they go far beyond this observation and provide evidence for an Aβ-dependent molecular cascade that involves the α7 nicotinic receptor, protein phosphatase 2B, and tyrosine phosphatase, ultimately culminating in enhanced endocytosis of the NMDA receptor. In the Almeida et al. study, cultured primary neurons from the well-studied Tg2576 AD mouse model were used to demonstrate both presynaptic (reduced synaptophysin protein levels) and postsynaptic (reduced AMPA glutamate receptor subunit and PSD-95 protein levels, general reduction in dendritic spines) deficits. A perhaps important difference in these two studies is that Almeida et al. relied on endogenous production of Aβ in the primary neuronal culture, which they have previously shown to result in substantial intracellular pools of Aβ.
As it becomes clear that Aβ can have fairly specific effects on synaptic function, an important question arises: Does Aβ have a natural role regulating synaptic function? If so, treatments that eliminate Aβ might have negative effects on synaptic function. However, Aβ is produced by many cells throughout the body, which probably would not be predicted for a protein with specific or important roles in synaptic function. If the Aβ peptide does not normally have a direct role in synaptic function, why does it have the observed effects on synaptic components? One possibility is that Aβ has a more general biological role (e.g., regulating cholesterol uptake), and a byproduct of an excess or abnormal form of this activity is the observed effects on synapses. Alternatively, Aβ1-42 (or some oligomer thereof) may simply be a toxic protein, and the apparently specific synaptic deficits result from low-grade toxicity affecting particularly vulnerable components of synaptic function. The case for highly Aβ-specific toxicity would be stronger if other peptides (e.g., random amphipathic peptides, or other proteins claimed to form toxic oligomers) could be shown not to have similar effects in the primary neuronal culture models.
Another general issue is the relationship between synaptic dysfunction in AD and the more extreme neuronal cell loss that occurs later in the disease. One possibility is that synaptic dysfunction itself leads to neuronal death. Alternatively, synaptic dysfunction might be the "tip of the iceberg" of a more general pathological process. However, a third possibility, that Aβ-dependent synaptic deficits and neuronal loss are actually independent processes, cannot yet be ruled out. If the studies discussed here can be extended by developing treatments that block Aβ-dependent synaptic deficits, it may be possible to determine the relationship between synaptic dysfunction and neuronal cell death using recent transgenic mouse models that appear to capture much of human AD pathology.
View all comments by Chris LinkBanner Research Institute
These papers, dealing with an effect of Aβ on postsynaptic mechanisms, when considered in combination with the recent paper from the Ferreira lab which shows an effect of Aβ on presynaptic mechanisms, show that there is more than one target through which Aβ can have a deleterious effect on synaptic function. Furthermore, other data indicating loss of dynamin 1 transcript in AD brain without loss of PSD 95 transcript (Yao et al., 2003) suggest that these effects on synaptic function may occur prior to the loss of synapses by still living neurons. [On the other hand, there are the Scheff data (reviewed in Scheff and Price, 2003) showing increased size of remaining synapses as other synapses are lost.] That still living neurons lose synapses in AD is suggested by data showing loss of synaptophysin message in selected affected single neurons in AD brain (e.g., Callahan et al., 2002) and by decreased synapse/neuron ratio in AD brain (Bertoni-Freddari et al., 1996). These data together suggest a progression of 1) decreased synaptic function, 2) loss of synapses by still living neurons and, finally, 3) loss of synapses by neuron death.
References:
Bertoni-Freddari C, Fattoretti P, Casoli T, Caselli U, Meier-Ruge W. Deterioration threshold of synaptic morphology in aging and senile dementia of Alzheimer's type. Anal Quant Cytol Histol. 1996 Jun;18(3):209-13. PubMed.
Callahan LM, Vaules WA, Coleman PD. Progressive reduction of synaptophysin message in single neurons in Alzheimer disease. J Neuropathol Exp Neurol. 2002 May;61(5):384-95. PubMed.
Kelly BL, Vassar R, Ferreira A. Beta-amyloid-induced dynamin 1 depletion in hippocampal neurons. A potential mechanism for early cognitive decline in Alzheimer disease. J Biol Chem. 2005 Sep 9;280(36):31746-53. PubMed.
Scheff SW, Price DA. Synaptic pathology in Alzheimer's disease: a review of ultrastructural studies. Neurobiol Aging. 2003 Dec;24(8):1029-46. PubMed.
Yao PJ, Zhu M, Pyun EI, Brooks AI, Therianos S, Meyers VE, Coleman PD. Defects in expression of genes related to synaptic vesicle trafficking in frontal cortex of Alzheimer's disease. Neurobiol Dis. 2003 Mar;12(2):97-109. PubMed.
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