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 Malinow

These 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 Ehlers

I 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 Kline

These 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...  Read more

These 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 Link

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...  Read more

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. Analytical & Quantitative Cytology & Histology. 18(3):209-13, 1996. Abstract Callahan LM. Vaules WA. Coleman PD. Progressive reduction of synaptophysin message in single neurons in Alzheimer disease. Journal of Neuropathology & Experimental Neurology. 61(5):384-95, 2002. Abstract Kelly BL, Vassar R, Ferreira A. Beta-amyloid-induced dynamin 1 depletion in hippocammpal neurons: A potential mechanism for early cognitive decline in Alzheimer's disease. J Biol Chem. 2005. Scheff SW. Price DA. Synaptic pathology in Alzheimer's disease: a review of ultrastructural studies. Neurobiology of Aging. 24(8):1029-46, 2003. Abstract 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. Neurobiology of Disease. 12(2):97-109, 2003. Abstract

View all comments by Paul Coleman

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.

View all comments by Vincent Marchesi

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...  Read more

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.

View all comments by John Cirrito

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...  Read more

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.

References:
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. Abstract

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. Abstract

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. Abstract

View all comments by Jane Sullivan

Comment on Herz et al.
This work addresses an exciting target in therapeutic approaches against Alzheimer disease: saving the synapse. Joachim Herz and colleagues recognized that some compounds promote synaptic strength, and have used this knowledge to counteract the negative effects of Aβ on the synapse. Specifically, they have found that Reelin, by signaling through the Src family kinases, prevents Aβ-induced synaptotoxicity. The research brings together an increasing understanding of the effects of Aβ (and Aβ oligomers) on synaptic deficits with growing research into the functions of Reelin on promoting synaptic strength.

There are several interesting aspects to this work. One, since it involves ApoE receptors in the mechanism of Reelin, it raises the possibility that APOE genotype affects the risk of AD at least partially through effects of ApoE on synapses. Two, it identifies non-traditional targets for AD therapeutic approaches, i.e., activation of ApoE receptors and Src family kinases, particularly for pathological processes that occur early in the disease...  Read more

Comment on Herz et al.
This work addresses an exciting target in therapeutic approaches against Alzheimer disease: saving the synapse. Joachim Herz and colleagues recognized that some compounds promote synaptic strength, and have used this knowledge to counteract the negative effects of Aβ on the synapse. Specifically, they have found that Reelin, by signaling through the Src family kinases, prevents Aβ-induced synaptotoxicity. The research brings together an increasing understanding of the effects of Aβ (and Aβ oligomers) on synaptic deficits with growing research into the functions of Reelin on promoting synaptic strength.

There are several interesting aspects to this work. One, since it involves ApoE receptors in the mechanism of Reelin, it raises the possibility that APOE genotype affects the risk of AD at least partially through effects of ApoE on synapses. Two, it identifies non-traditional targets for AD therapeutic approaches, i.e., activation of ApoE receptors and Src family kinases, particularly for pathological processes that occur early in the disease course (loss of synapses). Three, it underscores the idea that Reelin has important functions in the adult brain, and not just during neuronal migration in development.

This research supports some very interesting avenues for research. Does Aβ affect normal functions of ApoE receptors or Src family kinases? Do ApoE isoforms have differential effects on synaptic signaling processes relevant to their risk for AD? Is targeting the molecules identified in their nice model of synaptic dysfunction in AD useful in preventing the progression of AD? It’s a rich area.

View all comments by G. William Rebeck

The three papers [1-3] discussed in this Research News are highly relevant for the pathogenic mechanisms of Alzheimer disease. They are tied together by their common focus on the synapse, and the way in which APP, or its proteolytic fragment, Aβ, influences synaptic function. Yet, the papers project different views on how synaptic function is perturbed in AD. Two of them [1,2] describe possible ways by which the toxic effects of Aβ on synaptic function could be alleviated. The third paper [3] reports on a novel function of APP in the formation of the synapse, and proposes that this function may be perturbed in AD, causing the synaptic dysfunction that is characteristic for the disease. Thus, the old question of whether AD is the result of the gain of (toxic) function inflicted by the accumulated Aβ, or of the loss of function of APP by abnormal processing, is revived. Most likely, the synaptic pathology that accompanies AD is the result of a combination of gain- and loss-of-function events leading to the disruption of a number of cellular processes downstream from cleavage and...  Read more

The three papers [1-3] discussed in this Research News are highly relevant for the pathogenic mechanisms of Alzheimer disease. They are tied together by their common focus on the synapse, and the way in which APP, or its proteolytic fragment, Aβ, influences synaptic function. Yet, the papers project different views on how synaptic function is perturbed in AD. Two of them [1,2] describe possible ways by which the toxic effects of Aβ on synaptic function could be alleviated. The third paper [3] reports on a novel function of APP in the formation of the synapse, and proposes that this function may be perturbed in AD, causing the synaptic dysfunction that is characteristic for the disease. Thus, the old question of whether AD is the result of the gain of (toxic) function inflicted by the accumulated Aβ, or of the loss of function of APP by abnormal processing, is revived. Most likely, the synaptic pathology that accompanies AD is the result of a combination of gain- and loss-of-function events leading to the disruption of a number of cellular processes downstream from cleavage and intracellular transport of APP. Sooner or later, the enormous amount of research conducted on APP will clarify these molecular and cellular dysregulations.

Unfortunately, APP undergoes a complex cell biology, and may exert its multiple functions both as full-length protein and as cleaved fragments [4]. Thus, there are probably many functions to be lost and many toxic effects to be gained when the metabolism of APP is perturbed, as likely is the case in AD. From the researcher’s point of view, studying APP is both interesting and very challenging. Hopefully, all this exciting research will soon bring some relief to those predisposed to, or suffering from AD.

References:
1. Durakoglugil M, Chen Y, White CL, Kavalali ET, Herz J. Reelin signaling antagonizes beta-amyloid at the synapse. PNAS Early Edition. Sept 2009.

2. Wang H-Y, Stucky A, Liu J, Shen C, Trocme-Thibierge C, Morain P. Dissociating beta-Amyloid from Alpha7 Nicotinic Acetylcholine Receptor by a Novel Therapeutic Agent, S 24795, Normalizes Alpha7 Nicotinic Acetylcholine and NMDA Receptor Function in Alzheimer’s Disease Brain. J. Neurosci. 2009 Sept 2. 29(35):10961-10973. Abstract

3. Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, Zheng H. Presynaptic and Postsynaptic Interaction of the Amyloid Precursor Protein Promotes Peripheral and Central Synaptogenesis. J. Neurosci. 2009 Sept 2. 29(35):10768-10801. Abstract

4. Muresan, V., et al., The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites. J Neurosci, 2009. 29(11): p. 3565-78. Abstract

View all comments by Virgil Muresan
View all comments by Zoia Muresan

The results are very interesting and relate closely to findings we obtained in hAPP transgenic mice and humans with AD (1). In our study, we documented a depletion of reelin-positive pyramidal neurons in layer II of the entorhinal cortex in both the experimental models and the human condition. Because efferent projections of these cells could serve as a source of reelin in the hippocampus, we speculated that the depletion of reelin-producing pyramidal neurons in the entorhinal cortex might be associated with decreased reelin levels in the hippocampus, a hypothesis we were able to confirm in hAPP mice. Together with the new findings by Durakoglugil et al., these observations suggest that the Aβ-induced depletion of reelin adds insult to injury, as it would disable the very mechanism the brain could use to counteract the adverse effects of Aβ on synaptic functions.

References:
1. Chin J, Massaro CM, Palop JJ, Thwin MT, Yu G.-Q, Bien-Ly N, Bender A, and Mucke L (2007) Reelin depletion in the entorhinal cortex of human amyloid precursor protein transgenic mice and humans with Alzheimer’s disease. J. Neurosci. 27: 2727–2733. Abstract

View all comments by Lennart Mucke