Posts Tagged ‘brain synapses’

Long Term Memory and Prions

Larry H. Bernstein, MD, FCAP, Curator



updated 12/12/2015


Possible biochemical mechanism underlying long-term memories identified

Why is a prion-like molecular state necessary for persistence of memory? Could a transient memory be made permanent with a “Limitless” NZT-type neurotropic drug — or permanently forgotten?

It’s a nagging question: why do some of our memories fade away, while others last forever? Now scientists at the Stowers Institute for Medical Research have identified a possible biochemical mechanism: a specific synaptic protein called Orb2 can either block or maintain neural synapses (connections between neurons), which create and maintain long-term memories.

So for a memory to persist, the synaptic connections must be kept strong. But how? The researchers previously identified a synaptic protein called CPEB that is responsible for maintaining the strength of such connections in the sea slug (a model organism used in memory research). Recently, they identified a similar protein, called Orb2, in the fruit fly.

Now, using a fruit fly model system, they found that the synaptic connections are kept strong by the transformation of Orb2 from one molecular state to another. And that transformation causes Orb2 molecules to solidify and strengthen the memory connections in the brain.

The authors conclude their paper, published in the current issue of the journal Cell, with several questions. How and what triggers this transformation, how long does it persist? Is the continued presence of a prion-like state necessary for the persistence of memory, and is it correlated with or predictive of long-lasting memory? And most interestingly: can a transient memory about to be forgotten be stabilized by artificial recruitment of the prion-like state (perhaps by a neurotropic compound)?

And what about that ironic link with prions, associated with neurodegenerative disorders? Are prions some twisted form of memory that could one day even have value? We’ll be keeping an eye on where this fascinating research leads.

Technical details: the memory switch

In their latest study, the researchers determined that Orb2 exists in two distinct physical states: monomeric (a single molecule that can bind to other molecules) and oligomeric (a molecular complex).

Like CPEB, oligomeric Orb2 is prion-like — that is, it’s a self-copying cluster. (But unlike prions, oligomeric Orb2 and CPEB are not toxic.) Monomeric Orb2 represses, and oligomeric Orb2 activates a crucial step in the complex cellular process that leads to protein synthesis.

During this crucial step, messenger RNA (mRNA), which is an RNA copy of a gene’s recipe for a protein, is translated by the cell’s ribosome into the sequence of amino acids that will make up a newly synthesized protein. The monomeric form of Orb2 binds to the target mRNA, keeping it in a repressed state.

The Stowers scientists also determined that prion-like Orb2 not only activates translation into amino acids but imparts its translational state to nearby monomer forms of Orb2. As a result, monomeric Orb2 is transformed into prion-like Orb2, so its role in translation switches from repression to activation.

Self-sustaining activation maintains synaptic activity

Stowers Associate Investigator Kausik Si, Ph.D. thinks this switch is the possible mechanism by which fleeting experiences create an enduring memory. “Because of the self-sustaining nature of the prion-like state, this creates a local and self-sustaining translation activation of Orb2-target mRNA, which maintains the changed state of synaptic activity over time,” says Si.

The discovery that the two distinct states of Orb2 have opposing roles in the translation process provides “for the first time a biochemical mechanism of synapse-specific persistent translation and long-lasting memory,” he states.

“To our knowledge, this is the first example of a prion-based protein switch that turns a repressor into an activator,” Si adds. “The recruitment of distinct protein complexes at the non-prion and prion-like forms to create altered activity states indicates the prion-like behavior is in essence a protein conformation-based switch.

“Through this switch, a protein can lose or gain a function that can be maintained over time in the absence of the original stimuli. Although such a possibility has been anticipated prior to this study, there was no direct evidence.”

The research builds upon previous studies by Si and Eric Kandel, M.D., of Columbia University and other scientists. These studies revealed that both short-term and long-term memories are created in synapses.


Abstract of Amyloidogenic Oligomerization Transforms Drosophila Orb2 from a Translation Repressor to an Activator

Memories are thought to be formed in response to transient experiences, in part through changes in local protein synthesis at synapses. In Drosophila, the amyloidogenic (prion-like) state of the RNA binding protein Orb2 has been implicated in long-term memory, but how conformational conversion of Orb2 promotes memory formation is unclear. Combining in vitro and in vivo studies, we find that the monomeric form of Orb2 represses translation and removes mRNA poly(A) tails, while the oligomeric form enhances translation and elongates the poly(A) tails and imparts its translational state to the monomer. The CG13928 protein, which binds only to monomeric Orb2, promotes deadenylation, whereas the putative poly(A) binding protein CG4612 promotes oligomeric Orb2-dependent translation. Our data support a model in which monomeric Orb2 keeps target mRNA in a translationally dormant state and experience-dependent conversion to the amyloidogenic state activates translation, resulting in persistent alteration of synaptic activity and stabilization of memory.


New Finding on Synapse Destruction May Open Path to Alzheimer’s Therapy


A team led by scientists at the University of New South Wales in Australia say they have discovered how connections between brain cells are destroyed in the early stages of Alzheimer’s disease. They believe their work opens up a new avenue for research on possible treatments for the degenerative brain condition.

“One of the first signs of Alzheimer’s disease is the loss of synapses—the structures that connect neurons in the brain,” noted study leader, Vladimir Sytnyk, Ph.D., of the UNSW School of Biotechnology and Biomolecular Sciences. “Synapses are required for all brain functions, and particularly for learning and forming memories. In Alzheimer’s disease, this loss of synapses occurs very early on, when people still only have mild cognitive impairment, and long before the nerve cells themselves die. We have identified a new molecular mechanism which directly contributes to this synapse loss, a discovery we hope could eventually lead to earlier diagnosis of the disease and new treatments.”

The team studied a specific protein in the brain, neural cell adhesion molecule 2 (NCAM2), one of a family of molecules that physically connects the membranes of synapses and help stabilize these long lasting synaptic contacts between neurons. The researchers paper (“Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer’s disease”) is published in Nature Communications.

Using post-mortem brain tissue from people with and without the condition, they discovered that synaptic NCAM2 levels in the part of the brain known as the hippocampus were low in those with Alzheimer’s disease. They also showed in mice studies and in the laboratory that NCAM2 was broken down by beta-amyloid, which is the main component of the plaques that build up in the brains of people with the disease.

“Our research shows the loss of synapses is linked to the loss of NCAM2 as a result of the toxic effects of beta-amyloid,” pointed out Dr. Sytnyk. “It opens up a new avenue for research on possible treatments that can prevent the destruction of NCAM2 in the brain.”


Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer’s disease

Iryna Leshchyns’kaHeng Tai LiewClaire ShepherdGlenda M. HallidayClaire H. StevensYazi D. KeLars M. Ittner & Vladimir Sytnyk
Nature Communications Nov 2015; 6(8836)        doi:10.1038/ncomms9836

Alzheimer’s disease (AD) is characterized by synapse loss due to mechanisms that remain poorly understood. We show that the neural cell adhesion molecule 2 (NCAM2) is enriched in synapses in the human hippocampus. This enrichment is abolished in the hippocampus of AD patients and in brains of mice overexpressing the human amyloid-β (Aβ) precursor protein carrying the pathogenic Swedish mutation. Aβ binds to NCAM2 at the cell surface of cultured hippocampal neurons and induces removal of NCAM2 from synapses. In AD hippocampus, cleavage of the membrane proximal external region of NCAM2 is increased and soluble extracellular fragments of NCAM2 (NCAM2-ED) accumulate. Knockdown of NCAM2 expression or incubation with NCAM2-ED induces disassembly of GluR1-containing glutamatergic synapses in cultured hippocampal neurons. Aβ-dependent disassembly of GluR1-containing synapses is inhibited in neurons overexpressing a cleavage-resistant mutant of NCAM2. Our data indicate that Aβ-dependent disruption of NCAM2 functions in AD hippocampus contributes to synapse loss.


Learning and memory processes depend on the number and correct functioning of synapses in the brain. Cell adhesion molecules are enriched in the pre- and postsynaptic membranes. These molecules physically connect synaptic membranes, providing mechanical stabilization of synaptic contacts1, 2, 3, are necessary for the formation of new synapses during neuronal development4, 5, and maintain and regulate synaptic plasticity in adults6, 7, 8, 9, 10.

Alzheimer’s disease (AD) is a neurodegenerative brain condition predominantly of the aging population. One of the earliest signs of AD is the loss of synapses11, which can at least partially be linked to the toxicity mediated by Aβ12, 13, 14, a peptide that accumulates in the brains of AD patients. The impact of AD on synaptic adhesion and the role of synaptic cell adhesion molecules in the progression of the disease remains poorly understood.

The neural cell adhesion molecule 2 (NCAM2), sometimes designated OCAM, belongs to the immunoglobulin superfamily of cell adhesion molecules. NCAM2 participates in homophilic trans-interactions15, 16. During human embryonic development, NCAM2 is expressed in several tissues, including lung, liver, and kidney with the highest expression in the brain17. The expression level of NCAM2 peaks around postnatal day 21 and remains high during adulthood15, suggesting that the protein is necessary both during development and in adult brains. Accordingly, studies with cultured neurons and in NCAM2 deficient mice show that NCAM2 is important for the development of the brain, and the olfactory system in particular18, 19.

The NCAM2 gene is located on chromosome 21 in humans and NCAM2 overexpression has been suggested to be one of the factors contributing to the symptoms of Down syndrome17, which presents with early-onset AD pathology. Single-nucleotide polymorphisms in the NCAM2 gene have been reported as a risk factor related to the progression of AD in the Japanese population20. A recent genome-wide association study has found an association between single-nucleotide polymorphisms in the NCAM2 gene and levels of Aβ in the cerebrospinal fluid in humans, suggesting that NCAM2 is involved in the pathogenic pathway to the senile plaques that concentrate in AD brains21. Since genetic association studies indicate a link between NCAM2 and AD, we have analysed whether AD pathology influences levels of NCAM2 in synapses. Our results indicate that the synaptic adhesion mediated by NCAM2 is highly susceptible to Aβ toxicity and that proteolytic fragments of NCAM2 generated in an Aβ-dependent manner can directly contribute to the induction of synapse disassembly.


Synaptic NCAM2 is reduced in the hippocampus in AD

To analyse whether functions of NCAM2 are affected in AD, frozen post-mortem brain tissue of AD patients and non-affected controls (n=10 each) was analysed by western blot with antibodies against NCAM2. The detailed demographic data for the subjects analysed are presented inSupplementary Table 1. Total levels of NCAM2 were slightly increased in the hippocampus, but not significantly affected in the cerebellum or superior temporal cortex in AD (Supplementary Fig. 1). In contrast, levels of VGLUT1, a presynaptic marker-protein of excitatory synapses, were reduced in AD hippocampus (Supplementary Fig. 1), indicating a loss of excitatory synapses. Levels of VGAT, a presynaptic marker-protein of inhibitory synapses, were not significantly affected in any brain region analysed (Supplementary Fig. 1).

Changes in the protein levels in brain homogenates do not necessarily reflect changes in the protein levels in synapses. To analyse whether the synaptic function of NCAM2 is affected in AD, we compared the enrichment of NCAM2 in synaptosomes isolated from the brain tissue of individuals with AD and non-affected controls by western blot analysis of synaptosomes and total homogenates of the brains used for synaptosome preparations. Equal total protein amounts from each probe were applied to the gels to compensate for any possible differences in the yield of synaptosomes because of the synapse loss observed in AD. Western blot analysis with antibodies against actin, VGLUT1, VGAT, synaptophysin (a general presynaptic marker-protein), and PSD95 (a postsynaptic marker-protein), showed that these proteins were enriched to similar levels in synaptosomes from AD and control brains, indicating similar purities of intact synaptosome isolations (Fig. 1a). Western blot analysis showed that in control individuals NCAM2 was highly enriched in synaptosomes from the hippocampus and to a lower degree in synaptosomes from the temporal cortex and cerebellum (Fig. 1a,b). This synaptic enrichment of NCAM2 was significantly reduced in synaptosomes from AD hippocampi (Fig. 1a,b). The synaptic enrichment of NCAM2 was slightly lower in the AD versus control cerebellum, however the difference was not statistically significant (Fig. 1a,b).


Figure 1: Synaptic accumulation of NCAM2 is reduced in the hippocampus of AD-affected individuals.

Figure 2: Cleavage of the membrane-adjacent extracellular fragment of NCAM2 is increased in AD brains.

Figure 3: The extracellular domain of NCAM2 binds to Aβ.

Cleavage of NCAM2aa682-701 is increased in AD brains

NCAM2 binds to Aβ in vitro

Figure 4: NCAM2 accumulates in excitatory synapses of cultured hippocampal neurons.

NCAM2 accumulates in excitatory synapses of cultured hippocampal neurons.


(a) Low-magnification image of a cultured hippocampal neuron labelled by indirect immunofluorescence with antibodies against NCAM2, synaptophysin and MAP2. Note expression of NCAM2 along MAP2 positive dendrites. NCAM2 is also expressed in astrocytes (marked a) which are present in these cultures. Scale bar, 20μm. (b) High-magnification image of dendrites of neurons co-labelled with antibodies against NCAM2, synaptophysin and MAP2. Arrows show clusters of NCAM2 partially overlapping with synaptophysin accumulations. NCAM2-negative synapses are also observed (arrowheads). Scale bar, 10μm. (c) High-magnification image of a dendrite of a cultured hippocampal neuron labelled with antibodies against NCAM2, synaptophysin and PSD95. NCAM2 clusters partially overlap with accumulations of PSD95 and synaptophysin (arrows). Scale bar, 10μm. Three-dimensional analysis of the co-localization within the outlined area is on the right. Z-stack has been acquired with 0.15μm steps. The xz and yz sections along the dashed lines on the xy image are shown. Note co-localization of the NCAM2 cluster with synaptic markers. (d) Negative control, that is, labelling performed without primary antibodies, is shown. Scale bar, 10μm.


Figure 5: Aβ1–42 oligomers bind to NCAM2 at the cell surface of neurons.

Figure 6: Levels of NCAM2 are reduced in synaptosomes of cultured hippocampal neurons treated with Aβ1-42 oligomers.

Figure 7: NCAM2 co-localizes with Aβ1-42 in brains of APP23 transgenic mice.

Figure 8: NCAM2 binds to Aβ and its synaptic accumulation is reduced in the hippocampus of APP23 transgenic mice.

Aβ removes NCAM2 from synapses of hippocampal neurons

Western blot analysis showed that levels of soluble NCAM2 with the molecular weight of ~100kDa were significantly increased in culture medium from Aβ1-42-treated hippocampal neurons (Fig. 6b), further indicating that Aβ1-42 induces removal of NCAM2 off the neuronal cell surface. In contrast, levels of the soluble proteolytic products of CHL1, another synaptic cell adhesion molecule of the immunoglobulin superfamily26, 27, were not changed in the culture medium from Aβ1-42-treated hippocampal neurons (Fig. 6b). Incubation with Aβ1-42 did not increase levels of soluble NCAM2 in the culture medium from cortical neurons (Fig. 6b), suggesting that cortical neurons are more resistant to Aβ1-42-dependent NCAM2 proteolysis.

Aβ binds to and removes NCAM2 from synapses in APP23 mice

Disruption of NCAM2 adhesion promotes synapse disassembly

Figure 9: Disruption of NCAM2 functions at the neuronal cell surface promotes glutamatergic synapse disassembly.

Disruption of NCAM2 functions at the neuronal cell surface promotes glutamatergic synapse disassembly.


(ae) Cultured hippocampal neurons were either mock-treated or incubated with the recombinant soluble extracellular domains of NCAM2 (NCAM2-ED), antibodies against the extracellular domain of NCAM2 (NCAM2mAb), or Aβ1-42 oligomers. In a,b, neurons were labelled with antibodies against the extracellular domain of GluR1 before permeabilization of membranes with detergent, and co-labelled with antibodies against synaptophysin after permeabilization of membranes with detergent. Representative images of dendrites are shown (a). Note co-localization of cell surface GluR1 accumulations with synaptophysin clusters in mock-treated neurons, and increased levels of non-synaptic cell surface GluR1 accumulations in neurons treated with NCAM2-ED, NCAM2mAb or Aβ1-42. Graphs (b) show the percentage of synaptic and non-synaptic GluR1 clusters relative to total number of GluR1 clusters along dendrites and numbers of synaptophysin accumulations per dendrite length (mean+s.e.m.). *P<0.0001 (analysis of variance with Dunnett’s multiple comparison test, n>80 dendrites from 20 neurons were analysed in each group). In c, neurons were labelled with antibodies against the extracellular domain of NR1 before permeabilization of membranes with detergent, and co-labelled with antibodies against synaptophysin after permeabilization of membranes with detergent. Graphs show the percentage of synaptic and non-synaptic NR1 clusters relative to total number of NR1 clusters along dendrites (mean+s.e.m.). *P<0.0001 (analysis of variance with Dunnett’s multiple comparison test, n>85 dendrites from 20 neurons were analysed). In d,e, neurons were co-labelled with fluorescent phalloidin and synaptophysin antibodies. Representative images of dendrites are shown in d. Note higher labelling intensity and co-localization with synaptophysin of the phalloidin-labelled polymerized actin accumulations in control neurons versus neurons treated with Aβ1-42, NCAM2-ED or NCAM2mAb. Note increased numbers of filopodia and lamellipodia in neurons treated with Aβ1-42, NCAM2-ED or NCAM2 mAb. Graphs (e) show ratio of the dendrite area-to-length and phalloidin labelling intensity of dendrites of neurons. Mean values+s.e.m. are shown. *P<0.0001 (analysis of variance with Dunnett’s multiple comparison test, n=50 dendrites from 20 neurons were analysed in each group). Scale bar, 10μm (in a,d).

Cleavage-resistant NCAM2 reduces Aβ-dependent synapse loss

Figure 10: Aβ1-42 reduces the number of GluR1-containing synapses in the NCAM2-dependent manner.


(a) Representative images of dendrites of cultured hippocampal neurons transfected either with control negative miRNA (negative miR) or NCAM2miR and either mock-treated or incubated with Aβ1-42. Transfected neurons were identified by fluorescence of GFP, which is co-expressed together with miRNA. Neurons were co-labelled with antibodies against cell surface GluR1 and synaptophysin. Note that the number of synaptic GluR1 clusters is reduced and the number of non-synaptic GluR1 clusters is increased in neurons transfected with NCAM2miR. Scale bar, 10μm. (b,c) Graphs show mean+s.e.m. percentage of synaptic and non-synaptic GluR1 clusters relative to the total number of GluR1 clusters along dendrites (b) and numbers of synaptophysin accumulations per dendrite length normalized to the mean number in mock-treated neurons (c) for neurons described in (a). (df) Graphs show mean+s.e.m. percentage of synaptic and non-synaptic GluR1 clusters relative to the total number of GluR1 clusters along dendrites (d), number of synaptophysin accumulations per dendrite length normalized to the mean number in mock-treated neurons (e), and area/length ratio (f) in cultured hippocampal neurons transfected either with GFP alone or co-transfected with GFP and non-mutated NCAM2 (NCAM2WT) or NCAM2D693A mutant and either mock-treated or incubated with Aβ1-42. (g,h) Graphs show mean+s.e.m. percentage of non-synaptic GluR1 clusters relative to the total number of GluR1 clusters along dendrites (g) and area/length ratio (h) in cultured hippocampal neurons co-transfected with NCAM2 miR and either GFP, non-mutated NCAM2 (WT) or NCAM2D693A mutant (D693A) and either mock-treated or incubated with Aβ1-42. In bh, *P<0.01 (compared as indicated), ˆP<0.01 (compared with mock-treated neurons transfected with negative miR (b), GFP (df) or co-transfected with NCAM2miR and GFP (gh)), analysis of variance with Tukey’s multiple comparison test, n>50 dendrites from 20 neurons were analysed in each group.


Taken together, our results indicate that Aβ affects the numbers of GluR1-containing glutamatergic synapses in a NCAM2-dependent manner.

Alzheimer’s disease is characterized by loss of synapses, which is the strongest correlate of cognitive decline11, 29, 30, 31, 32 and possibly one of the earliest events in AD pathogenesis30, 33. Synapses are long lasting contacts between neurons, which are stabilized by a number of cell adhesion molecules that concentrate in pre- and postsynaptic membranes2, 5. Cell adhesion molecules play an essential role in maintaining synapse functionality and stability. Although cell adhesion molecules of many families are required for the synapse integrity8, 10, elimination of even one type of synaptic cell adhesion molecule is often sufficient to induce abnormalities in synapse ultrastructure and protein composition6, 7. In the present study, we show that levels of the synaptic cell adhesion molecule NCAM2 are markedly reduced in hippocampal synapses in AD brains and Aβ-forming APP23 mice. Our observations that disruption of NCAM2 interactions at the cell surface, knockdown of NCAM2 expression and Aβ exposure result in reduced numbers of glutamatergic synapses in hippocampal neurons suggest that abnormalities in NCAM2-mediated synaptic adhesion contribute to synapse loss in AD.

Although the mechanisms of synapse disassembly in AD remain poorly understood, previous studies indicated that synapse loss can be linked to Aβ-induced toxicity12, 34, 35. Our observations showing that synaptic levels of NCAM2 are similarly reduced in APP23 mice and in cultured hippocampal neurons from wild-type mice exposed to Aβ argue in favour of Aβ-dependent mechanisms in the disruption of NCAM2-mediated synaptic adhesion. We however do not exclude that other factors, such as disrupted trafficking of NCAM2 to synapses, may also contribute to the reduction of NCAM2 levels at synapses. Strikingly, the effects of Aβ on synaptic targeting of NCAM2 were particularly strong in hippocampal but not cortical or cerebellar neurons. The enhanced susceptibility of synaptic NCAM2 to Aβ-dependent proteolysis may therefore contribute to selective vulnerability of the hippocampus to AD.

Our observations that NCAM2 directly interacts with synthetic Aβ1-42, that Aβ1-42 forms a molecular complex with NCAM2 at the neuronal cell surface and that complexes of NCAM2 and oligomers of Aβ can be isolated from APP23 mouse brains, indicate that NCAM2 may function as a previously unrecognized receptor for Aβ at the neuronal cell surface. Previous studies have shown that Aβ can also bind to other cell adhesion molecules at the neuronal cell surface, among which are the prion protein36 and L137. In addition, a number of cell adhesion molecules have been shown to interact with APP, including the neural cell adhesion molecule 1 (NCAM1)38 and TAG1 (ref. 39). It remains to be investigated whether the NCAM2/Aβ complex comprises other adhesion molecules and cell surface proteins. Interestingly, NCAM1, a homologue of NCAM2, binds to prion protein40 and L1 (ref. 41). However, in spite of homology to NCAM2, NCAM1 binds to a region of APP which is different to the Aβ-containing region38.


Taken together, we show that Aβ induces synaptic loss and proteolysis of NCAM2 in cell culture and APP transgenic mouse models, providing a mechanistic explanation for synaptic NCAM2 changes in AD brains. The detrimental effects of proteolyically cleaved extracellular NCAM2 on synapses may augment the Aβ toxicity in the pathogenesis of AD. The exact molecular mechanisms underlying Aβ-induced NCAM2 changes, and to which degree it contributes to onset and progression of disease remains to be established. Nevertheless, our data reveal a new role of NCAM2 in AD that warrants further investigation.

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Neural Networks in Alzheimer’s

Larry H. Bernstein, MD, FCAP, Curator


SfN 2015 Recap: The Role of Synapses, Neural Networks in Alzheimer’s

Stephanie Guzowski, Editor



Perineuronal nets, shown in green, in three regions of the mouse brain. Credit: S.F. Palida et al.

Cognition and behavior rely on communication between individual neurons and extensive interactions between neural networks. But when synaptic dysfunction occurs, the results can be dire, leading to neurodegenerative symptoms in Alzheimer’s disease.

“The brain is the seed of our personal identity,” said Valina Dawson, Ph.D., director of neurogeneration and stem cell programs at Johns Hopkins University in Baltimore, Maryland. “It allows us to interact with our world but when things go wrong in the brain, it’s disastrous for the individual as well as the family.

“Our ability to treat these diseases is limited at the moment. We need new insight into what goes wrong.”

A lesser-known protein

Researchers, for years, have targeted amyloid beta (Aβ) in attempts to halt the progression of Alzheimer’s disease, and have recently, shown increased interest in the protein, tau.

But Paula Pousinha, Ph.D., at the French National Centre for Scientific Research, has focused her research on a lesser-known protein fragment: amyloid precursor protein intracellular domain (AICD). AICD is a fragment of amyloid precursor protein (APP), which is formed at the same time as Aβ in the brain. New evidence suggests that in addition to Aβ, AICD also disrupts communication between neurons during the progression of Alzheimer’s disease. Pousinha presented thesepublished findings at this year’s Society for Neuroscience (SfN) conference, which took place from October 17 to 21 in Chicago.

“Although AICD has been known for more than 10 years, it has been poorly studied,” said Pousinha.

Pousinha’s research team demonstrated that overexpressing AICD levels with AAV vector in rats’ brains “perturbs neuronal communication in the hippocampus,” a key structure necessary in forming memories and an area earliest affected in Alzheimer’s disease.

“In normal animals, if we apply to these neurons a high-frequency stimulation, afterward the neurons are stronger,” said Pousinha. “Neurons where we overexpressed AICD failed to have this potentization.”

Pousinha doesn’t negate the importance of Aβ in the development of neurodegenerative diseases. “Our study doesn’t exclude the pathological effects of Aβ,” she said. “We believe that Alzheimer’s disease is much more complex and has more than one candidate that has implications.

“It’s very important for the scientific community to understand the role of all these APP fragments of neuroinflammation — different pieces of the puzzle of how we can stop the disease progression.”

How do memories persist in the brain long term?

New research, also presented at this year’s SfN, has implications for understanding memory to develop treatments for Alzheimer’s disease and dementias. Sakina Palida, a graduate student at the University of California, San Diego found that localized modifications in the perineuronal net (PNN) at synapses could be a mechanism by which information is stably encoded and preserved in the brain over time.

“We still don’t understand how we stably encode and store memories in our brains for up to our entire lifetimes,” said Palida. The prevailing idea on how memories are maintained over time generally focus on postsynaptic proteins, said Palida. “But the problem with looking at intracellular synaptic proteins is that the majority turn over rapidly, of hours to at most a few days. So they’re very unstable.”

So, Palida and her team identified PNN as an ideal substrate for long-term memory. “Kind of like how you carve into stone — stone is a stable substrate — you retain the information regardless of what comes and goes over it.” They demonstrated that individual PNN proteins are highly stable, and that the PNN is locally degraded when synapses are strengthened.

And the team also demonstrated that mice lacking enzymes that degrade the PNN have deficient long-term, but not short-term, memory. “Which is a really exciting new result,” said Palida.

To track the PNN in live animals, Palida and her team fused a fluorescent protein to a small link protein in the PNN to allow tracking of PNN dynamics in real time. They also monitored PNN degradation in live cells after stimulating neurons with brain-derived neurotrophic factor (BDNF), a chemical secreted in the nervous system to enhance signaling — and observed localized degradation of the PNN at some newly formed synapses.

Crtl 1-Venus. Fusion of a fluorescent protein to small link proteins in the PNN allows tracking of PNN dynamics over time. Credit: S.F. Palida et al. Crtl1-Venus Neurons. Tracking PNN dynamics in live cells, in mouse brain tissue. Credit: S.F. Palida et al.

What’s next? “We’re currently making transgenic animals to express this protein, which would allow us to monitor PNN dynamics simultaneously with synaptic dynamics in a live animal brain, and really investigate this hypothesis further,” said Palida.

Increased APP intracellular domain (AICD) production perturbs synaptic signal integration via increased NMDAR function

*Paula A Pousinha1PubmedElisabeth Raymond1PubmedXavier Mouska1PubmedMichael Willem2PubmedHélène Marie1Pubmed

1660 Route de Lucioles, CNRS IPMC UMR 7275, Valbonne, France2Ludwig-Maximilians-University Munich, Munich, Germany

Alzheimer’s disease (AD) is a neurodegenerative disease that begins as mild short-term memory deficits and culminates in total loss of cognition and executive functions. The main culprit of the disease, resulting from Amyloid-Precursor Protein (APP) processing, has been thought to be amyloid-b peptide (Ab). However, despite the genetic and cell biological evidence that supports the amyloid cascade hypothesis, it is becoming clear that AD etiology is complex and that Ab alone is unable to account for all aspects of AD [Pimplikar et al. J Neurosci.30: 14946. 2010]. Gamma-secretase not only liberates Ab, but also its C-terminal intracellular counterpart called APP intracellular domain (AICD) [Passer. et al. JAlzheimers Dis.2: 289-301. 2000], which is known to also accumulate in AD patient’s brain [Ghosal et al. PNAS.106:18367. 2009], but surprisingly little is known about its functions in the hippocampus. To address this crucial issue, we increased AICD production in vivo in adult CA1 pyramidal neurons, mimicking the human pathological condition. Different ex-vivo electrophysiological and pharmacological approaches, including double- patch of neighbor neurons were used. We clearly demonstrate that in vivo AICD production increases synaptic NMDA receptor currents. This causes a frequency-dependent disruption of synaptic signal integration, leading to impaired long-term potentiation, which we were able to rescue by different pharmacological approaches. Our results provide convincing and entirely novel evidence that increased in vivo production of AICD is enough, per se, to cause synaptic dysfunction in CA1 hippocampal neurons.

131.21P2X2R-FE65 interaction induces synaptic failure and neuronal dyshomeostasis after treatments with soluble oligomers of amyloid beta peptide

300.15Early synaptic deficits in Alzheimer’s disease involve neuronal adenosine A2A receptors

215.08Homeostatic coupling between surface trafficking and cleavage of amyloid precursor protein

280.11A novel mechanism for lowering Abeta

383.22Impact of intracellular soluble oligomers of amyloid-β peptide on glutamatergic synaptic transmission

Society for Neuroscience Annual Meeting Showcases Strides in Brain Research

10/23/2015 – Stephanie Guzowski, Editor

CHICAGO – Nearly 30,000 researchers from more than 80 countries gathered this week at the annual Society for Neuroscience (SfN) meeting, the world’s largest conference focused on scientific discovery related to the brain and nervous system.

The 45th annual SfN meeting at McCormick Place convention center showcased more than 15,000 scientific presentations on advances in technologies and new research about brain structure, disease and treatments, and 517 exhibitors, according to event organizers.

Presentations covered a wide variety of topics including new technologies to study the brain, the science behind addiction, potential treatments for spinal cord injuries, and the role of synapses in neurological conditions.

Of particular focus was the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the large collaborative quest to develop technologies for a dynamic view of the brain. In early October, the National Institutes of Health announced its second round of funding to support goals, bringing the NIH investment to $85 million in fiscal year 2015.

Toxic Tau Could be Key to Alzheimer’s Treatment

01/06/2015 – Stephanie Guzowski, Editor



“But now, we know that tau is not simply a bystander but also a player,” Li said. “Both proteins work together to damage cell functions as the disease unfolds.”

Targeting tau

In the healthy brain, tau protein helps with the building and functioning of neurons. But when tau malfunctions, it creates abnormal clumps of protein fibers—neurofibrillary tangles—which spread rapidly throughout the brain. This highly toxic and altered form of the brain protein tau is called “tau oligomer.”

“There’s growing evidence that tau oligomers, not tau protein in general, are responsible for the development of neurodegenerative diseases, like Alzheimer’s,” said Julia Gerson, a graduate student in neuroscience at the University of Texas Medical Branch.

In Gerson’s research, which she presented at this year’s Society for Neuroscience meeting in Washington, D.C., Gerson and her team injected tau oligomers from people with Alzheimer’s into the brains of healthy mice. Subsequent testing revealed that the mice had developed memory loss.

“When we inject mice with tau oligomers, we see that they spend the same amount of time exploring a familiar object as an unfamiliar object,” said Gerson. “So they’re incapable of remembering that they’ve already seen this familiar object.”

What’s more, the molecules had multiplied throughout the animals’ brains. “This suggests that tau oligomers may spread from the injection site to other unaffected regions,” said Gerson.

Future treatments

Understanding tau’s connection to Alzheimer’s could have implications for potential therapies. “If we can stop the spread of these toxic tau oligomers, we may be capable of either preventing, or reversing, symptoms,” said Gerson. Gerson’s lab is currently investigating antibodies, which specifically fight tau oligomers.

Click to Enlarge. Normal brain vs. Alzheimer’s brain (Credit: Garrondo)

Erik Roberson, M.D., Ph.D., at the University of Alabama at Birmingham, and colleagues looked at how boosting the function of a specific type of neurotransmitter receptor, the NMDA receptor, provided benefit to people with the second most common type of dementia: frontotemporal dementia (FTD), a disease in which people experience rapid and dramatic changes in behavior, personality and social skills. People often quickly deteriorate and usually die about three years after diagnosis; there is also no effective treatment for FTD.

Since mutated tau impairs synapses—the connections between neurons—by reducing the size of NMDA receptors, “boosting the function of remaining NMDA receptors may help restore synaptic firing, and reverse behavioral abnormalities,” said Roberson.

Roberson’s, along with others’ work presented at the Society of Neuroscience meeting, focused on using animal models that mimic developing tau pathology. “These new mouse models, which contain both tau tangles and amyloid plaques” said Dr. Li, “offer the possibility of more accurately testing therapies directed at delaying the onset of amyloid beta plaques, tau accumulation and neuronal loss, all characteristic features of Alzheimer’s.”

Are clinical trials next?

Potentially, yes. “This arena of academic research has been ongoing for several years—it’s a younger area in terms of involvement of drug discovery,” said Sangram Sisodia, Ph.D., director of the Center for Molecular Neurobiology at the University of Chicago. “But I believe there is growing interest in pharma companies about targeting tau.

“The tau protein plays an incredibly complex role in the development of Alzheimer’s and other neurodegenerative diseases,” said Sisodia. “We are in the early stages of understanding that role, which will be crucial for developing effective preventions or treatments.”

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Reported by: Dr. Venkat S. Karra, Ph.D.


Brain structures involved in dealing with fear...


Major depression or chronic stress can cause the loss of brain volume, a condition that contributes to both emotional and cognitive impairment. Now a team of researchers led by Yale University scientists has discovered one reason why this occurs—a single genetic switch that triggers loss of brain connections in humans and depression in animal models.


The findings, reported in Nature Medicine, show that the genetic switch known as a transcription factor represses the expression of several genes that are necessary for the formation of synaptic connections between brain cells, which in turn could contribute to loss of brain mass in the prefrontal cortex.


“We wanted to test the idea that stress causes a loss of brain synapses in humans,” said senior author Ronald Duman, the Elizabeth Mears and House Jameson Professor of Psychiatry and professor of neurobiology and of pharmacology. “We show that circuits normally involved in emotion, as well as cognition, are disrupted when this single transcription factor is activated.”


The research team analyzed tissue of depressed and non-depressed patients donated from a brain bank and looked for different patterns of gene activation. The brains of patients who had been depressed exhibited lower levels of expression in genes that are required for the function and structure of brain synapses. Lead author and postdoctoral researcher H.J. Kang discovered that at least five of these genes could be regulated by a single transcription factor called GATA1. When the transcription factor was activated, rodents exhibited depressive-like symptoms, suggesting GATA1 plays a role not only in the loss of connections between neurons but also in symptoms of depression.


Duman theorizes that genetic variations in GATA1 may one day help identify people at high risk for major depression or sensitivity to stress.


“We hope that by enhancing synaptic connections, either with novel medications or behavioral therapy, we can develop more effective antidepressant therapies,” Duman said.










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