Introduction

Nicole C. Berchtold and Carl W. Cotman led this live discussion on 25 November 2003. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

Nicole C. Berchtold and Carl W. Cotman led this live discussion on 25 November 2003.

Participants: Carl Cotman and Nicole Berchtold, University of California, Irvine; Gabrielle Strobel, Alzheimer Research Forum; Qiurong Xiao, Memory Pharma; Fulya Karaman, Trakya University Medical Faculty, Turkey; Roland Pochet, Université Libre de Bruxelles, Belgium; Volkmar Lessmann, University of Mainz, Germany; Danling Wang, China; Leigh Holcomb, Texas A&M University, Neuropsychiatry Research Program; Margaret Fahnestock, McMaster University, Hamilton, Ontario; Jung Lee, student at Harvard college; Keith Crutcher, University of Cincinnati Medical Center; Taihung Duong, Indiana University School of Medicine-Terre Haute Center; Martin Ingelsson; Jorge Busciglio, University of California, Irvine; Shunwei Zhu, Karolinska Institutet, Huddinge Hospital University, Stockholm; Elana Sinsabaugh, caregiver; Steve Hess, Omaha, Nebraska; Abdellatif Benraiss, Cochin Institute/Paris.

Note: The transcript has been edited for clarity and accuracy.

Gabrielle Strobel
Welcome to today's chat everyone, and hello, Carl and Nicole. It's great to have you. Let's get started.

Roland Pochet
Are there any BDNF knockout (KO) mice?

Gabrielle Strobel
As I recall, Roland, there are and they were extensively studied with rescue experiments to establish a role of BDNF in LTP, etc. But Nicole and Carl know much more about this.

Margaret Fahnestock
Roland, there are BDNF KO mice. The original homozygotes die shortly after birth. The heterozygotes have been studied extensively.

Carl and Nicole
Yes, there are BDNF KO mice; however, the homozygotes do not survive. The heterozygotes do, and a number of studies have been published. The better approach now is the TrkB KO—TrkB being a receptor for BDNF.

Margaret Fahnestock
There are also conditional BDNF KO mice.

Roland Pochet
 Thanks!

Gabrielle Strobel
Carl and Nicole, does the field know anything about the molecular pathways controlling BDNF expression?

Volkmar Lessmann
Of course, neuronal and physical activity is the major regulator of BDNF expression.

Gabrielle Strobel
I know, but how does it turn on BDNF? What's the signal transduction, transcription factors?

Carl and Nicole
Regarding molecular pathways, CREB is involved in expression of exon 3, as well as another calcium-dependent response element, also CamKinase2 is involved in regulation of exon 1 BDNF transcript. Other transcription factors are the estrogen response element. There is also an AP-1 site on BDNF; however, the precise role is not really clear.

Gabrielle Strobel
Carl and Nicole , that is interesting. I just heard a talk by Jie Shen in New Orleans saying that presenilin conditional knockout in adult neurons reduces CREB pathway function (and BDNF expression). And CamKinase2 levels were also down in Shen's mice (see ARF related news story).

Carl and Nicole
That's interesting, and relevant.

Margaret Fahnestock
We know a lot about BDNF regulation from extensive work in the rat, much of it from Dr. Cotman's group. However, how some of the other rat BDNF promoters besides 1 and 3 are regulated, and whether these regulatory sites are operable in human BDNF has not been determined. It should be noted that consensus CRE sites exist upstream of the equivalent exons in the human BDNF gene, which suggests the human BDNF gene may be regulated in a manner similar to the rat gene. My lab implicated transcripts 1 and 3 in reduced BDNF expression in AD (Garzon et al., 2002), consistent with known activity-dependent BDNF regulation in the rat.

Carl and Nicole
Yes, that's an important point, that the human BDNF appears to be similarly constructed and regulated as the rodent gene; this is particularly relevant when trying to translate exercise research to humans.

Gabrielle Strobel
How much/frequent exercise is necessary to get an effect? I believe you had data on that in New Orleans, Nicole?

Carl and Nicole
In rodents, we've found that alternating days of activity is as effective as daily activity for increasing BDNF.

Gabrielle Strobel
So there is still hope for me....

Carl and Nicole
Also, BDNF appears to be "primed" by exercise, so that even when there is a fairly long gap between exercise sessions (two weeks), the second period of exercise, even a short one like two days, will ramp BDNF right back up again.

Gabrielle Strobel
I read that; it sounded almost like sort of an immune response where the second response is bigger and faster.

Carl and Nicole
That's an interesting analogy. It does seem like that!

Gabrielle Strobel
Are there drugs that can exploit what's known about BDNF transcriptional regulation?

Carl and Nicole
One class of drugs that can capitalize on the glutamatergic-regulation of BDNF is the ampakines, which enhance AMPA receptor function and are investigated for benefits to cognitive function. Also, the antidepressants, different classes, all seem to converge on BDNF.

Leigh Holcomb
The antidepressant effect on BDNF is very interesting, especially given the recent data from Santarelli et al., 2003 that neurogenesis is required for behavioral effects of antidepressants.

Gabrielle Strobel
Leigh, in New Orleans I saw a study saying that exercise in rodents also increases serotonin receptors and transporters. Maybe that is part of the antidepressant effect, as well.

Leigh Holcomb
Thanks for that information, Gabrielle.

Carl and Nicole
Also, it's interesting that exercise itself has antidepressant action, and enhances neurogenesis. BDNF may be one of the common regulatory mechanisms driving this (we elaborated on this in our TINS paper last year; see Cotman and Berchtold, 2002).

Volkmar Lessmann
If I recall it correctly, those mice that show the strongest increase of BDNF in hippocampus in response to exercise have no benefit from it in memory tasks. How would you explain this, Carl?

Carl and Nicole
We're not sure which study you refer to; however, this has not been our experience. We must note that exercise appears to enhance the rate of learning, rather than the final performance, so if the effect was assessed too late in the learning protocol, no effect will be seen.

Volkmar Lessmann
Thanks, Carl and Nicole for the information. Can't recall the citation at the moment, but this was observed in rats selected for high motivation of voluntary wheel-running. It was discussed that maybe these rats are so much interested in performing the exercise itself, they don't care where they are going, e.g., in a memory task.

Carl and Nicole
Volkmar, that's a good point. I do vaguely recall this study. Apparently, sometimes you can't move and think at the same time!

Gabrielle Strobel
That is funny. Turbo rats. Sounds like my toddler.

Taihung Duong
Is the increase in BDNF with exercise specific to certain brain cell types (pyramidal, granular, Purkinje)?

Shunwei Zhu
In which brain region do you see increased BDNF after exercise?

Carl and Nicole
The most robust and sustained increase is in the hippocampus; however, other regions where changes were seen early on (several days of exercise) are the cerebellum, caudal cortex region, and there is recent evidence that there is induction in the basal ganglia. Regarding cerebellar BDNF: We did this with nuclease protection assay and don't know about cellular specificity.

Danling Wang
Does BDNF also have a role in antioxidative stress?

Volkmar Lessmann
I have recently heard about transgenic mice models trying to exploit BDNF activity by means of GFP reporter under the different BDNF promoters.

Gabrielle Strobel
That's interesting, Volkmar. What did they show?

Carl and Nicole
We're not familiar with these transgenic mice you describe, Volkmar.

Volkmar Lessmann
I am not aware of any published results by now, but wanted to know whether anybody else is using this approach.

Gabrielle Strobel
Regarding neurogenesis: Brian Christie from University of British Columbia compared neurogenesis in the dentate gyrus of running and sedentary rats and found increased BDNF and glutamate receptors in the running animals, so there is more corroboration, as presented in New Orleans.

Roland Pochet
What is known about BDNF expression in spinal cord?

Carl and Nicole
BDNF and TrkB appear to increase in the spinal cord with exercise (Gomez-Pinilla and Edgerton).

Fulya Karaman
Do you have any knowledge about induction in basal ganglia after exercise in patients with Parkinson's disease (PD)? Are these results familiar to anyone?

Carl and Nicole
That would be an autopsy study; we're not actually familiar with the details there. However, a recent study by John Marshall shows exercise enhances behavioral recovery from 6-OHDA lesion.

Gabrielle Strobel
I don't know anything about BDNF in PD, but recall studies showing some benefit of exercise. (But that's not saying much, is it?) Nicole, are you in contact with AD care facilities about exercise in patients? Is this being "translated"?

Carl and Nicole
Many AD care facilities do use exercise. The recent Teri paper demonstrated that exercise reduced depression and improved quality of life in mild to moderate AD. However, the underlying basic science rationale for using exercise for AD benefits is not widely known to the AD care facilities.

Fulya Karaman
What kind of exercises should we advise for patients, and how frequently?

Carl and Nicole
Most of the studies have found benefits of mild aerobic exercise, such as walking or something a little more strenuous, for 30 minutes four or more times per week. Art Kramer has published a nice meta-analysis covering this issue (Colcombe and Kramer, 2003) that would probably be useful for you.

Gabrielle Strobel
I wonder, too, how much of an effect exercise can really have to stem such a serious disease. (Not that there is much competition from powerful drugs, unfortunately.) What do you think? Fair skepticism?

Margaret Fahnestock
Carl, how much is BDNF elevated by exercise? We showed that it is reduced to 25 percent of normal in AD. Could exercise counteract this?

Carl and Nicole
Margaret, exercise may, assuming that pathology does not interfere with the induction mechanisms for BDNF. BDNF protein is increased around 1.5- to twofold in the hippocampus, and this effect can be seen even after three months of exercise in rodents.

Margaret Fahnestock
I would like to be able to analyze a cohort of early AD patients for whom activity levels are known.

Qiurong Xiao
You mean that the high level BDNF would stay for three months?

Carl and Nicole
Qiurong, yes.

Danling Wang
Three months—so if the exercise ceases, will the level of BDNF drop back soon?

Carl and Nicole
Danling, you ask about the decay rate of BDNF. BDNF drops gradually back to reach baseline after about seven days of sedentary lifestyle. A second exercise period, though (even just a few days or maybe even hours), makes BDNF rise back to the previous high levels.

Danling Wang
What is the protective function of BDNF in the pathology of AD? To reduce the neurotoxin of β-amyloid, or prevent tau phosphorylation, or protect oxidative stress and only benefit behavioral change in some sense?

Carl and Nicole
Danling, those are excellent questions and need to be investigated!

Gabrielle Strobel
To pick up Danling's point about BDNF expression and oxidative stress: A poster in New Orleans said that a diet high in fats and sugars decreases BDNF, synapsin, and CREB expression in the hippocampus, and causes cognitive impairment. They modeled this in rats and said that vitamin E supplementation reversed all this. By Fernando Gomez-Pinilla.

Volkmar Lessmann
Actually, one could try 6-hydroxydopa (6-OHDA) lesions in BDNF knockout mice and look at whether exercise of the mice still improves outcome. Is anybody aware of such a study?

Carl and Nicole
Most BDNF conditional KO focus on BDNF loss in the hippocampus, though, so this model is not really relevant to PD and 6-OHDA lesion.

Margaret Fahnestock
Some studies show cognitive impairment in BDNF heterozygotes. It would be interesting to study exercise in these mice, and to see how much the BDNF could be elevated.

Carl and Nicole
Margaret, definitely!

Volkmar Lessmann
Yes, but heterozygous BDNF knockouts survive well, although they show similar defects in plasticity to homozygous. Maybe homozygous KOs are not necessary here as well!?

Margaret Fahnestock
Homozygotes are not viable, unless you go to the conditional BDNF KOs.

Shunwei Zhu
Carl, what is the relationship between BDNF and other neurotrophins (like NGF) with regard to exercise?

Carl and Nicole
Shunwei, most studies find that the most robust increases are in BDNF, though our early work shows that NGF and FGF are also induced in the hippocampus, but only early on and are not sustained.

Shunwei Zhu
And what is the pathway of BDNF when it is expressed following external or environmental stimulations in brain regions?

Carl and Nicole
Shunwei, BDNF activates TrkB receptors, and sets off a number of intracellular signaling pathways including Mapkinase, Phosphatidyl-inositol-3 Kinase and Phospholipase C γ.

Gabrielle Strobel
What exactly is the learning benefit from exercise? Is it known if it is applicable/relevant to human AD? Is it learning speed, or better retrieval, for example?

Carl and Nicole
Gabrielle, Colcombe and Kramer's work suggests that the main benefits are on executive function, the same aspects of cognition that decline with age. This includes multi-tasking, decision-making, set-shifting, etc.

Gabrielle Strobel
Thanks, that's informative. How well-established is the direct action of BDNF on synaptic plasticity? Early papers by Erin Schuman, Tobias Bonhoeffer, and Bai Lu, I believe, made waves about seven years ago, but I have not followed how well this has been substantiated with a mechanism. Because otherwise, BDNF's effect would lie more in signaling and changing gene expression. Wrong?

Carl and Nicole
BDNF has become well-accepted to be a critical modulator of plasticity, and a recent paper even listed BDNF effects on plasticity as a new class of plasticity effects along the ranks of LTP and LTD.

Margaret Fahnestock
When injected directly into rat brain, BDNF has an effect on excitability but does not cause sprouting.

Gabrielle Strobel
To be more precise: I know BDNF is important for LTP, etc. I understand BDNF gets expressed and secreted in response to neuronal activity. But how does BDNF, in turn, act on synapses to change their electrophysiological function? That's the part I don't understand.

Volkmar Lessmann
Gabrielle, the first reports of BDNF action in excitatory synapses were by M.M. Poo and our lab. In developing cultures, it is now well-established by several groups that BDNF raises release probability. It is not sure whether this effect is retained in older tissue, or whether the approaches of exogenous BDNF application simply tend to fail to make BDNF reach the synapses.

Carl and Nicole
Gabrielle, BDNF appears also to affect downstream genes, including ones specific to the synapse, that can increase synaptic efficacy, as well as increased presynaptic neurotransmitter release.

Fulya Karaman
What can be the reason for the long-lasting high levels of BDNF in rodents?

Carl and Nicole
Fulya, it could be that the daily (daylight hours) inactivity allows the next exercise session to be a sustaining and possibly new stimulus. It's an interesting question that we don't really know the answer to.

Shunwei Zhu
So does BDNF level in all brain regions increase at same time and to the same extent?

Taihung Duong
How closely related genetically are the human BDNF and the rat BDNF?

Carl and Nicole
BDNF is extremely well-conserved across species. But the human form has more splice variants than the rodent, and the rodent doesn't seem to have the polymorphisms that the human does.

Margaret Fahnestock
Human and rat BDNF are virtually identical at the protein sequence level. However, it appears that the genes are different. For example, the number of upstream exons and transcripts in the human brain is different than in rat.

Danling Wang
Where is BDNF synthesized, what is the secretion pathway, and how is it regulated?

Volkmar Lessmann
Danling, our recent studies using BDNF-GFP show targeting of BDNF to glutamate synapses and release upon tetanic synapse stimulation.

Carl and Nicole
Danling, BDNF is principally synthesized by glutamatergic neurons, and can be retrogradely and anterogradely transported. There's a lot of nice reviews out on this.

Jorge Busciglio
Carl and Nicole, is increased cerebral blood flow (CBF) relevant to the mechanism of exercise-induced BDNF upregulation?

Carl and Nicole
Jorge, increased CBF might be a factor, though neurotransmitter release and hormone changes induced with exercise are certainly also important.

Volkmar Lessmann
Regarding BDNF secretion: Is there anybody in the chat who was able to reproduce the fast current induced by BDNF application, as seen by Kafitz and coworkers?

Gabrielle Strobel
Does anyone know if a new generation of neurotrophic/neuroprotective drugs is under development? It's been a decade since initial clinical trials with CNTF and similar proteins failed.

Carl and Nicole
Gabrielle, we suggest a "new generation" drug for increasing neurotrophic and neuroprotective factors in the brain: It's called exercise!

Gabrielle Strobel
Carl and Nicole, I am with you. But that is a lifestyle change, and those are hard to implement, like getting people off burgers and fries.

Carl and Nicole
Hmmm, maybe we need to dangle the burgers and fries in front of people so they lunge for them....

Gabrielle Strobel
Good idea. Dangle them over a cliff and hand them a rope and some carabiners below. I'll belay.

Carl and Nicole
Gabrielle, yes, but remember that stress reduces BDNF!

Gabrielle Strobel
Only chronic stress, a 100-foot wall does not take that long to climb.

Shunwei Zhu
Is there any literature describing the correlation of BDNF level in blood and brain extract with exercise?

Carl and Nicole
Shunwei, we are currently investigating this. We don't think there is anything published on blood/brain BDNF correlation.

Danling Wang
How about CSF? Could BDNF be detected there?

Taihung Duong
Dr. Fahnestock, is BDNF reduced in all regions of the brain in AD?

Margaret Fahnestock
We've only looked at basal forebrain cholinergic targets—cortex and hippocampus—and it's reduced in both areas.

Fulya Karaman
Is there any reduction in the temporal lobe, Dr.Fahnestock?

Margaret Fahnestock
We've mostly looked at frontal and parietal cortex; I don't think we looked at temporal cortex.

Carl and Nicole
BDNF and CSF—I don't think this has been reported either. I doubt there would be much BDNF in CSF, because even in tissue, it is quite low, so it may be below detection threshold. Also, BDNF is a sticky molecule, and might not be "free-floating" in CSF.

Leigh Holcomb
Has anyone developed an aerobics tape for AD patients?

Carl and Nicole
Leigh, there are exercise tapes for older people with disabilities, but we're not sure if there are ones specifically directed for AD.

Volkmar Lessmann
To my knowledge, AD drugs mainly influence acetylcholine function. What is the possible connection to BDNF release or function?

Gabrielle Strobel
Volkmar, good question (though memantine acts on NMDA receptors).

Margaret Fahnestock
Cholinergic agonists should increase the drive on hippocampal neurons, inducing BDNF. I don't know if this has been shown, though.

Volkmar Lessmann
But memantine is an NMDAR blocker, right? Our studies show that synaptic NMDA receptor activity is likely to enhance synaptic BDNF secretion. But of course, such a connection is not always that straightforward....

Carl and Nicole
Ampakines are probably a better alternative to memantine. There was a recent report that memantine reduced performance in rodents. Unfortunately, ampakines are still under development. AChesterases should increase BDNF, but we're not familiar with any studies demonstrating this.

Gabrielle Strobel
Carl and Nicole, I believe ampakines are sort of the "cognitive enhancer" drugs developed by companies like Saegis? Who else is doing this?

Qiurong Xiao
Can you recommend a good BDNF antibody for Western blots?

Carl and Nicole
Qiurong, there are a number of BDNF antibodies, but the problem is that they don't all show the same thing on Westerns! Santa Cruz has a good one, as does Chemicon.

Gabrielle Strobel
Do I understand this right, that the only link between BDNF and AD specifically (as opposed to age-related neurodegeneration, in general) is its decrease in hippocampus? (Many things go wrong in the AD hippocampus.) What have I missed?

Carl and Nicole
Gabrielle, actually a more important link of BDNF to AD is the polymorphisms that increase incidence of AD. These polymorphisms interfere with normal intracellular trafficking and release of BDNF in response to stimuli.

Gabrielle Strobel
Carl and Nicole, yes, that is fascinating. I hope more groups will replicate those in their samples.

Carl and Nicole
Gabrielle, yes.

Qiurong Xiao
If the patient has the "bad" polymorphism of BDNF, does exercise help to reduce the risk for AD?

Carl and Nicole
Qiurong, excellent question! This absolutely needs to be investigated!

Danling Wang
Except for your KO mice, are there other animal models to reduce the BDNF?

Margaret Fahnestock
The Ts65Dn mouse exhibits downregulation of neocortical BDNF correlating with memory impairment (Bimonte-Nelson et al., 2003). This mouse is a trisomy 16, equivalent to trisomy 21 in humans.

Shunwei Zhu
Because as you have said that exercise has some antidepressive effect, does BDNF stimulate endorphin production?

Carl and Nicole
No link yet has been made between BDNF and endorphins.

Gabrielle Strobel
Carl, I only just discovered you are working with a colony of aging dogs. That is interesting. Have you done any BDNF-related work with them? Or else, what are you studying with them?

Carl and Nicole
In aging dogs, we showed reduced amyloid with antioxidants and behavioral enrichment, but the BDNF work is still in progress.

Taihung Duong
Is there any correlation between BDNF levels and the age of the rat? Do younger rats have increased levels of BDNF compared to older rats?

Margaret Fahnestock
We see no correlation between age and BDNF mRNA or protein levels in human cortical samples (Holsinger et al., 2000; Michalski and Fahnestock, 2003). Aging rats do not show decreases in BDNF (Lapchak et al., 1993), and the only animal studies in which BDNF decreases are reported with age, to my knowledge, are complicated by various interventions such as drug treatments, lesions, or behavioral testing.

Fulya Karaman
Are there any studies about exercise levels in patients with AD—I mean about their exercise levels before they got the disease, or in other words, is it true to say that people who do some exercise after an age level have a lower risk for getting AD?

Carl and Nicole
Fulya, a dose-response study hasn't been done yet; almost all are descriptive/retrospective except for Richards's recent paper (Richards et al., 2003).

Gabrielle Strobel
Margaret, that is interesting. Does the memory impairment in that mouse resemble what is seen with AD models?

Margaret Fahnestock
I'm not sure. I'd have to check the paper again.

Leigh Holcomb
BDNF polymorphism has also been linked to schizophrenia.

Carl and Nicole
Leigh, yes, BDNF polymorphisms are linked to schizophrenia, obsessive-compulsive disorder, anorexia, possibly bipolar disorder...not Parkinson's.

Volkmar Lessmann
I think that to judge the molecular consequences of human BDNF polymorphisms, one should be cautious when testing hypotheses in mice or rats. Of course, this is the only way to make it. But when a single amino acid can change BDNF physiology as much as shown in the Egan paper), how can you be sure that other species-dependent substitutions wouldn't do similar things.

Carl and Nicole
Volkmar, that is definitely a good observation. The rat and human genomes aren't identical, so it will require many studies before the relationship becomes clear.

Danling Wang
Are there are some other animal models to reduce BDNF, apart from KO mice?

Gabrielle Strobel
We have reached the end of the hour. You are all most welcome to chat away as long as you like. But before people start dropping out, let me thank Nicole and Carl for this session, and everyone for contributing to such an informative and lively hour. Clearly, this line of investigation bears watching. If anyone would like to make a closing statement, perhaps on a favorite question to solve next, now would be the time. Margaret and Volkmar, what to you is the most pressing open question at this point?

Margaret Fahnestock
That's a tough one. I'd really like to be able to study BDNF levels in a cohort of AD patients grouped by the amount of exercise they get.

Volkmar Lessmann
I wonder whether the fast actions of BDNF, which have received so much attention recently, are physiologically relevant.

Gabrielle Strobel
What do you mean?

Volkmar Lessmann
I am talking about the fast currents induced by application of BDNF to single neurons (Kafitz et al., 1999; Kovalchuk et al., 2002. Although this might not yet be relevant for AD, this story seems to change a lot in the BDNF field, as the authors claim.

Gabrielle Strobel
Volkmar, I don't know about this. What does it change?

Volkmar Lessmann
These authors claim that the most important cellular effects of BDNF are mediated via BDNF-induced synaptic-like excitation, rather than BDNF being a molecule working on the long range.

Margaret Fahnestock
Volkmar, how would you measure these fast currents in a living person?

Volkmar Lessmann
Margeret, no, of course not, but I am just talking about recent new concepts of BDNF action in more general terms, which nevertheless might be relevant for BDNF physiology in AD.

Gabrielle Strobel
Volkmar, that is exactly what I find confusing about BDNF....

Volkmar Lessmann
I don't feel long-range and short-term actions are confusing. Certainly both types of effects exist, but it is not easy to know which are at work in memory or AD in a specific experiment.

Margaret Fahnestock
We're currently working on trying to reliably detect BDNF protein in blood and CSF, but the operative word is "reliably."

Gabrielle Strobel
Margaret, you would need to understand transport and degradation dynamics in the different pools. This is a problem that besets the use of CSF Aβ/tau as biomarkers, as well.

Margaret Fahnestock
I know; it's not a likely avenue. But there are instances where BDNF levels from blood have been measured and conclusions drawn without thorough investigation of tissue BDNF levels. We'd like to at least see if we can correlate these.

Gabrielle Strobel
Can one study BDNF in living people? Any way to image it?

Volkmar Lessmann
Regarding imaging of BDNF: We think knocking in BDNF-GFP into the endogenous BDNF gene would be a fancy way to study BDNF targeting and secretion, at least in rodents.

Gabrielle Strobel
I have to leave, (which does not mean you have to). Thanks very much for coming, all of you! If you want to continue a private conversation that's not in the transcript, you can click on each other's names and talk that way. Goodbye, and schoenen Abend noch, Volkmar.

Margaret Fahnestock
I should go, too. Nice chatting with you, Volkmar.

Carl and Nicole
It's been great chatting with all of you and we look forward to meeting in person, those of you whom we don't know yet!

Jorge Busciglio
Thanks, everyone. I better go now and start with my exercises!

Leigh Holcomb
Thanks for sharing the information on the SFN meeting. I wasn't able to attend due to a sick baby.

Fulya Karaman
Thanks. It was so nice to attend this chat.

Shunwei Zhu
Thanks for the discussion.

Volkmar Lessmann
Thanks a lot everybody! Too many questions to answer everything in parallel, though.

Margaret Fahnestock
I think you did a great job, Gabrielle. This was a very interesting and stimulating chat!

Gabrielle Strobel
Thanks, Margaret! A ton of fun.

Danling Wang
Thanks a lot, I hope to see you later.

 

Background

Background Text
By Nicole C. Berchtold and Carl W. Cotman

Why Is BDNF interesting?

The protein brain-derived neurotrophic factor (BDNF) has been the focus of intense interest in the Alzheimer's field for a number of years. BDNF belongs to the neurotrophin family of growth factors and affects the survival and function of neurons in the central nervous system, particularly in brain regions susceptible to degeneration in AD. BDNF improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex. This discovery kindled hope in the early 1990s that Alzheimer's could be slowed or halted if brain levels of BDNF could be increased. The idea gained support with the observation that BDNF gene activity and protein levels are reduced in AD brains.

Further research on BDNF in the mid-90s revealed additional exciting functions of this molecule in the brain. Beyond promoting neuronal survival and resilience to injury, BDNF also has a powerful role in facilitating activity-dependent plasticity, which underlies the capacity for learning and memory. Brain regions where plasticity is particularly important include the hippocampus and cortex, critical centers for learning and memory. The hippocampus is a central component for encoding new information, and damage there severely impairs learning. Hippocampal function is compromised early on in the course of AD, and this is considered the principal cause of the memory problems that characterize this disease. The reduction of BDNF seen in AD could cripple the hippocampus in two ways: From a plasticity point of view, insufficient BDNF would weaken synaptic encoding strength or capacity, while from the neurotrophic angle, reduced BDNF makes hippocampal neurons more vulnerable to insult and degeneration.

BDNF is an unusual neurotrophic factor. Its widespread functions in the brain go beyond the traditional role of a growth factor to promote growth, survival., and maintenance of cells. Recently, a third role for BDNF has emerged, in that it appears to be an important factor in psychiatric conditions such as epilepsy, depression, obsessive compulsive disorder, and possibly bipolar disorder. While unlikely to be causally related to Alzheimer's, these mood disorders, particularly depression, often coexist with Alzheimer's and may have a common link through BDNF.

Below, we discuss evidence supporting a role for BDNF in learning and memory, followed by recent genetic data demonstrating a link between BDNF and AD.

 

BDNF in Learning and Memory

What we've learned from animal models

BDNF is produced by neurons, particularly in the hippocampus and cortex. Neuronal activity, i.e., during encoding of information, stimulates BDNF gene transcription, transport of BDNF mRNA into dendritic spines, and BDNF protein release into the synaptic cleft (Hartmann et al., 2001). BDNF can be transported into the dendrite and may also be synthesized locally in the spine. It has been speculated that one or both of these mechanisms may be able to target active synapses within dendrites. BDNF acts on neurons at both presynaptic and postsynaptic sites by binding to its tyrosine kinase receptor TrkB, and internalization of the BDNF-TrkB complex. Interestingly, internalization does not lead to termination of the BDNF signal., such as occurs for most other growth factor receptors. Rather, the internalized TrkB receptor remains phosphorylated and activated. It becomes a specialized compartment called a "signaling endosome," which seems to be critical for downstream signaling effects of BDNF on the cell body. (For an excellent review on BDNF regulation and plasticity, see Lu, 2003).

 

By enhancing synaptic transmission and neuronal excitability (Figurov et al., 1996; Griesbeck et al., 1996), BDNF modulates synaptic change, including hippocampal long-term potentiation (LTP), a neural mechanism associated with learning and adaptive behaviors in adult animals (Poo, 2001; Tyler et al., 2002). A critical role for BDNF/TrkB signaling in plasticity mechanisms is evidenced by in-vivo studies where BDNF/TrkB signaling has been impaired by genetic or immunopharmacological means. Mice deficient in BDNF/TrkB signaling have impaired learning and LTP and, importantly, restoring BDNF reverses both the electrophysiological and learning deficits (Levine et al., 1995; Korte et al., 1996; Patterson et al., 1996). In addition, BDNF-deficient mice show decreased synaptic innervation and reduced levels of synaptic vesicle proteins (Martinez et al., 1998; Pozzo-Miller et al., 1999), demonstrating that BDNF is important for normal synaptic signaling (Martinez et al., 1998).

What we've learned from human genetics

Recent genetic studies have established a decisive role for BDNF in human cognition. Polymorphisms in the DNA sequence of a gene can result in seemingly subtle differences in the final protein product, which nevertheless can profoundly change the functionality of the product protein. One polymorphism in the BDNF gene that does just that is caused by a single amino acid substitution in the coding region of the BDNF gene (val/met substitution at codon 66). This substitution derails trafficking of the BDNF protein within the cell such that it is no longer released in response to appropriate cellular cues. The effect of this is seen at the level of hippocampal function, as the polymorphism is associated with impaired memory and abnormal hippocampal activation. Remarkably, these cognitive decrements were revealed in a cohort of 641 cognitively intact adults aged 25-45 (Egan et al., 2003; see ARF related news story; Hariri et al., 2003). Having made it clear that deficiencies in BDNF function has serious cognitive consequences even in young people, these studies prompt the question of what the relationship is between abnormal BDNF and AD.

BDNF polymorphisms are risk factors for AD

Three different BDNF polymorphisms have been proposed as possible risk factors for AD based on genetic linkage studies. The val/met polymorphism (position 196, codon 66) described above conferred increased susceptibility to AD that appeared to be independent of ApoE genotype (Ventriglia et al., 2002). The single nucleotide polymorphism C270T has been associated with late-onset but not early-onset AD in a Japanese population (51 early onset; 119 late onset; 498 controls, Kunugi et al., 2001). Another study of the C-270T polymorphism in a German population (210 AD cases, 188 controls) found its frequency increased in AD, and risk appeared to be higher in AD patients lacking the ApoE4 allele (Riemenschneider et al., 2002). Except for the met-BDNF polymorphism, little is known about how the polymorphisms affect BDNF function. These questions are currently under study, and are likely to expand our understanding of the role of BDNF in AD, as well as in learning, memory, and cognitive function throughout life.

Can BDNF levels in the brain be increased?

Animal studies demonstrate that brain levels of BDNF are modified in response to certain types of stimulation that occur normally in our daily lives. Remarkably, two potent stimuli that rapidly increase BDNF levels in the hippocampus are exercise and learning. In rodents, voluntary daily wheel running consistently increases BDNF mRNA and protein levels in the hippocampus and other brain regions, including parts of the cortex (for review on exercise and BDNF, see Cotman and Berchtold, 2002; also see ARF related news story). In addition, learning itself increases brain BDNF levels, particularly in the hippocampus. Interestingly, in humans, regular exercise is associated with benefits to brain health and cognitive function, which may in part be due to increased availability of BDNF. Indeed, physically active adults not only have a lower risk of cognitive impairment, but also a lower risk of depression and of developing AD or dementia of any type (Friedland et al., 2001; Laurin et al., 2001). Furthermore, exercise improves depression not only in normal adults, but also in people with moderate to severe AD, demonstrating that exercise can be an effective intervention when the course of neurodegeneration/neuropathology has already progressed. Just this week, JAMA published results of a randomized intervention trial of 153 AD patients, in which exercise training (and caregiver education) improved physical health and depression (Teri et al., 2003). In addition, there is evidence that mental activity/learning may also be somewhat protective against AD. An association between BDNF and these positive effects of exercise (and learning) on depression and dementia has not yet been definitely established; however, BDNF may serve as a common molecular mechanism. Increasing BDNF availability in the brain (stimulated, for example, by exercise or learning) is rapidly gaining strength as an important approach to improving cognitive function throughout life and offsetting depression and dementia. We believe that future studies will find BDNF to be a critical molecule in AD.

Let's discuss these questions (and more)

  • What molecular pathways underlie BDNF regulation?
  • What experimental models exist to study this? What new models should be created?
  • How much exercise is necessary to keep BDNF levels elevated?
  • Can exercise really stem the disease? How powerful an effect does it have?
  • When would one have to start regulating BDNF levels to affect the course of AD? Would it work only prior to overt AD in mild cases, or also when the disease has progressed?
  • How do diet (e.g., blueberries) or environmental factors (e.g., stress) affect BDNF levels?
  • Do estrogen and androgens affect BDNF levels?
  • Are there other types of environmental enrichment that increase BDNF?
  • Can drugs be developed to boost BDNF levels?
  • Could a BDNF therapeutic be nasally delivered?
  • Why does BDNF expression diminish with age?
  • How does BDNF function overlap with that of other growth factors implicated in AD, such as NGF or GDNF?
  • Can BDNF ever act like a proinflammatory cytokine?

In-text references and further reading
Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002 Jun;25(6):295-301. Review. Abstract

Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003 Jan 24;112(2):257-69. Abstract

Friedland RP, Fritsch T, Smyth KA, Koss E, Lerner AJ, Chen CH, Petot GJ, Debanne SM. Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3440-5. Epub 2001 Mar 06. Abstract

Groth RD, Mermelstein PG. Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. J Neurosci. 2003 Sep 3;23(22):8125-34. Abstract

Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci. 2003 Jul 30;23(17):6690-4. Abstract

Hartmann M, Heumann R, Lessmann V. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J. 2001 Nov 1;20(21):5887-97. Abstract

Korte M, Griesbeck O, Gravel C, Carroll P, Staiger V, Thoenen H, Bonhoeffer T. Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12547-52. Abstract

Kunugi H, Ueki A, Otsuka M, Isse K, Hirasawa H, Kato N, Nabika T, Kobayashi S, Nanko S. A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease. Mol Psychiatry. 2001 Jan;6(1):83-6. Abstract

Laurin D, Verreault R, Lindsay J, MacPherson K, Rockwood K. Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol. 2001 Mar;58(3):498-504. Abstract

Levine ES, Dreyfus CF, Black IB, Plummer MR. Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8074-7. Abstract

Lu B. BDNF and activity-dependent synaptic modulation. Learn Mem. 2003 Mar-Apr;10(2):86-98. Review. Abstract

Martinez A, Alcantara S, Borrell V, Del Rio JA, Blasi J, Otal R, Campos N, Boronat A, Barbacid M, Silos-Santiago I, Soriano E. TrkB and TrkC signaling are required for maturation and synaptogenesis of hippocampal connections. J Neurosci. 1998 Sep 15;18(18):7336-50. Abstract

Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron. 1996 Jun;16(6):1137-45. Abstract

Poo MM. Neurotrophins as synaptic modulators. Nat Rev Neurosci. 2001 Jan;2(1):24-32. Review. Abstract

Pozzo-Miller LD, Gottschalk W, Zhang L, McDermott K, Du J, Gopalakrishnan R, Oho C, Sheng ZH, Lu B. Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci. 1999 Jun 15;19(12):4972-83. Abstract

Riemenschneider M, Schwarz S, Wagenpfeil S, Diehl J, Muller U, Forstl H, Kurz A. A polymorphism of the brain-derived neurotrophic factor (BDNF) is associated with Alzheimer's disease in patients lacking the Apolipoprotein E epsilon4 allele. Mol Psychiatry. 2002;7(7):782-5. Abstract

Russo-Neustadt A. Brain-derived neurotrophic factor, behavior, and new directions for the treatment of mental disorders. Semin Clin Neuropsychiatry. 2003 Apr;8(2):109-18. Review. Abstract

Teri L, Gibbons LE, McCurry SM, Logsdon RG, Buchner DM, Barlow WE, Kukull WA, LaCroix AZ, McCormick W, Larson EB. Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial. JAMA. 2003 Oct 15;290(15):2015-22. Abstract

Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD. From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem. 2002 Sep-Oct;9(5):224-37. Review. Abstract

Ventriglia M, Bocchio Chiavetto L, Benussi L, Binetti G, Zanetti O, Riva MA, Gennarelli M. Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease. Mol Psychiatry. 2002;7(2):136-7. No abstract available. Abstract

Wu W, Li L, Yick LW, Chai H, Xie Y, Yang Y, Prevette DM, Oppenheim RW. GDNF and BDNF alter the expression of neuronal NOS, c-Jun, and p75 and prevent motoneuron death following spinal root avulsion in adult rats. J Neurotrauma. 2003 Jun;20(6):603-12. Abstract

Zakharenko SS, Patterson SL, Dragatsis I, Zeitlin SO, Siegelbaum SA, Kandel ER, Morozov A. Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA1-CA3 synapses. Neuron. 2003 Sep 11;39(6):975-90. Abstract

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

No Available Comments

References

News Citations

  1. From Protein Trafficking to Episodic Memory: Tracing BDNF Genotypes
  2. Run For Your Brain: Exercise Boosts Hippocampal Gene Expression, Neurogenesis
  3. New Orleans: Symposium Probes Why Synapses Are Suffering

Webinar Citations

  1. BDNF and Alzheimer's Disease—What's the Connection?

Paper Citations

  1. . Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J. 2001 Nov 1;20(21):5887-97. PubMed.
  2. . BDNF and activity-dependent synaptic modulation. Learn Mem. 2003 Mar-Apr;10(2):86-98. PubMed.
  3. . Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12547-52. PubMed.
  4. . Neurotrophins as synaptic modulators. Nat Rev Neurosci. 2001 Jan;2(1):24-32. PubMed.
  5. . From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem. 2002 Sep-Oct;9(5):224-37. PubMed.
  6. . Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8074-7. PubMed.
  7. . Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron. 1996 Jun;16(6):1137-45. PubMed.
  8. . TrkB and TrkC signaling are required for maturation and synaptogenesis of hippocampal connections. J Neurosci. 1998 Sep 15;18(18):7336-50. PubMed.
  9. . Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci. 1999 Jun 15;19(12):4972-83. PubMed.
  10. . The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003 Jan 24;112(2):257-69. PubMed.
  11. . Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci. 2003 Jul 30;23(17):6690-4. PubMed.
  12. . Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease. Mol Psychiatry. 2002;7(2):136-7. PubMed.
  13. . A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease. Mol Psychiatry. 2001 Jan;6(1):83-6. PubMed.
  14. . A polymorphism of the brain-derived neurotrophic factor (BDNF) is associated with Alzheimer's disease in patients lacking the Apolipoprotein E epsilon4 allele. Mol Psychiatry. 2002;7(7):782-5. PubMed.
  15. . Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002 Jun;25(6):295-301. PubMed.
  16. . Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3440-5. PubMed.
  17. . Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol. 2001 Mar;58(3):498-504. PubMed.
  18. . Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial. JAMA. 2003 Oct 15;290(15):2015-22. PubMed.
  19. . Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. J Neurosci. 2003 Sep 3;23(22):8125-34. PubMed.
  20. . Brain-derived neurotrophic factor, behavior, and new directions for the treatment of mental disorders. Semin Clin Neuropsychiatry. 2003 Apr;8(2):109-18. PubMed.
  21. . GDNF and BDNF alter the expression of neuronal NOS, c-Jun, and p75 and prevent motoneuron death following spinal root avulsion in adult rats. J Neurotrauma. 2003 Jun;20(6):603-12. PubMed.
  22. . Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA1-CA3 synapses. Neuron. 2003 Sep 11;39(6):975-90. PubMed.
  23. . A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer's disease parietal cortex. J Neurochem. 2002 Sep;82(5):1058-64. PubMed.
  24. . Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003 Aug 8;301(5634):805-9. PubMed.
  25. . Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle. Eur J Neurosci. 2001 Mar;13(6):1078-84. PubMed.
  26. . Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci. 2003 Mar;14(2):125-30. PubMed.
  27. . Frontal cortex BDNF levels correlate with working memory in an animal model of Down syndrome. Behav Brain Res. 2003 Feb 17;139(1-2):47-57. PubMed.
  28. . Quantitation of BDNF mRNA in human parietal cortex by competitive reverse transcription-polymerase chain reaction: decreased levels in Alzheimer's disease. Brain Res Mol Brain Res. 2000 Mar 29;76(2):347-54. PubMed.
  29. . Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer's disease. Brain Res Mol Brain Res. 2003 Mar 17;111(1-2):148-54. PubMed.
  30. . BDNF and trkB mRNA expression in the hippocampal formation of aging rats. Neurobiol Aging. 1993 Mar-Apr;14(2):121-6. PubMed.
  31. . Does active leisure protect cognition? Evidence from a national birth cohort. Soc Sci Med. 2003 Feb;56(4):785-92. PubMed.
  32. . Schizophrenia, III: brain-derived neurotropic factor and genetic risk. Am J Psychiatry. 2003 Jul;160(7):1242. PubMed.
  33. . Neurotrophin-evoked rapid excitation through TrkB receptors. Nature. 1999 Oct 28;401(6756):918-21. PubMed.
  34. . Postsynaptic Induction of BDNF-Mediated Long-Term Potentiation. Science. 2002 Mar 1;295(5560):1729-34. PubMed.

Other Citations

  1. Nicole C. Berchtold

Further Reading

Papers

  1. . PAK3 mutation in nonsyndromic X-linked mental retardation. Nat Genet. 1998 Sep;20(1):25-30. PubMed.