02 Nov 2011

It does not take much to tilt the biochemical balance needed for optimal brain function. Take brain-derived neurotrophic factor (BDNF); changes in the levels of this trophic factor, or its activity, can make the difference between a neuron’s death or survival. Now, a study by Ahmad Salehi’s group at the Stanford University School of Medicine, California, shows that pilots who have a single nucleotide polymorphism in the BDNF gene perform less well in flight simulation as they age than do people without the genetic blip; their hippocampus also shrinks a little faster. Several studies already drew connections between decreased BDNF function and memory and cognitive deficits, including those seen in Alzheimer’s disease (see ARF Live Discussion). “But the interesting aspect of this paper is that they are looking at a more complex task, expected to involve more widely dispersed brain areas than just hippocampus,” said Margaret Fahnestock of McMaster University in Hamilton, Ontario, who was not involved in the work. “It widens the focus of BDNF from memory to more global effects on brain function.”

If the results, which appeared in the October 25 Translational Psychiatry online, are reproduced in larger studies, it may have implications for people carrying the polymorphism, which is believed to reduce BDNF activity. And they might benefit from a BDNF boost. “There are simple ways to increase BDNF levels, such as increasing physical activity, or caloric restriction,” said Salehi (see ARF related news story on Cotman and Berchtold, 2002). “This polymorphism could be used as a biomarker for targeting certain people for these interventions.”

The polymorphism consists of a G-to-A substitution in the BDNF gene, culminating in a valine for methionine amino acid swap at position 66 in the proBDNF protein, a precursor to mature BDNF. The methionine variant has not been shown to be a risk factor to AD. There is, however, ample evidence that people with AD have less BDNF (see ARF related news story on Li et al., 2009), and that boosting BDNF levels might improve AD symptoms (see ARF related news story on Erickson et al., 2010; Massa et al., 2010 and ARF related news story on Nagahara et al., 2009). Fahnestock’s lab has reported that large amyloid-β oligomers in particular are responsible for depleting BDNF levels in mouse models (see ARF related news story on Peng et al., 2009). “We think that the amyloid causes BDNF to decrease, and in turn, that contributes to the memory deficit,” said Fahnestock. The methionine substitution in BDNF also causes a decrease in BDNF function, but it does not, however, seem to play any role in the pathogenic changes leading to amyloid deposits and AD.

In 2003, Daniel Weinberger and Bai Lu at the National Institutes of Health in Bethesda, Maryland, showed that the methionine version of the protein affects proBDNF processing, thereby decreasing the amount of mature BDNF that is secreted from neurons in response to their activation. This defect is associated with episodic memory loss and hippocampal shrinkage in schizophrenic patients and family members, but not with changes in word recall, semantic memory, or working memory (see ARF related news story on Egan et al., 2003). Other labs reproduced the basic findings (see, e.g., Cathomas et al., 2010 and Hajek et al., 2011).

In Salehi’s lab, Marth Millan Sanchez and Devsmita Das, joint first authors on the paper, asked whether the decline in BDNF activity due to the methionine mutation could also be affecting other brain functions in people who have apparently normal memory. “Here we did not look at cognition per se, but rather at a large skill set involved in flying a plane,” said Salehi. The group recruited 144 pilots, including 55 with the methionine polymorphism and 89 without, ranging in age from 44 to 69 years (about 57 years old on average). They then asked the pilots to perform in a flight simulator test for 75 minutes, in which they faced flight scenarios with emergency situations, such as engine malfunctions or incoming air traffic. The pilots performed a version of this test annually for three years; they were also examined using a cognitive test called CogScreen-AE, which evaluates cognitive abilities relative to flying. One-third of participants (43 people) also underwent magnetic resonance imaging (MRI); 65 percent of the pilots screened at baseline returned for follow-up imaging at least once.

After three years, Sanchez and colleagues found that people with the methionine polymorphism had a twofold greater decline in their flight simulation test scores compared to those without the polymorphism; there was no difference in flight test scores based on ApoE gene status, which is a known risk factor for AD. The CogScreen-AE scores of the two groups of pilots, with or without the methionine polymorphisms, were the same. “They remember normally if you give them lists of words. We did not find a correlation between cognition and the polymorphism,” said Salehi. “But that does not mean that if we continue to follow these people for 10 years, their cognition might become affected.” The hippocampus of all pilots age 65 and over showed some shrinking but the shrinkage was greater in people with the methionine variant. In this study, hippocampus volume correlated with the ability to perform a complex task. “The presence or absence of the polymorphism can be used as a predictive way to understand loss of brain function, both structurally and functionally,” said Salehi. One question that this study raises is why the effects of the BDNF polymorphism only become evident later in life and not at earlier stages. “You might need an interaction between reduced BDNF activity and age-related decline in other mechanisms to see any effects in this test,” suggested Fahnestock.

A related question is how BDNF affects brain function. BDNF is a jack of all trades, promoting neuronal survival and differentiation, and synaptic plasticity. Recent work by Erik Dent’s group at the University of Wisconsin in Madison suggests that BDNF achieves the latter by influencing microtubules (Hu et al., 2008). In the October 26 Journal of Neuroscience, Dent’s group reports that as they telescope in and out of dendritic spines, microtubules deliver post-synaptic density 95 (PSD-95), a protein that boosts synaptic strength. This mechanism is regulated by BDNF, reports first author Xindao Hu and colleagues. Agents that inhibit microtubule polymerization prevent PSD-95 from accumulating in the spines in response to BDNF. “This could be a new pathway by which materials are brought into spines as they change morphologically,” said Dent. “Microtubule invasion only occurs in certain spines, probably the more active ones. Getting molecules to these active spines helps reinforce the changes induced by synaptic activity,” he added. Salehi welcomed the result. “BDNF may indeed be involved in regulating the transport machinery in spines,” he said.—Laura Bonetti

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References

Webinar Citations

1. BDNF and Alzheimer's Disease—What's the Connection? 25 Nov 2003

News Citations

1. Run For Your Brain: Exercise Boosts Hippocampal Gene Expression, Neurogenesis 22 Nov 2002
2. Research Brief: Low Spinal Fluid BDNF a Prelude to Memory Decline? 17 May 2009
3. Research Brief: BDNF Data Speak Volumes, Offer Therapeutic Target 25 Apr 2010
4. BDNF the Next AD Gene Therapy? 10 Feb 2009
5. Support Cast: Neural Stem Cell BDNF Prompts Memory in AD Mice 27 Jul 2009
6. From Protein Trafficking to Episodic Memory: Tracing BDNF Genotypes 30 Jan 2003

Paper Citations

1. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002 Jun;25(6):295-301. PubMed.
2. Li G, Peskind ER, Millard SP, Chi P, Sokal I, Yu CE, Bekris LM, Raskind MA, Galasko DR, Montine TJ. Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PLoS One. 2009;4(5):e5424. PubMed.
3. Erickson KI, Prakash RS, Voss MW, Chaddock L, Heo S, McLaren M, Pence BD, Martin SA, Vieira VJ, Woods JA, McAuley E, Kramer AF. Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci. 2010 Apr 14;30(15):5368-75. PubMed.
4. Massa SM, Yang T, Xie Y, Shi J, Bilgen M, Joyce JN, Nehama D, Rajadas J, Longo FM. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest. 2010 May 3;120(5):1774-85. PubMed.
5. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, Wang L, Blesch A, Kim A, Conner JM, Rockenstein E, Chao MV, Koo EH, Geschwind D, Masliah E, Chiba AA, Tuszynski MH. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med. 2009 Mar;15(3):331-7. PubMed.
6. Peng S, Garzon DJ, Marchese M, Klein W, Ginsberg SD, Francis BM, Mount HT, Mufson EJ, Salehi A, Fahnestock M. Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer's disease. J Neurosci. 2009 Jul 22;29(29):9321-9. PubMed.
7. 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. PubMed.
8. Cathomas F, Vogler C, Euler-Sigmund JC, de Quervain DJ, Papassotiropoulos A. Fine-mapping of the brain-derived neurotrophic factor (BDNF) gene supports an association of the Val66Met polymorphism with episodic memory. Int J Neuropsychopharmacol. 2010 Sep;13(8):975-80. PubMed.
9. Hajek T, Kopecek M, Höschl C. Reduced hippocampal volumes in healthy carriers of brain-derived neurotrophic factor Val66Met polymorphism: Meta-analysis. World J Biol Psychiatry. 2011 Jul 4; PubMed.
10. Hu X, Viesselmann C, Nam S, Merriam E, Dent EW. Activity-dependent dynamic microtubule invasion of dendritic spines. J Neurosci. 2008 Dec 3;28(49):13094-105. PubMed.

Further Reading

News

1. A Little BDNF May Help Your Canary Sing 5 Mar 2004
2. Sorrento: Trouble with the Pro’s 28 Mar 2005
3. Copper Mountain: Death and Trophin Receptors—New Insight, New Drugs? 3 Feb 2010
4. Huntingtin, BDNF, Neurodegeneration: Is Speed of the Essence? 9 Jul 2004
5. One Dose Versus Slow Drip—It Matters for BDNF 26 Feb 2010
6. Run For Your Brain: Exercise Boosts Hippocampal Gene Expression, Neurogenesis 22 Nov 2002
7. Research Brief: Low Spinal Fluid BDNF a Prelude to Memory Decline? 17 May 2009
8. Research Brief: BDNF Data Speak Volumes, Offer Therapeutic Target 25 Apr 2010
9. BDNF the Next AD Gene Therapy? 10 Feb 2009
10. Support Cast: Neural Stem Cell BDNF Prompts Memory in AD Mice 27 Jul 2009
11. From Protein Trafficking to Episodic Memory: Tracing BDNF Genotypes 30 Jan 2003