25 April 2010. A magnetic resonance imaging (MRI) study, reported in the April 14 Journal of Neuroscience, links reduced hippocampal volume and memory decline in older adults with lower serum levels of brain-derived neurotrophic factor (BDNF). The finding supports the claim that waning hippocampal BDNF expression, as noted in Alzheimer disease (see Murray et al., 1994), is an important factor in neurodegeneration, and that shoring up BDNF signaling might make for a therapy one day. On that score, a paper in the April 19 Journal of Clinical Investigation offers a glimmer of hope. Small molecules that mimic the trophic effects of BDNF prevent neurodegeneration in rodents, according to researchers led by Frank Longo, Stanford University, California. Alzforum previously reported on this data when Longo presented it at last February’s Keystone Symposium, “Alzheimer’s Disease Beyond Aβ.” (see ARF related news story).
The MRI study, led by first author Kirk Erickson at the University of Pittsburgh, Pennsylvania, and Arthur Kramer at the University of Illinois, Urbana, imaged 142 cognitively normal adults between the ages of 59 and 81 (mean age 66.5 years). Three quarters of the study participants were women. As with earlier studies, serum BDNF levels declined with age, as did volume of the left and right hippocampus. Spatial memory (participants had to remember the location of one, two, or three black dots briefly flashed on a computer screen) also faltered with age.
To test how these different parameters interact, the researchers carried out mediation analysis. Briefly, this looks to see how one parameter, for example, serum BDNF, influences how an independent variable (e.g., age) affects a dependent variable (e.g., hippocampal volume). Erickson and colleagues discovered that serum BDNF mediated age and hippocampal volume decline, mostly of the left hemisphere. The mediation of the right hippocampus was marginal. In turn, hippocampal volume, particularly the left hippocampus, mediated the effect of age on spatial memory performance—both response time and accuracy. Finally, left hippocampal volume mediated the association between BDNF and spatial memory performance—both response time and accuracy.
Although several studies have shown positive correlations between blood and brain BDNF, the authors note that it is debatable to what extent the former reflects the latter. “Our results build on these previous studies and demonstrate that serum BDNF levels are correlated with measurements of hippocampal volume, an important link that suggests some association between BDNF in the blood and measures of brain integrity,” they write. However, the real litmus test for how BDNF mediates hippocampal volume loss and memory will be a longitudinal study. “Nonetheless, our cross-sectional findings highlight the importance of BDNF as a factor associated with age-related hippocampal volume decay,” write the authors.
If preventing age-related decline in brain BDNF can protect the hippocampus, then the approach taken by Longo and colleagues may prove fruitful. Longo founded a start-up company, PharmatrophiX, to develop small molecules that mimic regions of BDNF involved in activation of the neurotrophin receptor tropomyosin-related kinase B (TrkB). As first author Stephen Massa and colleagues report, this approach has yielded prototypes with promising properties. The compounds specifically bind and activate TrkB in hippocampal cells in culture, in the process inducing pro-survival factors such as the kinases Akt and ERK. In vitro, LM22A-4 protects hippocampal cells against Aβ42, neuroblastoma cells against MPTP (a toxin that leads to parkinsonism), and striatal cells against quinilinic acid, often used to model Huntington disease. Given intranasally for a week, the compound LM22A-4 activates Akt and ERK in mouse hippocampus and striatum; given over two weeks by the same route, the compound restored motor performance in mice lost to traumatic brain injury (for more see ARF related news story).—Tom Fagan.
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. Journal of Neuroscience 2010 April 14; 30:5368-5375. Abstract
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. Journal of Clinical Investigation 2010 April 19. Abstract