Neuroscience
Surprisingly, in 1998, several labs reported a possible link between bleomycin hydrolase and Alzheimer's disease. A group led by Robert Ferrell and John Lazo at the University of Pittsburgh found that individuals with two copies of a particular allele (type) of the BH gene were four times more likely than the average person to develop sporadic Alzheimer's disease. Then, Carmela Abraham of Boston University and her collaborators purified BH from the brains of individuals with Alzheimer's disease while looking for amyloid precursor protein (APP), a protein that is processed to yield beta-amyloid, a component of the plaques that occur in the brains of Alzheimer's patients.
Leemor Joshua-Tor's lab is currently studying the connection between BH and APP processing, specifically the relevance of a BH polymorphism suspected of playing a role in this process. In addition, her lab is continuing its studies of the protease's effect on the anticancer drug bleomycin and ways to ameliorate the resulting drug resistance in order to preserve the drug's anticancer activity.
Roberto Malinow, a senior neurobiologist who was recently appointed by the Board of Trustees to the Harrison Chair of Neuroscience, has also discovered a possible link between his research and Alzheimer's disease.
Scientists at other institutions have shown that mutations in the presenilin 1 gene (PS1) are associated with the most common cause of familial Alzheimer's disease. Roberto's lab is studying mice that carry a mutant form of the PS1 gene--the same mutation that some human Alzheimer's patients carry. These mice provide an experimental model for studying certain molecular aspects of Alzheimer's disease. (Although the mice do not display the behavioral changes characteristic of Alzheimer's patients, this is not unexpected, as the same mutation in humans is present at birth, yet 30 or more years typically pass before the onset of the behavioral manifestations of the disease.)
Roberto's lab studies long-term and short-term potentiation (LTP and STP)--a strengthening of synaptic communication between neurons that occurs when neurons are repeatedly stimulated at high frequency. Roberto's lab found that LTP and STP are notably--and unexpectedly--elevated in brain cells of the PS1 mutant mice. Surprisingly, synaptic inhibition, which suppresses LTP and STP as well as the firing of electrical impulses, was also enhanced in the mutant mice. This increased synaptic inhibition may represent a compensatory homeostatic response to the increased ability to produce LTP and STP. Roberto's lab then further inhibited synaptic activity in these PS1 mutant brain cells by applying the drug benzodiazapine, which returned synaptic potentiation (LTP and STP) to normal levels.
Coincidentally, clinicians in Sweden recently reported that the regular use of the benzodiazapines Xanax and Valium correlated with a markedly reduced incidence of Alzheimer's disease in the patients studied. Although the mechanism of the drugs' action is known as it relates to their traditionally prescribed use as anti-anxiety agents, it was not clear how these drugs affected the likelihood of developing Alzheimer's disease. Roberto's studies of the relationship between the molecular biology of the PS1 gene and the activity of the benzodiazepines may reveal a greater understanding of ways to prevent or treat Alzheimer's disease.
Roberto's lab is also continuing to study factors involved in neuronal plasticity, i.e., the ways in which neurons change their activity or shape during development or as a result of learning, trauma, or other events. The researchers have developed improved tools for studying the activity of brain cells and the connections between them, called synapses. One new method developed by the Malinow lab involves the introduction, using a viral vector, of recombinant proteins whose movement in cells and at synapses can be monitored by electrophysiology and imaging techniques. By attaching these proteins to specific molecules important for learning and the formation of memories, Roberto can track the movement and activity of important nerve cell factors. The studies also utilize the sophisticated two-photon laser-scanning imaging system that Karel Svoboda brought to CSHL in 1997, as well as high-resolution electron microscopy, to track the movement of other important proteins in the brain during learning.
Karel, in collaboration with Roberto and postdoctoral fellow Mirjana Maletic-Savatic, used the new imaging system to observe and document the effect of synaptic stimulation on the shape of brain neurons. Karel custom-built a two-photon laser-scanning microscope to study living nerve cells in brain slices from rat hippocampus, a region of the brain that is important for the formation of memories. The researchers stimulated axons from one group of nerve cells that form synapses on a small dendritic branch of a neighboring cell--a strong but highly localized stimulus. They found that the stimulus triggers the growth of new dendritic protrusions called filopodia. Growth of filopodia begins within 20 minutes after the stimulation and continues for at least 40 minutes more. The new filopodia may ultimately form new synapses, an important phenomenon during development and learning and memory. By comparing stimulated and unstimulated dendritic regions, the researchers found that growth of filopodia evoked by strong electrical stimulation was limited to regions of the dendritic tree close to stimulated synapses.
Mirjana, Roberto, and Karel also found that the growth of dendritic filopodia requires activation of N-methyl-D-aspartate (NMDA) neurotransmitter receptors at the synapses under study. Other studies had shown that activation of these receptors is required for the formation of memories and for normal brain development. In the recent experiments, the blockade of NMDA receptors prevented stimulation-induced growth. Thus, synaptic transmission, and activation of NMDA receptors in particular, is required to produce this kind of dendritic growth.
In the cells affected by the synaptic stimulation, the growth of filopodia subsided about 45 minutes after the stimulus ended, but the filopodia remained, and some formed bulb-like tips which suggests that they may become functional synapses. Karel and Roberto will continue to study the structure of the outgrowths, as well as their signal transduction properties.
Meanwhile, Jerry Yin at CSHL and Marcia Belvin at the University of California at Berkeley have made a fascinating observation that suggests how and when memories are formed. Neuroscientists have long suspected that important brain functions take place while people are sleeping. Jerry and Marcia found that the activity of CREB, a protein that Tim Tully and Jerry Yin previously showed is important in memory formation, displays circadian, or 24-hour cyclical, patterns of activity. The Yin lab is trying to determine the functional connection between the nighttime peak in CREB activity and memory formation. Given what is known about memory formation in mammals, it is likely that some aspect of memory consolidation occurs at night, probably during sleep.