Beta-amyloid has fascinated scientists for years. Long considered a key player in the development and progression of AD, it held its secrets closely. In the past several years, however, it has gradually begun to give up many of these secrets. Scientists have learned an enormous amount about how beta-amyloid plaques are formed and the toxic effects that these structures as well as the earlier forms of beta-amyloid have on neurons and synapses. These findings have opened up new avenues of investigation and new possibilities for therapeutic targets. Here are a few highlights from recent beta-amyloid work.
Based on recent evidence, some scientists think that oligomers harm neurons by attaching themselves to a receptor site on dendrites where messages are received (this site is called the post-synaptic membrane). When this happens, the synapses can’t function properly and can’t receive messages from other neurons. Unable to communicate, the neurons lose function and eventually die. In test tube studies and in animal studies with AD transgenic mice (mice that are genetically programmed to develop features of AD, such as amyloid plaques and memory problems), scientists at Rockefeller University explored how this disruptive process may occur (Snyder et al., 2005). First, the researchers found that applying beta-amyloid to neuronal cells in culture promoted the movement of NMDA receptors away from the cell surface and into the cell. Cell surface receptors are binding sites for neuro-transmitters (see "A Brief Primer on AD" for more on these chemical messengers) and are essential in cell-to-cell communication and function. NMDA receptors are necessary for signal transmission across synapses in response to the neurotransmitter glutamate. Thus, beta-amyloid reduces signal transmission across these synapses, which reduces synaptic plasticity. Synaptic plasticity, the term neuroscientists use to describe the inherent capacity of the synapse to alter its behavior in response to neural activity, is the basis for learning and memory.
Next, the researchers examined the neurons of transgenic mice in tissue culture and found that they had reduced amounts of NMDA receptors on the surface of their neurons. When they reduced the production of beta-amyloid in these cultures, they found that NMDA receptor expression on the surface of neurons was restored. These findings are important because they show that the amount of beta-amyloid present affects the level of a key receptor, and that, in turn, interferes with the cell’s ability to function. These results suggest another way that beta-amyloid disrupts synaptic function and contributes to AD damage.
Another group of researchers, working at New York University School of Medicine, also focused on pathways involved in synaptic plasticity. These researchers hoped to discover a second pathway by which amyloid exerts its effects (Puzzo et al., 2005). In studies with transgenic mice, these investigators found that beta-amyloid also interferes with a particular molecular pathway, called the nitric oxide/cGMP/cAMP-responsive element-binding protein, or CREB, cascade. Beta-amyloid’s interference with this pathway suppressed synaptic plasticity in the hippocampus. The results from both of these synaptic plasticity studies suggest an approach to treating AD by blocking beta-amyloid’s effects on these particular molecules and cellular pathways.
In recent years, scientists have learned a lot about gamma-secretase, one of the enzymes that cleave APP into fragments. They now know that it is composed of four proteins: presenilin, nicastrin, Aph-1, and Pen-2. Gamma-secretase cannot be active unless all four of these proteins are present.
One of the gamma-secretase components—presenilin—has intrigued scientists for a long time, for another reason. To date, only four of the approximately 30,000 genes in the human genetic map (the “genome”) have been conclusively shown to affect AD development. Mutations in three genes—the APP gene found on chromosome 21, the PS1 gene on chromosome 14, and the PS2 gene on chromosome 1—are linked to the rare, early-onset form of AD. The APP gene is responsible for making APP, the precursor to beta-amyloid. PS1 and PS2 are responsible for making the presenilin protein. The fourth gene, APOE, affects the course of late-onset AD, depending on which allele, or variation, of the gene is inherited. (APOE-e2 may provide some protection against AD, APOE-e3 may play a neutral role in AD, and APOE-e4 increases the risk of developing AD.)
A Massachusetts General Hospital team of researchers supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) used a technique called fluorescence lifetime imaging microscopy to determine what effect mutations in the PS1 gene might have on the activity of the presenilin protein and, by extension, on the progress of early-onset familial AD (Berezovska et al., 2005). This highly sophisticated imaging technique allows scientists to follow biochemical reactions in fluorescently-labeled molecules, thus imaging biochemical activity in specific cellular compartments of living cells.
The researchers found that the mutation changed the spatial relationship of certain key molecules in the presenilin protein and also was associated with a consistent change in the configuration of the PS1-APP complex. They suggest that these changes may provide a molecular mechanism that underlies the pathology of early-onset AD across a wide range of PS1 mutations.
Identifying exactly how PS1 mutations cause early-onset AD may ultimately help investigators devise therapies to reduce the mutated gene’s effect on brain cells.
Though many investigators these days are focusing on the early, oligomer, stage of beta-amyloid activity, other investigators remain interested in exploring the end product: beta-amyloid plaques. Some scientists now think that plaque formation actually may be a protective action by the brain to sequester beta-amyloid so that it cannot harm neurons, but a research team at Massachusetts General Hospital and Harvard Medical School has found that plaques may still have a damaging effect on synapses (Spires et al., 2005). In studies with AD transgenic mice, they discovered that plaques cause a change to the trajectory of dendrites. Plaques get in the way of a dendrite’s normal path and cause the dendrite to curve around the plaque. They also reduce the number of spines, or doorknob-shaped structures, that extend out from the dendrites and that are essential to signal transmission between neurons. These physical changes have damaging physiological effects because they disrupt synapse networks, which weakens neurons’ ability to communicate with each other.
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