From the beginning, studies at the cellular and molecular levels have focused on understanding the wide range of processes that interfere with, or enhance, the function and survival of neurons and their connections. The aim is to identify targets that can be translated and developed into AD therapies. Such therapies may avoid or reduce the cell dysfunction and cell death that occur as the disease progresses and also may keep memory intact.
Interest in mechanisms at the basic level is ongoing, and the potential roles of different forms of beta-amyloid and abnormal tau in neuronal toxicity continue to be a source of intense investigation.
Beta-amyloidScientists now know a fair amount about the metabolism of amyloid precursor protein (APP), a large protein associated with the cell membrane that is the starting point for the beta-amyloid that forms plaques. Scientists also know the basic steps of beta-amyloid and plaque formation. They know that three different enzymes—alpha-secretase, beta-secretase, and gamma-secretase—are involved in cleaving APP into discrete fragments, the functions of which are still not completely understood. Depending on which enzymes are involved and where the cleaving occurs, APP processing can follow one of two pathways—a pathway that is helpful to neurons or one that is harmful because it leads to the formation of beta-amyloid and plaques.
Studies in this area have evolved to the point that investigators have begun initial testing in humans of potential therapies aimed at halting the synthesis of beta-amyloid, reducing its levels, or degrading early aggregates before harmful complexes have formed. At the same time, basic science investigators are still probing the mysteries of plaque formation and seeking to understand the potentially toxic effects that beta-amyloid exerts on neurons.
A key focus of beta-amyloid research has always been to understand how this protein peptide actually damages neurons. Recent research suggests that early, small, and soluble aggregates of amyloid, called beta-amyloid-derived diffusible ligands (ADDLs), or oligomers, may be the main culprits in harming neurons. Much evidence also suggests that synapses, the tiny gaps between neurons that are essential for neuronal communication, are oligomers’ prime targets. Several recent studies have examined the pathways that lead from beta-amyloid to eventual synaptic dysfunction or neuron death and studied how beta-amyloid oligomers target specific synaptic connections between neurons, causing them to deteriorate.
Another continuing line of research focuses on the possibility of harnessing an immunization response in people with AD that involves antibodies to beta-amyloid. Immunizing people against disease has been a cornerstone of medical practice for decades, and investigators have pursued the idea that it might be possible to immunize people against AD by injecting them with a beta-amyloid-related immunogen (a substance designed to elicit an immune response). This kind of injection would cause a person’s immune system to make antibodies that, in turn, would lower the levels of brain amyloid.
This technique, called active immunization, has been tested in AD transgenic mice that were actively immunized with a beta-amyloid immunogen. (Transgenic animals are those that have been specially bred to develop AD-like features, such as beta-amyloid plaques.) The mice had fewer plaques and improved performance on memory tests. This finding led to a clinical trial in humans to test the safety and effectiveness of active immunization with the beta-amyloid immunogen. However, about 6 percent of participants in the trial developed brain inflammation in response to the treatment, so the trial was stopped. Despite this setback, interest in developing an AD vaccine remains high.
Research into new ways of shaping the antibody response continues in the laboratory, and more refined antibody approaches are being tested in clinical trials.
In a second approach to protecting against AD, called passive immunization, antibodies are produced or manufactured outside the body. For example, humanized antibodies to beta-amyloid have been made in cell cultures using recombinant DNA techniques. The antibodies can then be isolated and administered to subjects. Scientists presume that passive immunotherapy produces less of an inflammatory response than active immunotherapy, and a number of investigators are pursuing this approach.
Additional insights about beta-amyloid have come from studies of neuronal networks. These studies show how beta-amyloid may damage normal electrical activity of hippocampal neurons, thereby diminishing the cells’ ability to communicate with each other.
Other aspects of beta-amyloid also are yielding their secrets to AD researchers.
TauTau is a leading player in AD pathology and is generating new excitement as an area of study. The focus on tau was spurred by the finding that a mutant form of this protein is responsible for frontotemporal dementia and parkinsonism linked to chromosome 17, another neurodegenerative disorder that shares some features with AD. That finding indicated that abnormalities in tau can cause dementia.
Recent research has provided other new insights. For example, some studies have suggested that tau’s influence on cell death may have more to do with its interference in the normal cell cycle process than with its involvement in the formation of neurofibrillary tangles. Other studies suggest that, like beta-amyloid, early soluble forms of abnormal tau (not the final neurofibrillary tangle) may be the trigger for cell death.
Transgenic mouse models have played a big role in pushing forward tau research because they can be studied methodically for clues to human diseases. For example, the “triple transgenic” mouse forms plaques and tangles similar to those in human AD over time in brain regions. Another new transgenic mouse model, which contains only human tau, forms clumps of damaging tau filaments in a region-specific fashion similar to that seen in humans with AD.
AD and Other Neurodegenerative DiseasesStudies of brain abnormalities resulting from common mechanisms in a number of neurodegenerative diseases are providing important insights into AD. Diseases such as AD, Lewy body disease, Huntington’s disease, frontotemporal dementia, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), Parkinson’s disease, and Creutzfeldt-Jacob disease have similar clinical symptoms, including memory loss, movement problems, and sleep-wake disorders.
People with any of these disorders also exhibit the same pathological hallmark—misfolded and mutant proteins in the brain. Under normal conditions, most misfolded proteins are either repaired or degraded, but when too many of these proteins are produced over a long period of time, the body’s repair and clearance process may be overwhelmed. The toxic misfolded proteins accumulate and lead to the age-related neurodegenerative disorder.
In 2007, several studies provided valuable insights into how this process may occur and why some neurodegenerative diseases have overlapping features.
AD and AgingAnother set of insights about AD derives from an apparent risk factor common to a number of neurodegenerative diseases: aging itself. Age-related changes, such as inflammation, changes in expression of certain proteins, and the generation of free radicals, may precede, follow, or exacerbate the neuronal damage that occurs in AD. In addition, age-related changes in one or more of the hundreds of varieties of proteins could result in inefficient functioning of certain synapses, predisposing neurons to failed communication and death. Scientists are investigating all of these possibilities.
Until recently, scientists believed that neurons in mammals were formed only during the fetal period and for a short time after birth. The belief was that once a mammal had reached a certain level of maturity early in life, neurons could only be lost. The notion that new neurons could develop later in life was radical. Finding that this was true, in fact, the case was revolutionary.
This shift in thinking over the past few years was based on studies showing that neurogenesis (the formation of new neurons) takes place in the adult brain, at least in a limited number of brain regions, such as the hippocampus. Neurogenesis declines during aging but can be stimulated by environmental influences, including physical activity and learning tasks.
This evidence raises a big question: Do these new neurons actually help brain regions function or are they merely a reservoir to replace dying neurons? Several recent studies, conducted by scientists from Johns Hopkins University, the Chicago Medical School of the Rosalind Franklin University of Medicine and Science, and the University of Arizona, have helped answer this question.
In studies with mice and rats, investigators showed that new neurons produced in the adult hippocampus are better able to adapt (an attribute called “plasticity”) and to mature (Ge et al., 2007). In fact, they found that because of their enhanced “excitability,” new neurons may help process information and form memories in the hippocampus (Ramirez-Amaya et al., 2006). The researchers also found that certain types of stress disrupted neurogenesis by decreasing the survival of the new neurons (Thomas et al., 2007).
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