Research into thinking and remembering brought mixed results in 2006: remarkable discoveries in some areas and exposure of the need to pause and reassess approaches in others.
A hallmark of Alzheimer’s disease pathology is the presence of beta-amyloid plaques in the brains of patients. Over the past decade or so, scientists have focused much of their work on these physical manifestations of the disease with the idea that if they could prevent the plaques from forming or remove them, they could mitigate the behavioral impact of the disease.
However, several groups reported data in 2006 suggesting that these plaques themselves may not be the underlying cause of the disease. The beta-amyloid plaques are aggregates of a small peptide that is clipped off a larger protein called the amyloid precursor protein and released into the space between neurons. Previous work with mice that express human amyloid precursor protein demonstrated that behavioral abnormalities, such as deficits in spatial memory, are apparent well before the plaques appear. Thus either the protein fragments are not the problem or smaller aggregations, which do not look like plaques, are damaging the neurons.
Hundreds or thousands of protein fragments make up a single plaque, but Sylvain Lesné at the University of Minnesota Medical School in Minneapolis and colleagues found that small aggregates of just 12 fragments appeared at the same time as the animals’ memory started to fail.
Moreover, when the researchers purified these small clumps from the brains of diseased animals and injected them into the brains of healthy animals, the healthy animals lost their ability to learn the physical layout of a maze. The research was reported in Nature.1
Similarly, researchers at the Buck Institute for Age Research in Novato, California, reported in Proceedings of the National Academy of Sciences that if the engineered mice expressed a protein variant from which beta-amyloid cannot be released, the mice lacked the plaques typical of Alzheimer’s but still developed memory problems.2
The culprit in these animals appeared to be a different small fragment of amyloid precursor protein called C-31. The researchers conclude that the plaques that lie between the neurons may start the problem but C-31 may strike the final blow by getting inside the nerve cells. The investigators from each group hypothesize that drugs that block either the formation of the small clumps or the release of C-31 may help limit the symptoms and damage of Alzheimer’s in humans.
Research involving humans also is calling into question the importance of beta-amyloid plaques as a cause of Alzheimer’s disease symptoms. Scientists have known for decades that not all individuals with plaques develop the disease. To find out how common it is for healthy adults to have plaques in their brains, researchers led by David Bennett of the Rush Alzheimer’s Disease Center at the University of Chicago have been following more than 2,000 healthy adults in two different communities. They reported their findings in Neurology.3
Study participants undergo neuropsychological testing each year to ensure that they are free of dementia at the end of their life. Yet, of the 134 participants who have died and donated their brains for postmortem evaluation, 2 had plaques in the neocortex of their brains and thus had a high likelihood of Alzheimer’s disease, on the basis of current pathology criteria, and another 48 had evidence of plaques in the limbic regions of their brains, which corresponds to an intermediate risk. The only difference Bennett and colleagues found in mental functioning between these 50 patients and the remaining 84 participants, who lacked evidence of plaques, was a slight drop in the functioning of their episodic, or event-driven, memory.
Bennett’s team drew two conclusions from these data. First, they suggest that even minor decreases in episodic memory may be a sign of early Alzheimer’s. Second, humans generally have more neurons than are needed for daily living, which the researchers call a “neurological reserve.” Thus many people can tolerate a significant amount of neuronal damage and Alzheimer’s disease pathology without showing dramatic memory loss or dementia.
Just what allows some patients with plaques to remain healthy while others, with the same amount of neuropathology, develop the disease is a key question and one many researchers are now focusing on.
Who Converts to Full-Blown Alzheimer’s
Related research sheds light on why not all older adults who develop memory problems will develop full-blown Alzheimer’s. There is no established test to distinguish between patients who will remain stable and those whose condition will deteriorate further. Such information would help physicians counsel patients and their families and develop care plans for individuals who are likely to convert to Alzheimer’s disease. Two studies reported in 2006 make significant strides in that direction.
In one study, researchers at the New York State Psychiatric Institute and Columbia University in New York, led by Matthias Tabert, followed 63 healthy adults and 148 patients with mild cognitive impairment, an intermediate state between normal memory functioning and dementia. The researchers report in Archives of General Psychiatry that within three years 34 patients with mild cognitive impairment converted to Alzheimer’s disease.4
The team found that patients with mild cognitive impairment whose only deficit was in memory were at relatively low risk of deteriorating, with only 2 out of the 20 patients in this group developing Alzheimer’s. By contrast, half of the 64 patients who originally had memory problems but also other cognitive deficits developed Alzheimer’s disease during the same period of time. Thus, neuropsychological testing of patients with mild cognitive impairment may differentiate between those two situations and predict who is at highest risk of further problems.
Meanwhile, researchers at the University of California in Los Angeles used physical characteristics to identify the patients with mild cognitive impairment who were at higher risk for developing Alzheimer’s.5 Using high-resolution magnetic resonance imaging, they reported in Archives of Neurology that patients who had less volume in the hippocampus were at greater risk of converting to Alzheimer’s disease than were those with greater volume. Additionally, patients who later converted to full-blown disease had more atrophy in a certain region of the hippocampus at the start of the study than the patients who remained stable. If we are going to be successful in developing treatments to either prevent or delay the onset of Alzheimer’s disease, identifying these “pre-Alzheimer’s” cases is essential.
A Cause of Frontotemporal Dementia
Although Alzheimer’s disease is the most talked-about form of dementia, it is not the only one. Frontotemporal dementia is the second most common dementia in people younger than 65. Patients with this type of dementia display abnormal behavior including personality changes and a lack of inhibition. They generally maintain their memory function, however.
Frontotemporal dementia has a strong genetic component, and mutations in a protein called microtubule-associated protein tau are already known to cause some forms of the disease. However, for patients who do not have tau gene mutations, the cause of the disease has been unknown. Two research groups found in 2006 that these patients have mutations in the gene for a growth factor called progranulin.
This gene is expressed in a wide variety of neurons in the cortex of the brain and in microglial cells, which are the immune cells of the brain. In two studies reported in Nature, the researchers hypothesize that progranulin is important for neuronal survival and that loss of even one copy of the progranulin gene is sufficient to cause neurodegeneration.6,7 In animal models, progranulin appears to induce the expression of other growth factors, which might contribute to cell survival.
The identification of the mutation that underlies this type of frontotemporal dementia opens avenues for the development of new therapies for these patients.
In Normal Memory, a Big Step Forward
Scientists have long hypothesized that memories are stored via changes in the strength of the synaptic connections between neurons. If so, then when a memory is laid down the strength of the synapse increases, as does its ability to communicate with its neighbor.
This process is called long-term potentiation, or LTP. Three studies now provide key evidence that LTP is the neural foundation that gives rise to memory.
Researchers have focused on three criteria: blocking LTP with chemical inhibitors should prevent learning, learning a specific task or information should invoke LTP in the brain region that handles that type of information, and wiping out LTP with chemicals after learning should cause amnesia and eliminate the learned behavior.
|Thanks for the memory : Researchers have found that long-term potentiation, which gives rise to memory, depends on a protein called PKM-zeta. When the protein is blocked, rats forget behavior they have learned. (Illustration by Benjamin Reece) |
Previous research demonstrated that the first criterion was met. In one of the experiments in 2006, Jonathan Whitlock and colleagues at the Howard Hughes Medical Institute and the Massachusetts Institute of Technology trained rats to avoid the dark region in their cage by giving them a mild electric shock when they entered it. The group reported in Science that as the animals learned this spatial information, LTP occurred in the animals’ hippocampi, which is the site of spatial learning in rodents.8
Agnès Gruart of the Universidad Pablo de Olavide in Sevilla, Spain, reported similar results in the Journal of Neuroscience.9 That team found that learning induced LTP in the hippocampus of mice and that drugs which prohibited neural transmission blocked both learning and LTP formation.
A group led by Eva Pastalkova at the SUNY Downstate Medical Center in Brooklyn, New York, took this idea one step further in a study they reported in the same issue of Science. They showed that when LTP was chemically reversed, the animals forgot their learned behavior.10 The treatment, however, did not preclude all synaptic transmission, nor did it prevent subsequent learning.
These studies provide important evidence that the longstanding hypothesis of how memories form is likely correct.