8.04.2004
Early Detection, Early Treatment
Aug. 4, 2004 -- Early removal of plaque in the brain is the key to treating Alzheimer's disease, mouse studies suggest.
That's easier said than done, although several anti-plaque treatments are in the pipeline. But the new findings seem to resolve the chicken-or-egg question at the heart of Alzheimer's research.
That crucial question: Which of the two brain lesions found in Alzheimer's patients causes the disease? Is it the plaque that clogs the brain? Or is it the tangled protein that gums up nerve cells?
Frank LaFerla, PhD, and colleagues at the University of California, Irvine, say they have the answer.
"We've demonstrated in the lab that removing plaques from the brain can indeed lead to a total clearance of tangle pathology," LaFerla says in a news release.
The only downside is that the tangles only go away if treatment starts early. Once the tangles reach a certain stage, they stay stuck in the brain after plaque removal.
Plaque and Tangles
The brain uses protein messengers to send and receive various signals. Badly formed proteins act like a monkey wrench in the brain machinery. That's why the brain has a system for clearing away bad proteins.
But the amyloid proteins that make up Alzheimer's plaque somehow defeat this system. They clog up the works. That, LaFerla says, lets Alzheimer's tangles build up.
To prove it, LaFerla's team used a strain of mice that gets both Alzheimer's plaque and Alzheimer's tangles. When given an antibody that makes the immune system destroy plaque, the mouse brains become completely free of plaque. A little later, the tangles go away, too -- unless you wait too long. Once the tangles reach a certain point, even a plaque-free brain can't clear them.
Anti-tangle antibodies removed early tangles. But that didn't make the plaque go away. And the antibodies didn't work on advanced tangles.
The findings appear in the Aug. 5 issue of Neuron.
LaFerla says it's important to find ways to diagnose Alzheimer's disease in its earliest stages so anti-plaque treatments -- once they're perfected -- can work the best. He also says it's important to look for ways to clear late-stage tangles.
"These findings raise the intriguing possibility that a multi-antibody-based approach -- one targeted against [plaque] and one targeted against [tangles] -- may provide the most significant benefit for the treatment of Alzheimer's disease," LaFerla and colleagues write.
Aug. 4, 2004 -- Early removal of plaque in the brain is the key to treating Alzheimer's disease, mouse studies suggest.
That's easier said than done, although several anti-plaque treatments are in the pipeline. But the new findings seem to resolve the chicken-or-egg question at the heart of Alzheimer's research.
That crucial question: Which of the two brain lesions found in Alzheimer's patients causes the disease? Is it the plaque that clogs the brain? Or is it the tangled protein that gums up nerve cells?
Frank LaFerla, PhD, and colleagues at the University of California, Irvine, say they have the answer.
"We've demonstrated in the lab that removing plaques from the brain can indeed lead to a total clearance of tangle pathology," LaFerla says in a news release.
The only downside is that the tangles only go away if treatment starts early. Once the tangles reach a certain stage, they stay stuck in the brain after plaque removal.
Plaque and Tangles
The brain uses protein messengers to send and receive various signals. Badly formed proteins act like a monkey wrench in the brain machinery. That's why the brain has a system for clearing away bad proteins.
But the amyloid proteins that make up Alzheimer's plaque somehow defeat this system. They clog up the works. That, LaFerla says, lets Alzheimer's tangles build up.
To prove it, LaFerla's team used a strain of mice that gets both Alzheimer's plaque and Alzheimer's tangles. When given an antibody that makes the immune system destroy plaque, the mouse brains become completely free of plaque. A little later, the tangles go away, too -- unless you wait too long. Once the tangles reach a certain point, even a plaque-free brain can't clear them.
Anti-tangle antibodies removed early tangles. But that didn't make the plaque go away. And the antibodies didn't work on advanced tangles.
The findings appear in the Aug. 5 issue of Neuron.
LaFerla says it's important to find ways to diagnose Alzheimer's disease in its earliest stages so anti-plaque treatments -- once they're perfected -- can work the best. He also says it's important to look for ways to clear late-stage tangles.
"These findings raise the intriguing possibility that a multi-antibody-based approach -- one targeted against [plaque] and one targeted against [tangles] -- may provide the most significant benefit for the treatment of Alzheimer's disease," LaFerla and colleagues write.
Scientists study how the brain remembers, forgets
WASHINGTON - After decades of studying how memory works, scientists are trying to figure out how we forget.
Their goal is to help people:
Forget painful things they don't want to remember, from an embarrassing moment in high school or a stupid mistake at work on up to a traumatic rape or accident.
Not forget things they do want to remember, such as where they left their keys or the name of the boss's spouse all the way, and slow the devastation of Alzheimer's disease.
Instead of just giving memory tests to people, neuroscientists are using recent technologies that observe the living brain at work, such as fMRI (functional magnetic resonance imaging) and PET (positron emission tomography).
In addition, legions of flies, snails and mice have given up their lives to provide insight into how people remember and forget, since some brain structures and functions are similar in humans and lowly pests.
Forgetting is basically the reverse of remembering. Memories form when new physical and chemical links, called synapses, are created between brain cells, called neurons, or when old synaptic links are strengthened.
An elaborate network of connections, rather like a computer wiring diagram, assembles a memory from separate parts of the brain that process the myriad sights, sounds, words, people, motions and emotions that crowd the senses every waking moment.
This step is known as "consolidation." It occurs when a memory is moved from a short-term holding room - a mental scratchpad called working memory that lasts a few seconds or minutes - to long-term storage elsewhere in the neural network.
When a memory is recalled, the process is called "retrieval." The memory isn't stored in a single place, but reassembled from bits and pieces scattered across the neural network. It never comes back exactly the way it went in because new experiences have reshaped the brain in the interim. Mistaken or garbled memories are common, as detectives and trial jurors learn to their sorrow.
Forgetting can be a failure of either consolidation or of retrieval. In addition, memories may fade or decay over time, or be wiped out by interference from other memories. For example, you probably remember what you had for breakfast yesterday, but not last year. Too many breakfasts have come in between.
Steven Schmidt, a psychologist at Middle Tennessee State University in Murfreesboro, likens forgetting to what happens when a stone is thrown into a lake.
"The lake `remembers' the input of the rock as a series of waves on its surface," he explained in an e-mail. "Consolidation is a process that `holds' that pattern of waves. If consolidation is disrupted, the wave patterns are not retained."
Like a water-skier breaking up the pattern of waves, the release of certain hormones in the brain may halt the process of consolidation. "The memory is simply not fully laid down," Schmidt said.
Interference results when a pattern of activated neurons no longer can be sustained, perhaps because a flood of new information has overwritten the original memory. An analogy would be throwing many rocks into the lake near where the first one hit the water.
"The wave patterns of the more numerous set of rocks will make it difficult to see the waves created by the first rock," Schmidt said.
Failure to retrieve a memory is the inability to access information previously stored in the brain. "In my lake metaphor," he said, "I throw a rock in on one shore and notice the pattern of activation. At a later date I may have difficulty recognizing that pattern on the water if I am standing on the other side of the lake."
Loss of memory also can result from emotional or physical causes, such as a blow to the head, a stroke, an infection or surgery. The brains of Alzheimer's patients are destroyed by plaques and tangles of alien material invading once-healthy neural networks.
This kind of damage "could make old memories inaccessible because the fragments would be present in the cortex, but not connected, so the episode could no longer be reassembled," Joseph LeDoux, a neuroscientist at New York University, wrote in his new book, "Synaptic Self."
"Patients lose memories because they lose the cells and synapses that lead to, or contain, those memories," Ivan Izquierdo, a Brazilian biochemist, said in an e-mail interview from Rio Grande do Sul.
Mansuo Hayashi, a brain researcher at the Massachusetts Institute of Technology in Cambridge, used mutant mice to show what happens when short-term memory isn't consolidated in long-term storage.
By altering a gene, she created a mouse with fewer, but bigger, synapses in the cortex, but left the hippocampus, a region where short-term memories are processed, alone. As a result, her mice learned the location of a platform in their cage, but after a few days they couldn't remember where it was.
"We showed their formation of memories is fine," Hayashi said. "However, their long-term storage is impaired."
In another intriguing experiment, Alison Barth, a neuroscientist at Carnegie Mellon University in Pittsburgh, found a way to make individual mouse neurons glow when they're processing a memory. To accomplish this feat, Barth attached a green fluorescent chemical to a gene that turns on when a nerve cell is activated.
"Our mouse is a novel tool that can be used to visualize, in living brain tissue, a single neuron that has been activated in response to an animal's experience," Barth reported in the July 21 issue of The Journal of Neuroscience. By observing precisely where a memory is forming, she said, scientists will be better able to understand and treat neurological diseases.
Forgetting, or at least reducing, painful memories - known as "therapeutic forgetting" - can be helpful to people such as soldiers or accident or rape victims.
A drug called propranolol can blunt the memory of a trauma, according to James McGaugh, the director of the Center for Neurobiology of Learning and Memory at the University of California, Irvine.
"The drug does not remove the memory - it just makes the memory more normal," McGaugh said in an e-mail report. "It prevents the excessively strong memory from developing, the memory that keeps you awake at night."
"The original memory is not erased," Izquierdo said. "It is literally pushed backstage by other connections. Animals and humans must preserve the memory of frightening events in order to be able to react to them if required, but must keep them sufficiently less accessible if they want to live any life worthy of the name from then on."
Michael Anderson, a psychologist at the University of Oregon in Eugene, used fMRI to find out what happens when people make a conscious effort - without drugs - to forget some words. He discovered that high-level areas of the cortex send signals to suppress low-level activity in the hippocampus, blocking recovery of the words.
"Memory suppression requires people to override or stop the retrieval process," Anderson reported in the Jan. 9 edition of the journal Science. "This work confirms the existence of an active process by which people can prevent awareness of an unwanted past experience. This process causes forgetting."
On the Web:
For more information, go to http://web.mit.edu/picowercenter and type in "memory" as the search term.
WASHINGTON - After decades of studying how memory works, scientists are trying to figure out how we forget.
Their goal is to help people:
Forget painful things they don't want to remember, from an embarrassing moment in high school or a stupid mistake at work on up to a traumatic rape or accident.
Not forget things they do want to remember, such as where they left their keys or the name of the boss's spouse all the way, and slow the devastation of Alzheimer's disease.
Instead of just giving memory tests to people, neuroscientists are using recent technologies that observe the living brain at work, such as fMRI (functional magnetic resonance imaging) and PET (positron emission tomography).
In addition, legions of flies, snails and mice have given up their lives to provide insight into how people remember and forget, since some brain structures and functions are similar in humans and lowly pests.
Forgetting is basically the reverse of remembering. Memories form when new physical and chemical links, called synapses, are created between brain cells, called neurons, or when old synaptic links are strengthened.
An elaborate network of connections, rather like a computer wiring diagram, assembles a memory from separate parts of the brain that process the myriad sights, sounds, words, people, motions and emotions that crowd the senses every waking moment.
This step is known as "consolidation." It occurs when a memory is moved from a short-term holding room - a mental scratchpad called working memory that lasts a few seconds or minutes - to long-term storage elsewhere in the neural network.
When a memory is recalled, the process is called "retrieval." The memory isn't stored in a single place, but reassembled from bits and pieces scattered across the neural network. It never comes back exactly the way it went in because new experiences have reshaped the brain in the interim. Mistaken or garbled memories are common, as detectives and trial jurors learn to their sorrow.
Forgetting can be a failure of either consolidation or of retrieval. In addition, memories may fade or decay over time, or be wiped out by interference from other memories. For example, you probably remember what you had for breakfast yesterday, but not last year. Too many breakfasts have come in between.
Steven Schmidt, a psychologist at Middle Tennessee State University in Murfreesboro, likens forgetting to what happens when a stone is thrown into a lake.
"The lake `remembers' the input of the rock as a series of waves on its surface," he explained in an e-mail. "Consolidation is a process that `holds' that pattern of waves. If consolidation is disrupted, the wave patterns are not retained."
Like a water-skier breaking up the pattern of waves, the release of certain hormones in the brain may halt the process of consolidation. "The memory is simply not fully laid down," Schmidt said.
Interference results when a pattern of activated neurons no longer can be sustained, perhaps because a flood of new information has overwritten the original memory. An analogy would be throwing many rocks into the lake near where the first one hit the water.
"The wave patterns of the more numerous set of rocks will make it difficult to see the waves created by the first rock," Schmidt said.
Failure to retrieve a memory is the inability to access information previously stored in the brain. "In my lake metaphor," he said, "I throw a rock in on one shore and notice the pattern of activation. At a later date I may have difficulty recognizing that pattern on the water if I am standing on the other side of the lake."
Loss of memory also can result from emotional or physical causes, such as a blow to the head, a stroke, an infection or surgery. The brains of Alzheimer's patients are destroyed by plaques and tangles of alien material invading once-healthy neural networks.
This kind of damage "could make old memories inaccessible because the fragments would be present in the cortex, but not connected, so the episode could no longer be reassembled," Joseph LeDoux, a neuroscientist at New York University, wrote in his new book, "Synaptic Self."
"Patients lose memories because they lose the cells and synapses that lead to, or contain, those memories," Ivan Izquierdo, a Brazilian biochemist, said in an e-mail interview from Rio Grande do Sul.
Mansuo Hayashi, a brain researcher at the Massachusetts Institute of Technology in Cambridge, used mutant mice to show what happens when short-term memory isn't consolidated in long-term storage.
By altering a gene, she created a mouse with fewer, but bigger, synapses in the cortex, but left the hippocampus, a region where short-term memories are processed, alone. As a result, her mice learned the location of a platform in their cage, but after a few days they couldn't remember where it was.
"We showed their formation of memories is fine," Hayashi said. "However, their long-term storage is impaired."
In another intriguing experiment, Alison Barth, a neuroscientist at Carnegie Mellon University in Pittsburgh, found a way to make individual mouse neurons glow when they're processing a memory. To accomplish this feat, Barth attached a green fluorescent chemical to a gene that turns on when a nerve cell is activated.
"Our mouse is a novel tool that can be used to visualize, in living brain tissue, a single neuron that has been activated in response to an animal's experience," Barth reported in the July 21 issue of The Journal of Neuroscience. By observing precisely where a memory is forming, she said, scientists will be better able to understand and treat neurological diseases.
Forgetting, or at least reducing, painful memories - known as "therapeutic forgetting" - can be helpful to people such as soldiers or accident or rape victims.
A drug called propranolol can blunt the memory of a trauma, according to James McGaugh, the director of the Center for Neurobiology of Learning and Memory at the University of California, Irvine.
"The drug does not remove the memory - it just makes the memory more normal," McGaugh said in an e-mail report. "It prevents the excessively strong memory from developing, the memory that keeps you awake at night."
"The original memory is not erased," Izquierdo said. "It is literally pushed backstage by other connections. Animals and humans must preserve the memory of frightening events in order to be able to react to them if required, but must keep them sufficiently less accessible if they want to live any life worthy of the name from then on."
Michael Anderson, a psychologist at the University of Oregon in Eugene, used fMRI to find out what happens when people make a conscious effort - without drugs - to forget some words. He discovered that high-level areas of the cortex send signals to suppress low-level activity in the hippocampus, blocking recovery of the words.
"Memory suppression requires people to override or stop the retrieval process," Anderson reported in the Jan. 9 edition of the journal Science. "This work confirms the existence of an active process by which people can prevent awareness of an unwanted past experience. This process causes forgetting."
On the Web:
For more information, go to http://web.mit.edu/picowercenter and type in "memory" as the search term.
