What we do The brain has evolved to allow animals to move around in their environments and learn from their experiences. Such learning is essential for survival and reproductive success, and so the nervous system has evolved an enormous array of learning mechanisms, termed plasticity mechanisms, to put in its survival toolkit. These plasticity “tools” are not only used for the purposes of learning and memory, but also for the normal development of the nervous system.
Brain Plasticity by Professor Cliff Abraham
Professor Cliff Abraham, co-director of Brain Research NZ – Ranghau Roro Aotearoa, has research interest in neural mechanisms of memory. He has played a leading role in promoting neuroscience research and teaching at the University of Otago and has promoted neuroscience at a national level by serving as chair of the Australasian Winter Conference on Brain Research, New Zealand’s annual neuroscience meeting in Queenstown, for 12 years.
The brain has evolved to allow animals to move around in their environments and learn from their experiences. Such learning is essential for survival and reproductive success, and so the nervous system has evolved an enormous array of learning mechanisms, termed plasticity mechanisms, to put in its survival toolkit. These plasticity “tools” are not only used for the purposes of learning and memory, but also for the normal development of the nervous system.
Is it possible that the same plasticity mechanisms that contribute to normal brain functions, such as learning, and memory, can also be used to recover from brain injury and to fight brain disease? There is now a considerable amount of evidence that this is indeed the case, although the molecular mechanisms of each part of the puzzle are so complicated that it is extremely challenging to put them together for a full understanding. Still, one piece at a time, the international community is making progress.
My lab team, together with many colleagues at Otago and elsewhere, has been undertaking basic neuroscience research in an attempt to understand the mechanisms of memory storage, with the aim and hope that understanding these normal mechanisms will provide insights into what goes wrong in memory disorders such as Alzheimer’s disease and how to treat them.
It is now clear that a fundamental element of memory storage is the experience-dependent changing of the communication between neurons at their synaptic connections. Strengthening some connections while weakening others helps the specific neural circuits activated by experience to become better connected than before and thus more easily reactivated during memory retrieval.
Working with Professor Warren Tate and Associate Professor Joanna Williams at Otago, we have been investigating the roles of genes and proteins in memory mechanisms, using animal and cellular models. When changing the structure and function of a nerve cell’s connections, the production of proteins is ramped up by the cell’s molecular machinery, often directed by specific changes in the expression of memory-related genes. Existing and new proteins are modified, shuttled into (or out of) the synaptic contact zones, and the synaptic structures physically change shape as supported and directed by the enzymes manipulating the pool of proteins in the cell.
In Alzheimer’s disease, these processes slowly begin to unravel. The processes of synaptic strengthening and enlargement become impaired, while synaptic weakening and shrinking become more prevalent. As these processes begin in some of the key brain regions for storage of personal memories, such as the hippocampus and its connected brain regions, it is no surprise that early signs of Alzheimer’s include impairment of the storage of new memories. While frequently termed a loss of short-term memory, this actually represents a loss of the ability to convert perfectly gained short-term memory into the long-tern memory store that lasts hours, days, weeks and years. Already formed long-term memories are at first preserved, but then gradually deteriorate as the dementia progresses into its more severe forms.
So, what can be the link between the synaptic plasticity processes of normal memory and the synaptic plasticity failure mechanisms that underpin memory decline? Not surprisingly there are many possible mechanistic connections. However, my lab is focusing on one particular protein that we believe plays a central role in both processes. The story begins with a large protein called amyloid precursor protein (APP for short). This parent protein not only supports brain development and synaptic connectivity, but it can also be chopped up by enzymes into smaller pieces that themselves have important functions in the cell.
One of the key daughter proteins of APP is termed secreted APP-alpha (we’ll call it sAPPa for short). We have shown that this protein plays a particularly important role in the synaptic strengthening that underlies normal memory function. Either reducing the production of this sAPPa with drugs, or blocking its function with antibodies, impairs synaptic strengthening and memory. These deficits are very reminiscent of what happens when memory is impaired in Alzheimer’s disease, as discussed above. Remarkably, we can rescue synaptic function and memory under these impairment conditions by providing the protein back to the impaired cells as if it were a drug itself.
We have gone on to show that sAPPa operates by activating the expression of certain genes, quietening down the activity of other genes, and elevating the production of particular proteins near where they are needed, at the synapses. It also drives the insertion of vital proteins underpinning memory-related synaptic strengthening into those synaptic contact zones. Others have also shown that the loss of sAPPa reduces the number of synaptic contacts, and that delivering more sAPPa to the network helps restore their number.
Does a loss of sAPPa occur during Alzheimer’s disease? There is very good evidence now that this indeed happens. Moreover, the loss of sAPPa correlates rather well with an increase of a different product of APP, termed amyloid-beta (A-beta), which is a much smaller protein fragment. Importantly, a single APP protein can be chopped into either sAPPa or A-beta, but not both. So, in Alzheimer’s disease, the processing of APP changes to producing more A-beta. When there is too much A-beta around, it binds together and forms large aggregates that are toxic to nerve cells. In the extreme, the A-beta aggregates so much that they become visible with a standard microscope, while causing brain inflammation and even more impaired function.
Putting these findings together, it is now evident that altered APP processing in Alzheimer’s disease produces a double whammy effect. There is less of the sAPPa that is helpful for neural connectivity, synaptic strengthening and memory, and more of the A-beta that is toxic. What can we do about this problem?
In collaboration with Associate Professor Stephanie Hughes’ team, we have completed a trial using gene therapy in a mouse model of Alzheimer’s disease to elevate the levels of sAPPa protein in that key memory structure, the hippocampus. After injecting into the hippocampus, a very large number of viral particles (not dangerous or disease-causing!) loaded with the gene for sAPPa, we found that after 2-6 months this treatment restored the ability for normal synaptic plasticity and hippocampus-dependent spatial memory. Interestingly, this rescue of function did not reduce the production or aggregation of the A-beta peptide, meaning that function was rescued even in the face of ongoing neuropathology. We concluded that the treatment increased the resilience of the brain to pathology, and this could be the wave of the future for brain disease treatments generally. We also call this effect an example of increasing “cognitive reserve”.
Thankfully, similar work has been reported by a team in Germany, so we believe that we have come across a very robust and reliable effect. Unfortunately, we are not yet ready for a clinical trial. It is not realistic to think that we can undertake gene therapy in millions of people with dementia by using intracranial injections. Moreover, this method of treatment does not spread to the whole brain. So, we need methods and approaches that don’t involve neurosurgery to deliver the needed protein to the brain.
The alternative is to deliver treatments peripherally, such as by intravenous injection or orally. But then the treatments have to find their way across the “blood-brain barrier”, evolved to protect the brain from most outside influences, letting in only the nutrients needed to sustain the brain cells. Thus, we need to adopt strategies that circumvent this barrier. One strategy is to identify very small fragments of the sAPPa protein that are nonetheless still functional and helpful for memory yet are more able to cross the blood-brain barrier than a large protein such as sAPPa. The other is to develop virus-based gene therapies that can sneak through the barrier. We are currently working flat out on both approaches, both of which are showing very early but promising signs.
It is intriguing to think that societies may be already self-medicating to enhance brain resilience and cognitive reserve. The incidence of Alzheimer’s is going down in western countries at least for people of a given age band. Better healthcare, better education, better diet, more awareness of the importance of exercise and social connectedness are almost certainly playing a role. If we can find additional means of staving off the cognitive and physical decline through therapies, then the onset of Alzheimer’s may be pushed so far back as to be much less consequential to our quality of life during ageing.
In closing I want to thank our funding agencies. The Neurological Foundation of New Zealand has given us significant amounts of funding over the years to support our work in this area. Thus, your donations have made a real difference to us, as have your tax dollars, some of which channel to the Health Research Council which also funds our work. We hope that we can repay that faith.
Brain Plasticity by Professor Cliff Abraham
Professor Cliff Abraham, co-director of Brain Research NZ – Ranghau Roro Aotearoa, has research interest in neural mechanisms of memory. He has played a leading role in promoting neuroscience research and teaching at the University of Otago and has promoted neuroscience at a national level by serving as chair of the Australasian Winter Conference on Brain Research, New Zealand’s annual neuroscience meeting in Queenstown, for 12 years.
The brain has evolved to allow animals to move around in their environments and learn from their experiences. Such learning is essential for survival and reproductive success, and so the nervous system has evolved an enormous array of learning mechanisms, termed plasticity mechanisms, to put in its survival toolkit. These plasticity “tools” are not only used for the purposes of learning and memory, but also for the normal development of the nervous system.
Is it possible that the same plasticity mechanisms that contribute to normal brain functions, such as learning, and memory, can also be used to recover from brain injury and to fight brain disease? There is now a considerable amount of evidence that this is indeed the case, although the molecular mechanisms of each part of the puzzle are so complicated that it is extremely challenging to put them together for a full understanding. Still, one piece at a time, the international community is making progress.
My lab team, together with many colleagues at Otago and elsewhere, has been undertaking basic neuroscience research in an attempt to understand the mechanisms of memory storage, with the aim and hope that understanding these normal mechanisms will provide insights into what goes wrong in memory disorders such as Alzheimer’s disease and how to treat them.
It is now clear that a fundamental element of memory storage is the experience-dependent changing of the communication between neurons at their synaptic connections. Strengthening some connections while weakening others helps the specific neural circuits activated by experience to become better connected than before and thus more easily reactivated during memory retrieval.
Working with Professor Warren Tate and Associate Professor Joanna Williams at Otago, we have been investigating the roles of genes and proteins in memory mechanisms, using animal and cellular models. When changing the structure and function of a nerve cell’s connections, the production of proteins is ramped up by the cell’s molecular machinery, often directed by specific changes in the expression of memory-related genes. Existing and new proteins are modified, shuttled into (or out of) the synaptic contact zones, and the synaptic structures physically change shape as supported and directed by the enzymes manipulating the pool of proteins in the cell.
In Alzheimer’s disease, these processes slowly begin to unravel. The processes of synaptic strengthening and enlargement become impaired, while synaptic weakening and shrinking become more prevalent. As these processes begin in some of the key brain regions for storage of personal memories, such as the hippocampus and its connected brain regions, it is no surprise that early signs of Alzheimer’s include impairment of the storage of new memories. While frequently termed a loss of short-term memory, this actually represents a loss of the ability to convert perfectly gained short-term memory into the long-tern memory store that lasts hours, days, weeks and years. Already formed long-term memories are at first preserved, but then gradually deteriorate as the dementia progresses into its more severe forms.
So, what can be the link between the synaptic plasticity processes of normal memory and the synaptic plasticity failure mechanisms that underpin memory decline? Not surprisingly there are many possible mechanistic connections. However, my lab is focusing on one particular protein that we believe plays a central role in both processes. The story begins with a large protein called amyloid precursor protein (APP for short). This parent protein not only supports brain development and synaptic connectivity, but it can also be chopped up by enzymes into smaller pieces that themselves have important functions in the cell.
One of the key daughter proteins of APP is termed secreted APP-alpha (we’ll call it sAPPa for short). We have shown that this protein plays a particularly important role in the synaptic strengthening that underlies normal memory function. Either reducing the production of this sAPPa with drugs, or blocking its function with antibodies, impairs synaptic strengthening and memory. These deficits are very reminiscent of what happens when memory is impaired in Alzheimer’s disease, as discussed above. Remarkably, we can rescue synaptic function and memory under these impairment conditions by providing the protein back to the impaired cells as if it were a drug itself.
We have gone on to show that sAPPa operates by activating the expression of certain genes, quietening down the activity of other genes, and elevating the production of particular proteins near where they are needed, at the synapses. It also drives the insertion of vital proteins underpinning memory-related synaptic strengthening into those synaptic contact zones. Others have also shown that the loss of sAPPa reduces the number of synaptic contacts, and that delivering more sAPPa to the network helps restore their number.
Does a loss of sAPPa occur during Alzheimer’s disease? There is very good evidence now that this indeed happens. Moreover, the loss of sAPPa correlates rather well with an increase of a different product of APP, termed amyloid-beta (A-beta), which is a much smaller protein fragment. Importantly, a single APP protein can be chopped into either sAPPa or A-beta, but not both. So, in Alzheimer’s disease, the processing of APP changes to producing more A-beta. When there is too much A-beta around, it binds together and forms large aggregates that are toxic to nerve cells. In the extreme, the A-beta aggregates so much that they become visible with a standard microscope, while causing brain inflammation and even more impaired function.
Putting these findings together, it is now evident that altered APP processing in Alzheimer’s disease produces a double whammy effect. There is less of the sAPPa that is helpful for neural connectivity, synaptic strengthening and memory, and more of the A-beta that is toxic. What can we do about this problem?
In collaboration with Associate Professor Stephanie Hughes’ team, we have completed a trial using gene therapy in a mouse model of Alzheimer’s disease to elevate the levels of sAPPa protein in that key memory structure, the hippocampus. After injecting into the hippocampus, a very large number of viral particles (not dangerous or disease-causing!) loaded with the gene for sAPPa, we found that after 2-6 months this treatment restored the ability for normal synaptic plasticity and hippocampus-dependent spatial memory. Interestingly, this rescue of function did not reduce the production or aggregation of the A-beta peptide, meaning that function was rescued even in the face of ongoing neuropathology. We concluded that the treatment increased the resilience of the brain to pathology, and this could be the wave of the future for brain disease treatments generally. We also call this effect an example of increasing “cognitive reserve”.
Thankfully, similar work has been reported by a team in Germany, so we believe that we have come across a very robust and reliable effect. Unfortunately, we are not yet ready for a clinical trial. It is not realistic to think that we can undertake gene therapy in millions of people with dementia by using intracranial injections. Moreover, this method of treatment does not spread to the whole brain. So, we need methods and approaches that don’t involve neurosurgery to deliver the needed protein to the brain.
The alternative is to deliver treatments peripherally, such as by intravenous injection or orally. But then the treatments have to find their way across the “blood-brain barrier”, evolved to protect the brain from most outside influences, letting in only the nutrients needed to sustain the brain cells. Thus, we need to adopt strategies that circumvent this barrier. One strategy is to identify very small fragments of the sAPPa protein that are nonetheless still functional and helpful for memory yet are more able to cross the blood-brain barrier than a large protein such as sAPPa. The other is to develop virus-based gene therapies that can sneak through the barrier. We are currently working flat out on both approaches, both of which are showing very early but promising signs.
It is intriguing to think that societies may be already self-medicating to enhance brain resilience and cognitive reserve. The incidence of Alzheimer’s is going down in western countries at least for people of a given age band. Better healthcare, better education, better diet, more awareness of the importance of exercise and social connectedness are almost certainly playing a role. If we can find additional means of staving off the cognitive and physical decline through therapies, then the onset of Alzheimer’s may be pushed so far back as to be much less consequential to our quality of life during ageing.
In closing I want to thank our funding agencies. The Neurological Foundation of New Zealand has given us significant amounts of funding over the years to support our work in this area. Thus, your donations have made a real difference to us, as have your tax dollars, some of which channel to the Health Research Council which also funds our work. We hope that we can repay that faith.
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