Final Report Summary - ECMNEURO (Perineuronal net treatments for neurodegenerative disease)
ECMNeuro, summary of outcomes.
The main concept of ECMNeuro was to develop a new set of ideas and methods for restoring memory in neurodegenerative diseases such as Alzheimer’s disease. The overall concept was that it should be possible to make the brain work better and restore memory function in brains damaged by these diseases despite the presence of disease pathology. At the time the grant began and now there is no treatment that can stop the progression of Alzheimer’s disease, so cognitive enhancement treatments that enable the brain to continue to function in the presence of disease damage are therefore the best options. The idea was to use reactivated plasticity to enable to brain to rewire itself to bypass the neurons damaged by the disease and so restore function. Having established this principle the next step was planned to be the development of new pharmaceutical compounds for treatment of memory loss. As detailed below, the project has achieved these aims. It has also moved into an associated area, the loss of memory in ageing. It has found out why memory becomes less effective with age and shown how memory might be restored.
1. Restoring memory in a model of Alzheimer’s disease.
Alzheimer’s disease produces two types of brain pathology, plaques and tangles, and it is mainly the tangles formed of tau protein that damage neurons. A model of Alzheimer’s disease in which a mutant form of tau protein is produced in the mouse brain gave Alzheimer’s-like pathology and profound loss of several types of memory from 4 months of age. Plasticity was re-activated in these animals by injecting the enzyme chondroitinase, which digests the cartilage-like perineuronal nets that surround some neurons to turn off plasticity. Animals treated with these injections showed a complete recovery of function in several types of memory. This confirmed the principle that memory can be restored by re-activating plasticity.
Unfortunately chondroitinase is not suitable for treating Alzheimer’s disease because it has to be injected directly into the brain. Alternatives were therefore sought. Antibodies are now used for treating several types of disease, so various antibodies that bind to perineuronal nets were screened. One of these, CAT-316, can block the inhibitory properties of perineuronal nets and this antibody was shown to be very effective at restoring memory in the Alzheimer’s animals.
The perineuronal nets act in various ways, including through binding to effector molecules. One of these, Semaphorin 3A, has been identified and is a potential future treatment target.
Memory loss in ageing and its restoration
Even without Alzheimer’s disease aged humans suffer deficits in forming and retrieving memories. Testing aged mice showed a similar memory deficit, beginning at 18 months and worsening until animals are incapacitated by old age (around 24 months). Because of the effectiveness of chondroitinase-mediated plasticity activation in Alzheimer’s models, the same treatment was tested in ageing. The effect was a robust restoration of memory, which indicated that perineuronal nets might be involved in the loss of memory with ageing. An examination of the changes in composition of perineuronal nets with age showed a strong change in the type of sulphation of the net proteoglycans. As animals become aged, almost all the 6-sulphated proteoglycans disappear to be replaced by 4-sulphated proteoglycans. 6-sulphated proteoglycans are permissive to plasticity, while the 4-sulphated type are inhibitory. This led to the hypothesis that memory is lost in ageing due to the perineuronal nets becoming increasingly inhibitory due to loss of 6-sulphated proteoglycans. This was tested by using transgenic animals which lack the 6-sulphation enzyme, leading to very inhibitory nets and low plasticity. As predicted, these animals show profound memory loss and other ageing-related changes very early in life. On the other hand, replacing 6-sulphated proteoglycan in aged animals restores their memory to normal. The conclusion is that loss of 6-sulphated proteoglycan in perineuronal nets with ageing leads to memory loss.
Producing new treatments for memory loss.
A useful treatment for memory loss in Alzheimer’s disease and ageing would ideally be medicine that could be taken by mouth. Suitable pharmaceuticals have therefore been sought for. One possible treatment is to inhibit the formation of perineuronal nets. The backbone of the nets is a sugar chain called hyaluronan, produced by hyaluronan synthase. An orally-administered inhibitor of hyaluronan synthase, 4MU, is already a licenced medicine for liver conditions. This compound is currently being trialled in rodents for promoting recovery after spinal cord injury and for memory restoration. The compound is well tolerated and can enter the brain and spinal cord, where it inhibits the formation of perineuronal nets. Treatment improves recovery of function after spinal cord injury in rodents. Tests on memory restoration are starting.
A second approach is to change the sulphation pattern of the perineuronal nets. These become inhibitory in old age due to an excess of inhibitory 4-sulphated proteoglycan, and blocking 4-sulphated proteoglycan with an antibody was an effective memory restorant in Alzheimer’s models. Small molecule pharmaceuticals that block the enzyme responsible for 4-sulphation are therefore under development. The design of these molecules is based on computer modelling of the structure of the enzyme, and on modification of compounds that are effective on similar enzymes. At present three families of effective and specific compounds have been found which work at a suitable concentration. These compounds are being further modified to enhance their effectiveness and to enable them to penetrate into brain cells where the enzyme is situated.
Overall, ECMNeuro has developed a set of new concepts and treatments that may be used in the future to restore memory in aged people and those suffering from neurodegenerative diseases.
The main concept of ECMNeuro was to develop a new set of ideas and methods for restoring memory in neurodegenerative diseases such as Alzheimer’s disease. The overall concept was that it should be possible to make the brain work better and restore memory function in brains damaged by these diseases despite the presence of disease pathology. At the time the grant began and now there is no treatment that can stop the progression of Alzheimer’s disease, so cognitive enhancement treatments that enable the brain to continue to function in the presence of disease damage are therefore the best options. The idea was to use reactivated plasticity to enable to brain to rewire itself to bypass the neurons damaged by the disease and so restore function. Having established this principle the next step was planned to be the development of new pharmaceutical compounds for treatment of memory loss. As detailed below, the project has achieved these aims. It has also moved into an associated area, the loss of memory in ageing. It has found out why memory becomes less effective with age and shown how memory might be restored.
1. Restoring memory in a model of Alzheimer’s disease.
Alzheimer’s disease produces two types of brain pathology, plaques and tangles, and it is mainly the tangles formed of tau protein that damage neurons. A model of Alzheimer’s disease in which a mutant form of tau protein is produced in the mouse brain gave Alzheimer’s-like pathology and profound loss of several types of memory from 4 months of age. Plasticity was re-activated in these animals by injecting the enzyme chondroitinase, which digests the cartilage-like perineuronal nets that surround some neurons to turn off plasticity. Animals treated with these injections showed a complete recovery of function in several types of memory. This confirmed the principle that memory can be restored by re-activating plasticity.
Unfortunately chondroitinase is not suitable for treating Alzheimer’s disease because it has to be injected directly into the brain. Alternatives were therefore sought. Antibodies are now used for treating several types of disease, so various antibodies that bind to perineuronal nets were screened. One of these, CAT-316, can block the inhibitory properties of perineuronal nets and this antibody was shown to be very effective at restoring memory in the Alzheimer’s animals.
The perineuronal nets act in various ways, including through binding to effector molecules. One of these, Semaphorin 3A, has been identified and is a potential future treatment target.
Memory loss in ageing and its restoration
Even without Alzheimer’s disease aged humans suffer deficits in forming and retrieving memories. Testing aged mice showed a similar memory deficit, beginning at 18 months and worsening until animals are incapacitated by old age (around 24 months). Because of the effectiveness of chondroitinase-mediated plasticity activation in Alzheimer’s models, the same treatment was tested in ageing. The effect was a robust restoration of memory, which indicated that perineuronal nets might be involved in the loss of memory with ageing. An examination of the changes in composition of perineuronal nets with age showed a strong change in the type of sulphation of the net proteoglycans. As animals become aged, almost all the 6-sulphated proteoglycans disappear to be replaced by 4-sulphated proteoglycans. 6-sulphated proteoglycans are permissive to plasticity, while the 4-sulphated type are inhibitory. This led to the hypothesis that memory is lost in ageing due to the perineuronal nets becoming increasingly inhibitory due to loss of 6-sulphated proteoglycans. This was tested by using transgenic animals which lack the 6-sulphation enzyme, leading to very inhibitory nets and low plasticity. As predicted, these animals show profound memory loss and other ageing-related changes very early in life. On the other hand, replacing 6-sulphated proteoglycan in aged animals restores their memory to normal. The conclusion is that loss of 6-sulphated proteoglycan in perineuronal nets with ageing leads to memory loss.
Producing new treatments for memory loss.
A useful treatment for memory loss in Alzheimer’s disease and ageing would ideally be medicine that could be taken by mouth. Suitable pharmaceuticals have therefore been sought for. One possible treatment is to inhibit the formation of perineuronal nets. The backbone of the nets is a sugar chain called hyaluronan, produced by hyaluronan synthase. An orally-administered inhibitor of hyaluronan synthase, 4MU, is already a licenced medicine for liver conditions. This compound is currently being trialled in rodents for promoting recovery after spinal cord injury and for memory restoration. The compound is well tolerated and can enter the brain and spinal cord, where it inhibits the formation of perineuronal nets. Treatment improves recovery of function after spinal cord injury in rodents. Tests on memory restoration are starting.
A second approach is to change the sulphation pattern of the perineuronal nets. These become inhibitory in old age due to an excess of inhibitory 4-sulphated proteoglycan, and blocking 4-sulphated proteoglycan with an antibody was an effective memory restorant in Alzheimer’s models. Small molecule pharmaceuticals that block the enzyme responsible for 4-sulphation are therefore under development. The design of these molecules is based on computer modelling of the structure of the enzyme, and on modification of compounds that are effective on similar enzymes. At present three families of effective and specific compounds have been found which work at a suitable concentration. These compounds are being further modified to enhance their effectiveness and to enable them to penetrate into brain cells where the enzyme is situated.
Overall, ECMNeuro has developed a set of new concepts and treatments that may be used in the future to restore memory in aged people and those suffering from neurodegenerative diseases.