Treatment of neurodegenerative diseases (AD)
The aim of this project is to screen different plant extracts and monosubstances for their ability to attenuate pathology in mouse models of Alzheimer’s disease (AD).
Our research will (i) help to find new drugs against the disease, (ii) provide valuable new insights into its pathogenesis and (iii) identify novel targets and optimal time windows for treatment of patients.
The experiments will be carried out in mice. Including experimental animals, breeding animals for experiments and strain maintenance, and siblings with undesired genotypes, this application describes the use of up to 15,996 animals with a maximum severity grade of “mild”.
The 3 Rs were taken into consideration during the planning of this project. The development of neurodegenerative diseases involves a complex interplay of different cell types in three-dimensional tissues. To date, there are no in vitro models that can effectively reproduce these complex settings to deliver reliable results. Thus, animal models are required to identify therapeutic targets and optimal time windows for effective treatment of neurodegenerative diseases. Moreover, before drugs can advanced to clinical studies in humans, animal models provide an inevitable mean to exclude severe side effects. While we cannot replace certain experiments, we reduce animal numbers by phasing experiments in such a way that only research paths yielding statistically significant and thus relevant results will be pursued further, hence minimizing the number of animals needed to obtain robust results. Furthermore, all methods and animal models that we plan to use in this project have been established in our research group for a while. All treatments which can cause pain or significant stress in animals will be performed under general anaesthesia. Thus, we expect the harm inflicted on the animals to be minimal.
Our research will (i) help to find new drugs against the disease, (ii) provide valuable new insights into its pathogenesis and (iii) identify novel targets and optimal time windows for treatment of patients.
The experiments will be carried out in mice. Including experimental animals, breeding animals for experiments and strain maintenance, and siblings with undesired genotypes, this application describes the use of up to 15,996 animals with a maximum severity grade of “mild”.
The 3 Rs were taken into consideration during the planning of this project. The development of neurodegenerative diseases involves a complex interplay of different cell types in three-dimensional tissues. To date, there are no in vitro models that can effectively reproduce these complex settings to deliver reliable results. Thus, animal models are required to identify therapeutic targets and optimal time windows for effective treatment of neurodegenerative diseases. Moreover, before drugs can advanced to clinical studies in humans, animal models provide an inevitable mean to exclude severe side effects. While we cannot replace certain experiments, we reduce animal numbers by phasing experiments in such a way that only research paths yielding statistically significant and thus relevant results will be pursued further, hence minimizing the number of animals needed to obtain robust results. Furthermore, all methods and animal models that we plan to use in this project have been established in our research group for a while. All treatments which can cause pain or significant stress in animals will be performed under general anaesthesia. Thus, we expect the harm inflicted on the animals to be minimal.
Etterevaluering
Betydelig belastende
Begrunnelse for etterevalueringen
The aim of the investigations was to determine the effects of different treatments on the modulation of Alzheimer’s disease (AD) in mouse models of this disease.
The researchers have performed investigations of plant extracts and re-purposed compounds used to treat other diseases and assessed their effects to prevent (early effects) or reduce the deposition (late effects) of beta-amyloid in the brain of the experimental mice.
The responsible researcher states that the group now has a much better understanding of which points in time are crucial for the specific treatment start in the model system.
The research group has performed evaluation experiments using different treatment paradigms (depending on disease progression) and different treatments (extracts/drugs). They are now able to determine when a specific drug acting on beta-amyloid production or the inflammatory reaction against beta-amyloid could be used. The extracts/drugs aiming at the inflammatory component of the disease progression have a much later effect than those aiming at the production/export of beta-amyloid. These results have been published as part of an article summarizing the group`s work of the past years (Bascuñana P et al. 2022, PMID: 36830699). The results from using DMF for AD treatment have been published in a separate article (Möhle L et al. 2021, PMID: 34233173).
The responsible researcher states that the research group can confirm that under specific conditions, an immunomodulatory or anti-inflammatory treatment could be effective at later stages during the disease course of AD.
This opens for detailed clinical studies for testing several available anti-inflammatory treatments in patients.
The results of the current and earlier experiments help to understand the full picture of disease progress and the need for the right points in time for starting a specific treatment.
Despite the differences between mice and humans, the knowledge of the disease progress and development in mice together with the time-course in humans enables the researchers to compare these effects also with the situation ‘early versus late’ in AD patients. Until now, it has not been clear how the modulation of the inflammatory component of AD influences the onset and the progression of AD. The researchers are now able to state that late treatment could still have beneficial effects for patients, not just early start as previously often anticipated. Through these data, the researchers are now able to open a wider treatment window for patients.
The models used in the experiments are until now the models which are best understood. Despite several caveats with transgene models for AD, long-term experience and thorough characterization (more than a decade) are key factors to interpret the results from animals with respect to possible translation to patients.
However, one important difference exists that needs to be considered when transferring data from mouse experiments to patients; mice have a milder neuronal loss than patients have. Therefore, for the transfer of results these differences must be taken into serious consideration. In patients the neuronal loss and the deposition of hyperphosphorylated tau protein is one of the hallmarks for clinical progress.
570 animals have been used for treatment experiments with plant extracts or compounds (moderate severity, daily gavage). 355 animals were used to induce Cre-recombination with tamoxifen (moderate, injections). 5023 animals were used for strain maintenance, breeding and post-mortal tissue collection (mild severity). All maintained strains are not affected by obvious phenotypes (mild severity).
The initial application included all groups that might be needed for generating biological and statistical meaningful results. The calculated total number is high, but all animals will probably not be needed in the final setup when integrating all preliminary results into the experimental flow.
The responsible researcher states that the group always revises the setup by reducing the numbers of animals or experiments (reducing costs, reducing animals, reducing work force) if the first preliminary results enable the researchers to determine the treatment effects.
The plan of the setup is to be able to transfer the data from mouse experiments directly to patients, as the research group already has done (e.g. www.renovare-500.com).
Due to the Covid-19 situation from spring 2020 and the partial closure of the university and lab facilities, the research group was not able to perform all planned experiments.
Despite the recent developments of new in vitro models for brain structure investigations, the investigation of neurodegenerative diseases relies on animal disease models to generate the pathological protein deposition and the tissue reaction as well as the gradual neuronal loss.
The experiments have given the research group detailed insights in the effects of different preparations of medications. For later medical application, the preparation determines the rate of absorbance and finally also the biological effects in vivo.
The animals in the treatment groups were treated daily by oral gavage. The responsible researcher states that the mice did not experience negative effects, due to careful and experienced performance of the procedure.
The researchers have performed investigations of plant extracts and re-purposed compounds used to treat other diseases and assessed their effects to prevent (early effects) or reduce the deposition (late effects) of beta-amyloid in the brain of the experimental mice.
The responsible researcher states that the group now has a much better understanding of which points in time are crucial for the specific treatment start in the model system.
The research group has performed evaluation experiments using different treatment paradigms (depending on disease progression) and different treatments (extracts/drugs). They are now able to determine when a specific drug acting on beta-amyloid production or the inflammatory reaction against beta-amyloid could be used. The extracts/drugs aiming at the inflammatory component of the disease progression have a much later effect than those aiming at the production/export of beta-amyloid. These results have been published as part of an article summarizing the group`s work of the past years (Bascuñana P et al. 2022, PMID: 36830699). The results from using DMF for AD treatment have been published in a separate article (Möhle L et al. 2021, PMID: 34233173).
The responsible researcher states that the research group can confirm that under specific conditions, an immunomodulatory or anti-inflammatory treatment could be effective at later stages during the disease course of AD.
This opens for detailed clinical studies for testing several available anti-inflammatory treatments in patients.
The results of the current and earlier experiments help to understand the full picture of disease progress and the need for the right points in time for starting a specific treatment.
Despite the differences between mice and humans, the knowledge of the disease progress and development in mice together with the time-course in humans enables the researchers to compare these effects also with the situation ‘early versus late’ in AD patients. Until now, it has not been clear how the modulation of the inflammatory component of AD influences the onset and the progression of AD. The researchers are now able to state that late treatment could still have beneficial effects for patients, not just early start as previously often anticipated. Through these data, the researchers are now able to open a wider treatment window for patients.
The models used in the experiments are until now the models which are best understood. Despite several caveats with transgene models for AD, long-term experience and thorough characterization (more than a decade) are key factors to interpret the results from animals with respect to possible translation to patients.
However, one important difference exists that needs to be considered when transferring data from mouse experiments to patients; mice have a milder neuronal loss than patients have. Therefore, for the transfer of results these differences must be taken into serious consideration. In patients the neuronal loss and the deposition of hyperphosphorylated tau protein is one of the hallmarks for clinical progress.
570 animals have been used for treatment experiments with plant extracts or compounds (moderate severity, daily gavage). 355 animals were used to induce Cre-recombination with tamoxifen (moderate, injections). 5023 animals were used for strain maintenance, breeding and post-mortal tissue collection (mild severity). All maintained strains are not affected by obvious phenotypes (mild severity).
The initial application included all groups that might be needed for generating biological and statistical meaningful results. The calculated total number is high, but all animals will probably not be needed in the final setup when integrating all preliminary results into the experimental flow.
The responsible researcher states that the group always revises the setup by reducing the numbers of animals or experiments (reducing costs, reducing animals, reducing work force) if the first preliminary results enable the researchers to determine the treatment effects.
The plan of the setup is to be able to transfer the data from mouse experiments directly to patients, as the research group already has done (e.g. www.renovare-500.com).
Due to the Covid-19 situation from spring 2020 and the partial closure of the university and lab facilities, the research group was not able to perform all planned experiments.
Despite the recent developments of new in vitro models for brain structure investigations, the investigation of neurodegenerative diseases relies on animal disease models to generate the pathological protein deposition and the tissue reaction as well as the gradual neuronal loss.
The experiments have given the research group detailed insights in the effects of different preparations of medications. For later medical application, the preparation determines the rate of absorbance and finally also the biological effects in vivo.
The animals in the treatment groups were treated daily by oral gavage. The responsible researcher states that the mice did not experience negative effects, due to careful and experienced performance of the procedure.