Final Report Summary - APPTOTAU (Elucidating pathways from hereditary Alzheimer mutations to pathological tau phenotypes)
Elucidating pathways from hereditary Alzheimer mutations to pathological tau phenotypes
Alzheimer’s disease (AD) is the leading cause of dementia and an estimated 46 million people in the world live with Alzheimer’s disease (AD) or related dementias. AD is a devastating medical problem with enormous emotional and financial burden on the aging European population. Two well established molecular hallmarks of AD are Amyloid-beta plaque deposition and Tau neurofibrillary tangle formation. For years, major drug development efforts have been focused on removing Amyloid-beta from the AD-patient brain in order to halt, or reverse, disease progression. The treatment is based on the hypothesis that Amyloid-beta is the driver of AD-pathogenesis by induction of Tau hyperphosphorylation, Tau aggregation and subsequent death of brain cells. Unfortunately, amyloid-targeting therapies although successful in removing Amyloid-beta, have not been successful in halting the cognitive decline in AD-patients. This indicates that other processes, besides Amyloid-beta, in the AD-brain could contribute to Tau pathology and neurodegeneration.
Here we took an unbiased approach to identify new cellular pathways, and interventional drugs, that can inhibit Tau pathology in AD-patient neurons. For this we generated induced-pluripotent stem-cell (iPSC)-derived neurons from a hereditary AD patient that exhibits AD pathology, increased Amyloid-beta secretion and Tau hyperphosphorylation, “in a dish”. By expanding these neurons at a large scale, we were able to test >1700 repurposed drugs (e.g. drugs that currently are being used for another disease indication) for their efficacy to reduce Tau pathology in AD-neurons. We identified over 70 drugs that could potentially be used to target Tau in AD. Most interesting was a group of drugs (statins) that target cholesterol metabolism. Polymorphisms in genes that regulate cholesterol-metabolism have previously been shown to increase the risk for AD, increased levels of neuronal cholesterol enhance Amyloid-beta generation and long-term statins usage is associated with lower AD incidence. An effect of cholesterol metabolism on Tau however is not known.
We found that statins by inhibition of cholesterol synthesis reduced Tau-pathology in iPSC-derived neurons from all subjects tested including familial and sporadic AD-neurons, as well as in healthy control neurons. This indicates that cholesterol metabolism is a broadly conserved molecular regulator of Tau biology. We found that statins were able to reduce the levels of phosphorylated Tau (pTau) by activation of the proteasome system that degrades pTau thereby preventing its (pathogenic) accumulation. While statins could reduce pTau levels, they did not do this very efficiently, but required high levels of drugs that are unlikely to be achieved in patient brain. In addition, at these high concentration statins were toxic for astrocytes indicating that they are not ideal drugs to target Tau pathology in AD-patients. Based on our findings however, we discovered other, more specific cholesterol-targeting drugs that reduced pTau by targeting cholesterol-export, that are currently further exploited a potential drugs for clinical use.
In addition, we showed that the regulation of Tau pathology by cholesterol-metabolism is not dependent on Amyloid-beta. As previously reported, we also confirmed that cholesterol metabolism regulates the generation of (toxic) Amyloid-beta in our AD-patient neurons. Reducing cholesterol levels, through statins or the novel cholesterol-targeting drugs discovered in the project, reduced both Amyloid-beta and pTau. By genetic modification of the Amyloid-precursors protein we generated mutant iPSC-derived neurons in which lowering cholesterol did no longer reduce Amyloid-beta levels. While in these neurons, Amyloid-beta was no longer decreased by statins, we found that lowering cholesterol still potently reduced pTau. Similar results were obtained in iPSC-derived neurons that did not express the Amyloid-precursor protein at all. Together, these results indicate Amyloid-beta and Tau are co-regulated by cholesterol, yet that the effect of cholesterol on Tau is Amyloid-beta independent. This has important consequences for our understanding of AD aetiology and treatment; simply removing Amyloid-beta from the brain by Amyloid-targeting therapies might not suffice to halt the progression of cholesterol-induced Tau pathology and neurodegeneration in AD patients. In addition, a high number of AD-cases is driven by genetic variants in genes that regulate cholesterol-metabolism, but it was previously unknown how precisely this was coupled to AD-pathology. The results from this proposal indicate that alterations in cholesterol metabolism can directly drive Tau pathology, thereby greatly contributing to disease pathologies. This also indicates, that (at least a subset) of AD-patients could benefit from treatment with cholesterol-reducing agents, which will be further exploited in the future.
As discussed above we have discovered a number of novel, and more specific, cholesterol-targeting drugs. We are currently working to advance these drugs into clinical testing in AD-patients. The hypothesis that these would either halt disease progression or prevent AD from occurring when taken as preventative drugs. If successful, this would impact the lives of many AD-patient and their caretakers. Stakeholders herein are the general society, medical doctors (clinician neurologists) and pharmaceutical organizations in both the US and the EU. We are working with pharma and AD-clinical centres to test, and further improve these drugs, for clinical use in AD. The findings from this funded research program form the basis for these novel drug discovery efforts. We expect these first novel cholesterol-targeting drugs to be tested in early phase clinical trials within 2-5 years. If successful, these could proceed to late-stage clinical testing and, if effective in reducing cognitive decline, to prescription drugs for AD in 10-15 years.
By discovery of a novel pathway by which cholesterol-regulates Tau pathology, and identification of novel-cholesterol targeting drugs that reduce AD-pathologies, this project is also proof of principle that iPSC-derived patient neurons from individual patients can be used to perform large-scale drug discovery. This has the potential to significantly speed-up drug development for AD, as well as for other neurodegenerative diseases for which there is currently no cure. This affects the manner in which scientist, policy-makers and pharmaceutical companies think about drug-discovery and could economize the development of drugs tailored to specific patients, or group of patients, that suffer for neurodegenerative diseases.
Contact information:
Dr. Rik van der Kant
Vrije Universiteit Amsterdam
W&N building, room B-431
De Boelelaan 1085
1081 HV Amsterdam
The Netherlands
Rikkant@gmail.com
Alzheimer’s disease (AD) is the leading cause of dementia and an estimated 46 million people in the world live with Alzheimer’s disease (AD) or related dementias. AD is a devastating medical problem with enormous emotional and financial burden on the aging European population. Two well established molecular hallmarks of AD are Amyloid-beta plaque deposition and Tau neurofibrillary tangle formation. For years, major drug development efforts have been focused on removing Amyloid-beta from the AD-patient brain in order to halt, or reverse, disease progression. The treatment is based on the hypothesis that Amyloid-beta is the driver of AD-pathogenesis by induction of Tau hyperphosphorylation, Tau aggregation and subsequent death of brain cells. Unfortunately, amyloid-targeting therapies although successful in removing Amyloid-beta, have not been successful in halting the cognitive decline in AD-patients. This indicates that other processes, besides Amyloid-beta, in the AD-brain could contribute to Tau pathology and neurodegeneration.
Here we took an unbiased approach to identify new cellular pathways, and interventional drugs, that can inhibit Tau pathology in AD-patient neurons. For this we generated induced-pluripotent stem-cell (iPSC)-derived neurons from a hereditary AD patient that exhibits AD pathology, increased Amyloid-beta secretion and Tau hyperphosphorylation, “in a dish”. By expanding these neurons at a large scale, we were able to test >1700 repurposed drugs (e.g. drugs that currently are being used for another disease indication) for their efficacy to reduce Tau pathology in AD-neurons. We identified over 70 drugs that could potentially be used to target Tau in AD. Most interesting was a group of drugs (statins) that target cholesterol metabolism. Polymorphisms in genes that regulate cholesterol-metabolism have previously been shown to increase the risk for AD, increased levels of neuronal cholesterol enhance Amyloid-beta generation and long-term statins usage is associated with lower AD incidence. An effect of cholesterol metabolism on Tau however is not known.
We found that statins by inhibition of cholesterol synthesis reduced Tau-pathology in iPSC-derived neurons from all subjects tested including familial and sporadic AD-neurons, as well as in healthy control neurons. This indicates that cholesterol metabolism is a broadly conserved molecular regulator of Tau biology. We found that statins were able to reduce the levels of phosphorylated Tau (pTau) by activation of the proteasome system that degrades pTau thereby preventing its (pathogenic) accumulation. While statins could reduce pTau levels, they did not do this very efficiently, but required high levels of drugs that are unlikely to be achieved in patient brain. In addition, at these high concentration statins were toxic for astrocytes indicating that they are not ideal drugs to target Tau pathology in AD-patients. Based on our findings however, we discovered other, more specific cholesterol-targeting drugs that reduced pTau by targeting cholesterol-export, that are currently further exploited a potential drugs for clinical use.
In addition, we showed that the regulation of Tau pathology by cholesterol-metabolism is not dependent on Amyloid-beta. As previously reported, we also confirmed that cholesterol metabolism regulates the generation of (toxic) Amyloid-beta in our AD-patient neurons. Reducing cholesterol levels, through statins or the novel cholesterol-targeting drugs discovered in the project, reduced both Amyloid-beta and pTau. By genetic modification of the Amyloid-precursors protein we generated mutant iPSC-derived neurons in which lowering cholesterol did no longer reduce Amyloid-beta levels. While in these neurons, Amyloid-beta was no longer decreased by statins, we found that lowering cholesterol still potently reduced pTau. Similar results were obtained in iPSC-derived neurons that did not express the Amyloid-precursor protein at all. Together, these results indicate Amyloid-beta and Tau are co-regulated by cholesterol, yet that the effect of cholesterol on Tau is Amyloid-beta independent. This has important consequences for our understanding of AD aetiology and treatment; simply removing Amyloid-beta from the brain by Amyloid-targeting therapies might not suffice to halt the progression of cholesterol-induced Tau pathology and neurodegeneration in AD patients. In addition, a high number of AD-cases is driven by genetic variants in genes that regulate cholesterol-metabolism, but it was previously unknown how precisely this was coupled to AD-pathology. The results from this proposal indicate that alterations in cholesterol metabolism can directly drive Tau pathology, thereby greatly contributing to disease pathologies. This also indicates, that (at least a subset) of AD-patients could benefit from treatment with cholesterol-reducing agents, which will be further exploited in the future.
As discussed above we have discovered a number of novel, and more specific, cholesterol-targeting drugs. We are currently working to advance these drugs into clinical testing in AD-patients. The hypothesis that these would either halt disease progression or prevent AD from occurring when taken as preventative drugs. If successful, this would impact the lives of many AD-patient and their caretakers. Stakeholders herein are the general society, medical doctors (clinician neurologists) and pharmaceutical organizations in both the US and the EU. We are working with pharma and AD-clinical centres to test, and further improve these drugs, for clinical use in AD. The findings from this funded research program form the basis for these novel drug discovery efforts. We expect these first novel cholesterol-targeting drugs to be tested in early phase clinical trials within 2-5 years. If successful, these could proceed to late-stage clinical testing and, if effective in reducing cognitive decline, to prescription drugs for AD in 10-15 years.
By discovery of a novel pathway by which cholesterol-regulates Tau pathology, and identification of novel-cholesterol targeting drugs that reduce AD-pathologies, this project is also proof of principle that iPSC-derived patient neurons from individual patients can be used to perform large-scale drug discovery. This has the potential to significantly speed-up drug development for AD, as well as for other neurodegenerative diseases for which there is currently no cure. This affects the manner in which scientist, policy-makers and pharmaceutical companies think about drug-discovery and could economize the development of drugs tailored to specific patients, or group of patients, that suffer for neurodegenerative diseases.
Contact information:
Dr. Rik van der Kant
Vrije Universiteit Amsterdam
W&N building, room B-431
De Boelelaan 1085
1081 HV Amsterdam
The Netherlands
Rikkant@gmail.com