Community Research and Development Information Service - CORDIS

Periodic Report Summary 1 - APPTOTAU (Elucidating pathways from hereditary Alzheimer mutations to pathological tau phenotypes)

Project objectives
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 Abeta plaque deposition and Tau neurofibrillary tangle formation. While therapies targeting Abeta plaques have been developed, not much is known about the events that lead to the formation of Tau pathology and no drugs exist that target Tau. Here we aim to generate a screening system in human induced pluripotent stem cell (iPSC) derived AD-patient neurons to identify novel (drugable) pathways that regulate Tau, and contribute to early Tau pathology, in human AD-patient neurons.
The objectives of this project are:
1) Discover novel pathways that connect hereditary Alzheimer’s mutations in APP to Tau tangle formation.
2) Map these pathways in detail and design (chemical) interventions to decrease Tau pathology in human AD-patient neurons.
3) Determine the pathological effects of early Tau pathology on AD-relevant phenotypes such as microtubule transport and synaptic plasticity in human iPSC-derived neurons, and rescue these pathological effects with potential drug-candidates.

Work performed since the beginning of the project and main results.
In order to discover novel pathways that connect mutations in APP to Tau tangle pathology, a unbiased screening set-up was optimized. For this screen, induced iPSC-derived neurons from a patient with a familial duplication of the APP gene were grown in the lab and treated with >1600 different chemical compounds. 65 compounds that potently reduced phosphorylated Tau (pTau) were selected for validation. Among these were known pTau regulators such as drugs that alter microtubule dynamics but also a number of drugs that target cell-biological pathways that were previously unrecognized in the regulation of Tau pathology. In particular, a number of compounds that target cholesterol-metabolism were identified as regulators of pTau in these APP-duplication patient neurons. This pathway was mapped in more detail. First it was shown that lowering cholesterol decreases pTau in multiple APP-duplication AD patients as well as in a high number of other familial- and sporadic Alzheimer’s disease patient neurons and “control” neurons from healthy subject. Furthermore, it was found that cholesterol also regulates Abeta generation, but that the effect of cholesterol-metabolism on pTau was independent of APP and Abeta. The pathways by which cholesterol regulates pTau were mapped to show that cholesterol alters the rate by which pTau is degraded in the neuron. These discoveries indicated that cholesterol is a upstream regulator of both major AD-pathologies (Abeta and pTau) independently and therefore could be a primary driving factor in AD.

Expected final results and their potential impact and use.
In the last year of the project, the role of cholesterol in AD will be further studied. pTau is considered to be toxic for neurons as it interferes with transport of numerous nutrients through neurons, eventually causing synaptic dysfunctions and disrupting communication between neurons. It will be tested whether treating high pTau AD-neurons with cholesterol-reducing drugs can correct neuronal transport and synaptic function.
This is important for our understanding of AD, and future treatment plans. A high number of AD-cases is caused by genetic variants in genes that regulate cholesterol-metabolism, but it was previously unknown how this was coupled to AD-pathology. The results from this proposal indicate that alterations in cholesterol metabolism can drive Tau pathology. This also indicates, that (at least a subset) of AD-patients could benefit from treatment with cholesterol-reducing agents. Indications for this already exist, as people who take statins (cholesterol-reducing drugs) have been reported to have lower AD-incidence. The results here (1) substantiate the rationale that reducing cholesterol in AD-patients could be beneficial and prevent AD and (2) provide new cholesterol-targeting drug-candidates that can reduce Tau pathology in AD patients. As AD is a major medical problem and has a huge emotional and financial burden on the European population, there is large potential that these results can improve AD treatment, reduce AD incidence and reduce the economic costs of AD in the future. Based on the fundamental new findings here, new treatment plans and new drugs can be tested in clinical trials in human AD-patient populations within the next 5 years. If these treatments indeed prove successful, they are predicted to decrease the number of people that develop Alzheimer’s disease in the next two decades.


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Life Sciences
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