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Table 3 Opportunities and Challenges of translating preclinical studies of tau

From: The informed road map to prevention of Alzheimer Disease: A call to arms

Area of focus Model Need Opportunity for translation
Conformational specificity of aggregated tau (disease specific) – Transgenic models/knock in;
– iPSC/iNeuron (mutation related tau/AD; non-genetic disease specific (PSP/CBD))
– Brain organoids
– Greater fidelity to AD: amyloid and tau co-pathology
– Specific ultrastructural conformation of AD tau
– Better evidence of soluble tau/p-tau changes (CSF/blood)
– Expand transgenic tau (MAPT) models to include mutations with evidence of AD type pathology (R406W)
– Establish standards within the preclinical field of testing tau therapeutics that represent multiple conformational species of tau (2).
Soluble (extracellular) vs aggregated tau (biomarker validation) – AD transgenic models (with/without tau injection paradigm)
– iPSC/iNeuron
– Better understanding of the role of extracellular tau and the various truncated p-tau species (impact on neuronal function; response to stressors (e.g. extracellular amyloid)
– Impact of targeting specific soluble tau species in AD prevention
– Determine extent of soluble CSF/plasma tau and p-tau profiles identified in humans with AD and tau transgenics
– Preclinical studies targeting specific kinases related to amino acid specific phosphorylation
– Preclinical studies targeting specific soluble p-tau isoforms
Abeta-tau interaction (AD tauopathy) – Tau injections (AD specific) in AD transgenic models
– Brain organoid
– iPSC/iNeuron models (AD mutations)
– AD specific models that include both Amyloid and tau pathologies (preferably on different APOE backgrounds) – Measurement of soluble tau in Amyloid targeted therapies
Seeding propensity of tau (tau strains) – Transgenic models/knock in;
– iPSC/iNeuron (mutation related tau/AD; non-genetic disease specific (PSP/CBD/sporadic AD))
– Brain organoids (mutation related tau/AD; non-genetic disease specific (PSP/CBD/sporadic AD))
  – Use of Tau PET in preclinical studies (same tracers as in clinical studies)
– Standardize methods for determining seeding propensity of tau for consistent reference across the field
– Include multiple AD patient tau “seeds” in preclinical models that are representative of various clinical features (rapidly progressive vs slowly progressive)