Table 3 Opportunities and Challenges of translating preclinical studies of tau

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)