Differentiated target-driven approach developing precision immunotherapy.

We are targeting the single-most noxious protein responsible for dissemination of tau pathology in the Alzheimer’s brain.

Numerous studies have suggested that tau spreading in AD begins with release of an abnormal form of tau from neurons in the region of the brain known as the entorhinal cortex and its subsequent internalization by synaptically connected neurons.  Repetition of this process ultimately leads to disseminated tau pathology causing extensive and widespread brain damage.

However, a significant gap has existed regarding the specific nature of the tau species responsible for spreading as well as a lack of distinction made between pathological and pathogenic forms. This has led to often misleading data from poorly designed preclinical models and repeated failures in human clinical trials

TauC3 a C-terminally truncated form of tau which correlates with cognitive decline at the earliest stages of AD, is by far the most noxious form of tau and long been known to precede and drive formation of intracellular tangles.

TC3B hypothesizes that soluble oligomers composed of tauC3, also play an essential role in the spreading of tau pathology whereas other tau species do not. 

TauC3 is produced from full-length tau (FLT) by caspase-3 cleavage at the C-terminus.  TauC3 has a much higher propensity to aggregate than does FLT and rapidly forms soluble high molecular weight (sHMW) oligomeric tau.  Soluble HMW tauC3 containing oligomers are released by presynaptic neurons, rapidly internalized by postsynaptic neurons and transported within axons.

In contrast, insoluble tau fibrils and low molecular weight tau are only inefficiently internalized by neurons suggesting that they do not contribute significantly to the spread of tau in AD.