In 1991, Professor Heiko Braak of Germany reported a tool that directly measured the development of Alzheimer’s related pathology in patients. Braak graded the presence, distribution, and density of tau tangles in the brain and defined six distinct stages of Alzheimer’s progression (Braak stages).
The TauRx research team built on the findings of Braak and demonstrated a strong correlation between the degree of tau protein neurofibrillary pathology in the brain as measured using Braak staging, the amount of aggregated tau in pre-tangle brain regions and the degree of cognitive incapacitation as measured by scores on the mini mental state exam (MMSE). The Braak neuropathological staging system for Alzheimer’s disease provides a way to directly measure the relationship between tau aggregate formation and cognitive decline (loss of memory).
Clinical Progression Correlates to Braak Stage
- The spread of tau protein aggregates in the brain correlates with clinically observed cognitive deficit and progression of functional brain scan deficit.
- The pattern of distribution and the density of tau protein aggregates throughout the brains of Alzheimer’s patients are very similar.
- Neurofibrillary tangles first form in the medial temporal lobe regions of the brain, then spread into the limbic and neocortical regions.
- The basis for this neuroanatomical spread has been established recently in mouse models where abnormal tau can be exchanged between neurons. In effect, the early stage aggregates of tau (oligomers) act as infectious particles, spreading the pathology from one brain region to the next.
- Once initiated inside a neuron, the tau aggregation cascade, is self-replicating, consuming the normal tau pool in the cell, and converting it to toxic aggregates which continue to accumulate to the point of destruction of the neuron. By end-stage, there is almost complete conversion of normal tau protein into the aggregated form.
Reference Braak and Braak. (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239-259.
TauRx’s second-generation tau aggregation inhibitor (TAI) is a novel chemical form of methylthioninium (MT). In its chloride salt form (methylene blue, or methylthioninium chloride (MTC)) it is an active moiety with a long history of use in the treatment of a variety of conditions.
It works by undoing the tangles that cause dementia, thereby slowing and potentially even stopping memory loss. This second-generation investigational drug has improved bioavailability, tolerability and safety profile compared with its predecessor, rember®, which was used in Phase 2 clinical trials in Alzheimer’s.
TauRx has “composition of matter” patents and “use” patents covering the application of its TAIs for the treatment and prevention of Alzheimer’s and FTD. The company is also exploring the use of TAIs in several other neurodegenerative diseases associated with tau pathology, as well as other disorders deriving from the aggregation of other proteins in the brain, including Parkinson’s disease and Huntington’s disease.