Tangled up in tau

Tau fibrils purified from the brains of people with Alzheimer’s Disease (AD) and injected into the ventral hippocampus of non-transgenic mice eventually produce tau inclusions in brain regions that are anatomically connected to the site of injection. Injection of extracts from brains without tau pathology does not produce the same time-related spread. And neither do recombinant tau fibrils produced synthetically, which are different in conformation. So there must be something special about tau produced within cells.

The hypothesis of cell to cell transmission of tau, and the hypothesis that strain-specific tau underlies different diseases, were explored by Virginia Lee (Perelman School of Medicine, University of Pennsylvania, USA) in a plenary lecture.

Homogenates from the brains of humans with tauopathies induce tau inclusions in the brains of mice, providing support for the transmission hypothesis 

Protein aggregation and progression are common features with neurodegenerative diseases.  Intracellular accumulation of misfolded, hyperphosphorylated tau is a feature not only of Alzheimer’s Disease, but also of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP).

The lesions that typify these conditions can be replicated in mice by intracerebral injection of brain homogenates from people who had tauopathies, and the tau aggregates formed can be propagated between mouse brains. Six to nine months after extracts from AD brains are injected into the ventral hippocampus, pathology is seen, for example, in the locus coeruleus.

Tau filaments propagate themselves and spread cell to cell

In AD, pathology is mainly cortical and the deficits primarily cognitive. In PSP the deficits are primarily motor, and the pathology mainly subcortical. CBD seems a mixture of the two. Different isoforms of tau may be involved.

Injecting wild-type mice with tau taken from human brains with each of the three conditions shows a pattern of regional spread that depends to a large extent on the site of inoculation and the connectome. But there is a suggestion that specific tau isoforms might influence the type of cell affected during this spread. In CBD, for example, it looks as if there may be neuron to astrocyte transfer of tau aggregates.