Researchers have found an imaging method that enables the visualisation of tau protein in the brains of living patients. This technique could provide new insights in Alzheimer’s and other neurodegenerative diseases which involve tau protein malfunction.
Tau proteins are important for the stabilisation of microtubules, especially in the brain. In Alzheimer’s disease, they are deposited in neurones, forming neurofibrillary tangles. It is still unknown if their role in Alzheimer’s disease is causal or not, but fact is that the amount of neurofibrillary tangles increases as the disease progresses. Finding a way of tracking the distribution of tau protein is thus an important goal in Alzheimer’s research.
Based on what they knew about the chemical structure of tau protein, researchers synthesised a class of fluorescent tau ligands, PBBs. By comparing their binding distribution with that of PIB, a previously confirmed biomarker of amyloid-ß, the other hallmark Alzheimer protein, they selected the three PBBs most suitable for live tau imaging. In mouse models, both in vitro and in vivo, the researchers established the affinity of PBBs for tau lesions, the absence of nonspecific binding to other compounds in the brain and their ability to cross the blood-brain barrier. The researchers then intravenously injected PBBs in live mice and thanks to their fluorescence could track their distribution in the brain. Importantly, the researchers established that PBB retention differed sufficiently between transgenic mice with a human tau protein mutation and normal controls.
Moving on from mouse models, the team conducted a small exploratory clinical trial with Alzheimer’s patients. The two biomarkers for tau and amyloid-ß were radioactively labelled, so that the patients’ brains could be scanned using positron emission tomography (PET). Interestingly, the spatial distribution of PBB3 (tau) overlapped far better than PIB (amyloid-ß) with the brain regions implicated in cognitive decline in Alzheimer’s. Previously, our neuropathological knowledge of Alzheimer’s came from post-mortem histological assays, which are difficult to link to behavioural characteristics of Alzheimer patients. This new live imaging method will hopefully begin to bridge the neuroscientific gap between biology and psychology in Alzheimer’s disease and other tauopathies.
This article was published in I, Science, Winter 2013
Source: Maruyama, M. et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 79, 1094-1108 (2013).
 phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazoliums, for the eager chemists amongst you.