The accumulation of a phosphate-laden, soluble form of tau protein in an important memory center of ageing mice is associated with loss of nerve cell connections or synapses and deterioration of memory, RIKEN researchers have found. Not only does this constitute the first sign of the onset of Alzheimer’s disease (AD), they suggest, but reduction or prevention of the build-up of such hyperphosphorylated tau may well lead to an effective treatment.
Two consistent biochemical hallmarks of AD in the brain are the presence of deposits of misfolded proteins known as amyloid beta plaques and insoluble aggregates of hyperphosphorylated tau proteins inside nerve cells called neurofibrillary tangles (NFT). Tau proteins help stabilize the internal skeleton of cells by interacting with microtubules. They are regulated by phosphates that can attach at various points along the molecule. Both NFTs and amyloid beta plaques form well before the onset of AD, and the role they play has been the subject of intense scrutiny.
In a recent paper in The EMBO Journal (1), researchers from RIKEN’s Brain Science Institute in Wako detail their work using transgenic mice to which a gene for human tau protein had been added together with a promoter to stimulate its activity in the nerve cells of the forebrain after birth. The researchers found that the human tau protein became hyperphosphorylated as the mice aged, but did not form NFTs. There was also no evidence of nerve cell loss.
Using the Morris water maze, whereby mice learn the position of a submerged escape platform in a tank of water by remembering cues to its position, the researchers determined that the transgenic mice also displayed impaired learning ability as they grew older compared with normal mice (Fig. 1). And with manganese-enhanced MRI imaging, a new technique for analyzing brain activity in small animals, they were able to match this with reduced activity and fewer synapses in the entorhinal cortex of the brain, critical to spatial memory. All of this occurred without NFT formation and before any possible appearance of amyloid beta plaques.
“Once NFTs form, we cannot rescue the nerve cells,” says research team spokesman, Akihiko Takashima. “But before the formation of NFTs, tau proteins form small soluble aggregates, and we know of several enzymes that can inhibit this. So we are now trying to detect the aggregates by means of the small compounds which bind to them or through positron emission tomography.”
1. Kimura, T., Yamashita, S., Fukuda, T., Park, J-M., Murayama, M., Mizoroki, T., Yoshiike, Y., Sahara, N. & Takashima, A. Hyperphosphorylated tau in parahippocampal cortex impairs place learning in aged mice expressing wild-type human tau. The EMBO Journal 26, 5143–5152 (2007).
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