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New Studies Affirm Tau's Infectious Spread
Cure Alzheimer’s Fund a Longtime Supporter of Tau Research
by Rudy Tanzi
The New York Times has a front-page story on the spreading of tau
pathology from neuron to neuron, citing papers from the laboratories of Dr. Brad Hyman of Massachusetts General Hospital and Dr. Karen Duff of Columbia University. Cure Alzheimer's Fund has been supporting key research along these lines over the past two years, and is playing a major role going forward.
Alzheimer's has two famous hallmarks: Abeta peptide "plaques" outside of brain cells and tau "tangles" inside the cells. In its healthy mode, the tau protein provides "scaffolding" for cell structure. In its pathogenic mode, it forms into tangles which eventually choke and kill the cell.
In 2009, evidence first emerged suggesting that tau pathology (tangles)
spreads from neuron to neuron. Our research, and increasingly that of others, shows that Abeta and tau work together to initiate Alzheimer's disease. The pathology appears to begin with excess clumps of Abeta called oligomers, which then initiate tauopathy (tangles). The tauopathy then spreads from nerve cell to nerve cell.
The first papers showing that tauopathy spreads from neuron to neuron were published in 2009:
Propagation of tau misfolding from the outside to the inside of a cell
Frost B, Jacks RL, Diamond MI.
J. Biol. Chem. 2009 284 (11): 12845-12852. Epub 2009 March 11.
Transmission and spreading of tauopathy in transgenic mouse brain.
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M.
Nat Cell Biol. 2009 Jul;11(7):909-13. Epub 2009 Jun 7.
The 2009 studies initially met with the expected amount of skepticism, but
were later confirmed by other groups, including that of Dr. Virginia Lee at the University of Pennsylvania in her Spring 2011 paper:
Seeding of normal Tau by pathological Tau conformers drives pathogenesis of
Guo JL, Lee VM.
J Biol Chem. 2011 Apr 29;286(17):15317-31. Epub 2011 Mar 3.
After Dr. Lee confirmed the initial studies, Cure Alzheimer's Fund began
supporting studies of spreading tauopathy in her lab. Her subsequent
research has built much of the framework for the studies cited in The New York Times article.
In recent presentations I have been referring to AD as a "beta-amyloid
triggered tauopathy". Genetic studies show that AD begins with excess accumulation of beta-amyloid, but pathology-based studies show that tangles are needed for dementia. If the initial accumulation of excess Abeta in the brain can be stopped, the tauopathy can be nipped in the bud. But once tauopathy starts, both Abeta and Tau need to be attacked because the tauopathy will keep spreading to new brain regions. This is the new paradigm Dr. Lee has been investigating with Cure Alzheimer's support.
Cure Alzheimer's Fund will also soon be funding important new research by Dr. Dennis Selkoe and Dr. Dominic Walsh of Brigham and Women's Hospital in Boston on complementary Tau protein work and the role of Abeta oligomers in driving tangle formation.
Taken together, all of these studies are giving us a much more vivid–and
target-rich–picture of Alzheimer's disease.