Major breakthrough in Alzheimer research: Looking for Alzheimer's causes at cellular level

Jul 23, 2010

(PhysOrg.com) -- Researchers from the University of Sydney's Alzheimer's and Parkinson's Disease Laboratory have achieved a major breakthrough by finding the causes of Alzheimer's disease at a cellular level and thereby identifying a potential therapy as a result.

The groundbreaking new study led by Professor Jürgen Götz and Dr Lars Ittner, based at the University's Brain and Mind Research Institute (BMRI), is published today in the prestigious international scientific journal Cell.

The researchers have discovered how a protein called TAU affects and mediates the toxicity of amyloid-b, which together with TAU causes the symptoms of Alzheimer's disease.

Professor Götz said this significant breakthrough made by Dr Ittner and their team has implications for how the disease develops and how it may be treated.

"Alzheimer's disease is a major health threat to Australia's ," he said.

"More than 250,000 Australians are currently diagnosed with dementia, with numbers reaching epidemic proportions. Of all diseases with a , Alzheimer's is the most prevalent, predicted to affect one in 85 people globally by 2050."

"The main clinical feature of Alzheimer's disease is a progressive loss of cognition, accompanied by aggression and mood disturbance, and eventually, the patients need to be institutionalised. The toll of Alzheimer's disease on the patients, their families and the caretakers is enormous. And unfortunately, to date Alzheimer's disease is incurable."

"A handful of approved drugs provide if at all only very modest symptomatic relief, without curing the disease. Therefore, to develop effective treatments, it is absolutely necessary that the basic mechanisms underlying these disorders be understood. This was our challenge."

The brain of all Alzheimer's patients is characterized by two types of insoluble deposits; amyloid-b plaques and neurofibrillary tangles, the latter formed by the protein TAU.

In a milestone work published in Science in 2001, Professor Götz had already showed that the two hallmark proteins amyloid-b and TAU act together in disease, but their exact connection remained unexplained.

"It was always clear to me that finding this link could be the key to understanding the disease," Professor Götz said.

Dr Ittner said they focused on the relationship between the two, which produced a finding that challenges the accepted research paradigm.

"TAU was always thought to be a protein exclusively localised to the axons of neurons, but at the same time amyloid-b exerts its toxic effects at the dendritic site of the synapse, which is at the other end of the neuron," he said.

"The more data we obtained the clearer it became to us that TAU must have an as yet unrecognised function in the dendrite, so finally we had to break with the dogma of TAU being an exclusively axonal protein."

It was this thinking that achieved the major breakthrough.

The researchers found that TAU is essential for the positioning of yet another protein, the kinase FYN, at the dendritic site of the synapse, which then renders the neuron vulnerable to amyloid-b.

"By genetically deleting TAU or introducing a non-functional variant of TAU, we found we could prevent the development of symptoms in mouse models of Alzheimer's disease."

"These mice showed normal survival and their memory appeared to be perfectly fine."

In the second part of the study, Professor Götz and Dr Ittner explored the potential of their discovery for a treatment of Alzheimer's disease.

"We translated our findings into a novel therapeutic approach by using a small peptide that mimics the effects of removing TAU from the synapse, and we were thrilled to see that this not only fully prevented the pathology in our Alzheimer's disease models but cleared their memory deficits," Dr Ittner said.

"Although there is still a long way to go we believe we may have found a way of treating Alzheimer's disease," adds Professor Götz.

This breakthrough has encouraged Professor Götz and Dr Ittner in their endeavours to find a cure for . Their teams at the University of Sydney's renowned Brain and Mind Research Institute (BMRI) will continue in their determination to find a cure.

Explore further: Cell death proteins key to fighting disease

More information: Cell: www.cell.com/

Provided by University of Sydney

5 /5 (17 votes)

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baudrunner
not rated yet Jul 23, 2010
Amyloid-b aggregations actually accumulate near the neuron's calcium ion channels, effectively propping them open, which leads to a flood of calcium ions invading the host cell, which then compromise the Tau protein, which is the protein responsible for maintaining the structural integrity of the three-dimensional scaffolding of the cell, after which the cell collapses, and rips apart through apoptosis, or cell suicide. To get at the root cause of Altzheimer's, Gotz should discover how the amyloid-b protein is malformed in the hydrophobic layer of the cell wall, where technically no enzymatic action should take place, since enzymes require a water molecule to catalyze a reaction. Vernon Ingram, who originated molecular medicine, was at the stage of addressing this issue when he passed away at the age of 82. There is possibly a static binding site on the normal amyloid protein precursor which picks up an errant oxygen molecule which fell off its hemoglobulin receptor site.
baudrunner
not rated yet Jul 23, 2010
So how does an oxygen molecule fall of the receptor site of the hemoglobin transporter molecule? It is known that receptor sites on normal cells get "tired" and withdraw into the cell wall after expelling the blocker molecule to regenerate. This is what happens in the ecstasy user's brain when the flood of serotonin molecules have saturated the dendritic serotonin receptors to the point that they expel the serotonin and withdraw into the cell wall, no longer able to provide the euphoric buzz that serotonin is responsible for. It is for this reason that ecstasy users get depressed, because all of the serotonin gets broken up by monoamine oxidase and it takes about two weeks to rebuild the serotonin supply in the serotonin dedicated neuron. Altzheimer's patients are old, and their hemoglobin is not as fresh as when they were young. Maybe iron supplements can help to prolong the course of the disease, but there is likely no cure.
Nartoon
not rated yet Jul 24, 2010
What a time to be a mouse. They can cure Cancer, Alzheimers, and any number of other diseases in mice, but they are all years away from even human trials. These diseases and more are killing millions of people yearly in the world, why not let a few terminal patients choose to trial these breakthroughs, I'm sure they wouldn't mind, and normal testing could continue as well so as not to write off therapies if they don't work on terminal patients. In the case of Alzheimers they can pretty much know when you have it and that it will progress over a few years, while these people are still cognizant let them choose between a test procedure or existing drugs that basically do nothing.

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