NeuRA Magazine #20


A new understanding of the intricate biological steps that lead to the development of Alzheimer’s opens the door to new treatments that could halt the progression of the disease.
“We’ve been looking at Alzheimer’s disease all wrong,” says Prof Lars Ittner, discussing his latest study. “Until now, research has missed the first essential step in the development of Alzheimer’s, which involves tau and its protective effect.”

This startling new discovery is a result of research that Prof Ittner has been conducting since 2010, when he first identified that two proteins – tau and amyloid-beta – together created a toxicity in the brain that lead to Alzheimer’s disease. This work was published in Cell.

To further understand why this toxicity occurred, Prof Ittner recruited his brother, Dr Arne Ittner, a cell biologist, to participate in the study. Together, the brothers worked to understand the complex relationship between tau and amyloid-beta.

This led them to their most recent discovery, which has changed the way they view the development of Alzheimer’s disease altogether. Their study revealed that tau, which has long been thought to contribute to the cell death that leads to Alzheimer’s, actually has a protective effect on the brain in the early stage of disease.

This finding, which was published in the journal Science, overturns previously held ideas of how the disease develops and opens the door to new treatment options that could halt or slow the progression of the AD.

Plaques and tangles
Around 354,000 Australians are living with Alzheimer’s and other dementia-related illnesses. This figure is likely to rise to 900,000 by 2050, unless a treatment is found in the meantime.

There are many theories about what causes Alzheimer’s, but the most well-supported concept involves “plaques” and “tangles”. Plaques are clusters of amyloid-beta, which builds up between nerve cells. And tangles are formed by tau, which accumulates within nerve cells.

The accumulation of these plaques and tangles is associated with degeneration of brain tissue and memory loss. The Ittners’ research has revealed that a crucial step in the process that leads to tangles has been misunderstood.

Initially, it was thought that amyloid-beta prompted a change in tau, causing it to become toxic. However, results from the new study suggest that tau changes itself in order to protect neurons, and that amyloid-beta assaults this protective functionality until it is progressively lost. This is the stage at which toxicity levels cause the destruction of neurons and results in the memory loss and confusion associated with Alzheimer’s disease.

Potential therapy
Their study revealed that a third protein, kinase p38γ, aided tau in its efforts to protect against damage. But, as levels of p38γ became depleted in the brain, so too were the protective benefits reduced.

“This is a change in concept,” Prof Ittner explains. “We have completely changed our view on the whole disease process involving this protein, p38γ, which is central to the disease. When other researchers recognise this, it will change their views on the disease process too.”

Crucially, this study has revealed that p38γ is a potential therapeutic target. Using animal model studies, the brothers found that Alzheimer-like symptoms emerged in mice when p38γ was blocked. When they reintroduced the protein, however, the symptoms disappeared.

“This finding has opened the door to possible treatments, given time,” says Lars. “The protein has a relatively clear function,” adds Arne, which he believes makes it a particularly valuable treatment target.

“As the protein is lost during the progression of the disease, you lose the protective function. But there is still remaining protein left, so if you can stimulate that function, we may be able to delay the onset of deficits.

“The development of therapeutics is a whole different area of research, but this will push the boundaries forward,” says Lars.

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Abdominal muscle stimulation to improve bowel function in spinal cord injury

Bowel complications, resulting from impaired bowel function, are common for people living with a spinal cord injury (SCI). As a result, people with a SCI have high rates of bowel related illness, even compared with those with other neurological disorders. This includes high rates of abdominal pain, constipation, faecal incontinence and bloating. These problems lower the quality of life of people with a SCI and place a financial burden on the health system. A treatment that improves bowel function for people with a SCI should reduce illness, improve quality of life and lead to a large cost saving for health care providers. Bowel problems have traditionally been managed with manual and pharmacological interventions, such as digital rectal stimulation, enemas, and suppositories. These solutions are usually only partially effective, highlighting the need for improved interventions. The abdominal muscles are one of the major muscle groups used during defecation. Training the abdominal muscles should improve bowel function by increasing abdominal pressure. During our previous Abdominal FES research with people with a SCI, we observed that Abdominal FES appeared to lead to more consistent and effective bowel motion. However, this evidence remains anecdotal. As such, we are going to undertake a large randomised controlled trial to investigate the effectiveness of Abdominal FES to improve the bowel function of people with a SCI. This study will make use of a novel measurement system (SmartPill, Medtronic) that can be swallowed to measure whole gut and colonic transit time. We will also assess whether Abdominal FES can change constipation-related quality of life and the use of laxatives and manual procedures, as well as the frequency of defecation and the time taken. A positive outcome from this study is likely to lead to the rapid clinical translation of this technology for people living with a SCI.