6/15/2016

Researchers Block Action of Alzheimer’s Tau Protein in Mice


NEUROSCIENCE NEWS

Summary: Researchers report a drug called phenylbutyrate may protect against damage caused by the tau protein in Alzheimer’s disease.
Source: Alzheimer’s Research UK.
A research team at King’s College London has used a new approach to study a hallmark dementia protein called tau in mice, revealing that a drug called phenyl butyrate can protect against damage caused by the protein.

The findings are published in the journal Brain and funded by Alzheimer’s Research UK and the Wellcome Trust.
One of the key hallmark features of Alzheimer’s is an abnormal build-up of a protein called tau in the brain, but there are several different neurodegenerative diseases that are caused by abnormal tau. These so-called ‘tauopathies’ can have a range of symptoms from memory and thinking problems to severe movement disorders.

The team, led by Dr Diane Hanger at the Maurice Wohl Clinical Research Institute, King’s College London, studied donated brain tissue from the London Neurodegenerative Diseases Brain Bank at King’s College London. They had previously identified a fragment of tau protein that was found in the brains of people with a tauopathy called progressive supranuclear palsy and wasn’t present in healthy brains.
They bred mice to produce low levels of this form of the tau protein, which they called Tau35. Despite only producing a relatively low level of the protein, the mice developed memory, thinking and movement problems that became progressively worse with age. The findings indicate the importance of the tau protein in orchestrating damage in the brain in diseases like Alzheimer’s. The researchers then studied the function of nerve cells in the mice in more detail. The study revealed that the tau fragment caused defects in how the cells get rid of unwanted or damaged proteins – one mechanism through which tau could damage nerve cells in the brain.

When the mice were eight and a half months old they started experiencing significant memory and motor symptoms. At this stage, they were treated daily for six weeks either with an injection of phenylbutyrate or sterile water as a control. Phenylbutyrate is a drug already used to treat urea cycle disorders – inherited metabolic disorders that affect how ammonia is removed from the bloodstream. Previous research had suggested the drug could target some aspects of Alzheimer’s in mice and it has also been explored in clinical studies for cancer, cystic fibrosis and neurodegenerative diseases like motor neurone disease and Huntington’s disease. After treatment with phenyl butyrate, the mice showed improvements to their memory and motor symptoms suggesting phenylbutyrate could rescue damage caused by the tau protein.

Dr Diane Hanger, said: “Tau protein is becoming an increasingly attractive target for the development of new medicines for dementia, because it’s central to several different neurodegenerative diseases including Alzheimer’s. This new approach to studying the effect of low levels of tau protein in mice helps us to recreate aspects of these diseases in a way that more closely represents what’s seen in patients. By studying these mice, we’re starting to identify key mechanisms driving damage in the brain and we hope that teams across the world can use this method to study these complex diseases and search for new treatments.”
Phenylbutyrate is a drug already being investigated for benefits in a range of conditions and it was interesting to see it may also have the potential to protect against damage caused by tau protein in mice. The findings are an important basis for future drug development studies to understand the mechanism through which phenylbutyrate may protect against neurodegeneration and whether this could point us towards new treatments. In future we’re keen to continue building on our new approach to learn more about the mechanisms driving neurodegeneration in these mice, with the aim of identifying promising targets for the development of new treatments.”
Image shows the tau protein.
After treatment with phenylbutyrate, the mice showed improvements to their memory and motor symptoms suggesting phenylbutyrate could rescue damage caused by the tau protein. NeuroscienceNews.com image is in the public domain.Dr Simon Ridley, Director of Research at Alzheimer’s Research UK, said: “The human brain is a hard-to-reach organ, making it difficult to study the molecular changes in diseases like Alzheimer’s in a living system. This study has allowed the research team to better understand how tau can damage cells in diseases like Alzheimer’s, as well as a range of other neurodegenerative diseases associated with the protein. It’s important to expand the tools researchers have to study the diseases that cause dementia, as they provide a way both to understand these diseases and to screen new drugs.
“While clinical trials in people will always be the gold standard to prove the benefit of any new drug for diseases like Alzheimer’s, research in mice is an important part of the drug development process. We must continue to invest in research to understand the biology of the different forms of dementias as well as using this to narrow down the most promising new therapeutic approaches to drive towards clinical trials.”
ABOUT THIS ALZHEIMER’S DISEASE RESEARCH ARTICLE
Funding: The study was funded by Alzheimer’s Research UK and the Wellcome Trust.
Source: Alzheimer’s Research UK 
Image Source: This NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate” by Marie K. Bondulich, Tong Guo, Christopher Meehan, John Manion, Teresa Rodriguez Martin, Jacqueline C. Mitchell, Tibor Hortobagyi, Natalia Yankova, Virginie Stygelbout, Jean-Pierre Brion, Wendy Noble, and Diane P. Hanger in Brain. Published online June 12 016 doi:10.1093/brain/aww137
Post Polio Litaff, Association A.C _APPLAC Mexico

The Polio Crusade

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Erradicación de La poliomielitis

Polio Tricisilla Adaptada

March Of Dimes Polio History

Dr. Bruno

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A 41-year-old man developed an acute illness at the age of 9 months during which, following a viral illness with headache, he developed severe weakness and wasting of the limbs of the left side. After several months he began to recover, such that he was able to walk at the age of 2 years and later was able to run, although he was never very good at sports. He had stable function until the age of 18 when he began to notice greater than usual difficulty lifting heavy objects. By the age of 25 he was noticing progressive difficulty walking due to weakness of both legs, and he noticed that the right calf had become larger. The symptoms became more noticeable over the course of the next 10 years and ultimately both upper as well as both lower limbs had become noticeably weaker.

On examination there was wasting of the muscles of upper and lower limbs on the left, and massively hypertrophied gastrocnemius, soleus and tensor fascia late on the right. The calf circumference on the right exceeded that on the left by 10 cm (figure1). The right shoulder girdle, triceps, thenar eminence and small muscles of the hand were wasted and there was winging of both scapulae. The right quadriceps was also wasted. The wasted muscles were also weak but the hypertrophied right ankle plantar flexors had normal power. The tendon reflexes were absent in the lower limbs and present in the upper limbs, although the right triceps was reduced. The remainder of the examination was normal.

Figure 1

The patient's legs, showing massive enlargement of the right calf and wasting on the left

Questions

1
What is that nature of the acute illness in infancy?
2
What is the nature of the subsequent deterioration?
3
What investigations should be performed?
4
What is the differential diagnosis of the cause of the progressive calf hypertrophy?

Answers

QUESTION 1

An acute paralytic illness which follows symptoms of a viral infection with or without signs of meningitis is typical of poliomyelitis. Usually caused by one of the three polio viruses, it may also occur following vaccination and following infections with other enteroviruses.1 Other disorders which would cause a similar syndrome but with upper motor neurone signs would include acute vascular lesions, meningoencephalitis and acute disseminated encephalomyelitis.

QUESTION 2

A progressive functional deterioration many years after paralytic poliomyelitis is well known, although its pathogenesis is not fully understood.2 It is a diagnosis of exclusion; a careful search for alternative causes, for example, orthopaedic deformities such as osteoarthritis or worsening scoliosis, superimposed neurological disorders such as entrapment neuropathies or coincidental muscle disease or neuropathy, and general medical causes such as respiratory complications and endocrinopathies.3

QUESTION 3

Investigations revealed normal blood count and erythrocyte sedimentation rate and normal biochemistry apart from a raised creatine kinase at 330 IU/l (normal range 60–120 IU/l), which is commonly seen in cases of ongoing denervation. Electromyography showed evidence of denervation in the right APB and FDI with polyphasic motor units and complex repetitive discharges, no spontaneous activity in the left calf and large polyphasic units in the right calf consistent with chronic partial denervation. Motor and sensory conduction velocities were normal. A lumbar myelogram was normal. Magnetic resonance imaging (MRI) scan of the calves is shown in figure2.

Figure 2

Axial T1 weighted MRI scan (TR 588 ms, TE 15 ms) of the calves, showing gross muscle atrophy and replacement by adipose tissue on the left, and hypertrophy of the muscles on the right, with only minor adipose tissue deposition

QUESTION 4

The differential diagnosis of the progressive calf hypertrophy is given in the box.

Causes of calf muscle hypertrophy

Chronic partial denervation

  • radiculopathy

  • peripheral neuropathy

  • hereditary motor and sensory neuropathy

  • spinal muscular atrophy

  • following paralytic poliomyelitis

    Neuromyotonia and myokymia

  • Isaac's syndrome

  • generalised myokymia

  • neurotonia

  • continuous muscle fibre activity due to: chronic inflammatory demyelinating polyradiculopathy, Guillain Barre syndrome, myasthenia gravis, thymoma, thyrotoxicosis, thyroiditis

    Muscular dystrophies

    Myositis

    Infiltration

  • tumours

  • amyloidosis

  • cysticercosis

    Link here