Protein kinase p38γ appears to play a protective role in Alzheimer’s diseaseAlzheimer’s is characterised by 2 main phenomena: beta amyloid plaques, and tau tangles. Both of these are associated with cell death and toxicity, but there is still a great deal of debate around which comes first and how important they are. Now, an Australian research team has stumbled upon a surprising finding; the phosphorylation of tau proteins that occurs in response to rising beta amyloid is actually initially a protective response, despite causing accumulation and tangle formation. A misinterpretation It was previously believed that beta amyloid is able to induce a particular chemical modification on tau proteins, which makes them more vulnerable to clumping and tangle formation. In contrast to this doctrine however, new research suggests that certain types of phosphorylation could be a defensive response to beta amyloid – acting to protect neurons in the initial stages of the disease. As deterioration worsens and continues however, this protection is dialled down and lost. The result is severe memory deficits and neuron death.
“Amyloid-beta induces toxicity in the neurons but the first step in tau phosphorylation is actually to decrease this toxicity. This is a completely new mindset; that the reason tau becomes modified is actually to protect from damage”Using brain samples from the Sydney Brain Bank and mice, the researchers studied a protein called kinase p38γ which plays a role in tau phosphorylation. Their experiments revealed that p38γ levels decline markedly as Alzheimer’s progresses, eventually remaining in only a small residual amount. This suggests that the protein plays some kind of defensive and helpful role in combating neural decline and associated memory deficits. When they tested this hypothesis in mice, they found that when they increased levels of p38γ in mice with the disease it was able to block memory deficits to a degree. It appears that the protein is somehow able to prevent detrimental changes to tau protein by beta amyloid, thus preventing neural decline.
“We found that p38γ, which initially offers protection, fades away early in the brains of people with AD, suggesting a loss of protection. Part of our study involved reintroducing p38γ and increasing its activity. We saw that, in mice, it could prevent memory deficits from happening, so it has true therapeutic potential. If we can stimulate that activity, we may be able to delay or even halt the progression of Alzheimer’s disease”The research raises interesting questions, and reminds us how difficult it is to work out what processes are a response, and which are a instigating cause. It does bring to light the complex role of tau in Alzheimer’s disease however, and how tricky it’s been for scientists to unravel what’s really driving decline in the deadly condition. We will have to wait to see further study of this protein to determine whether it could be applied to human use. Read more at MedicalXpress