A drug that is usually used for treatment of psoriasis has been found to stimulate the activity of the enzyme ADAM10 in the brain of Alzheimer’s patients (AD), providing encouraging results for treating the disease.
The study, which was recently published in the journal Neurology, entitled “Increased CSF APPs-a levels in patients with Alzheimer disease treated with acitretin,” was a joint collaboration between Dr. Kristina Endres and Professor Falk Fahrenholz of the Department of Psychiatry and Psychotherapy of the Mainz University Medical Center along with Professors Klaus Liebl and Andreas Fellgiebel from the Department of Psychiatry and Psychotherapy, and Professor Stefan Teipel and his team at the German Center for Neurodegenerative Diseases (DZNE) in Rostock.
Accumulating evidence shows that Alzheimer’s disease is triggered by an increased cleavage of the amyloid precursor protein by beta-secretase, leading to the formation of amyloid-beta (Ab) peptides that damage nerve cells.
Studies have shown that the activity of beta-secretases cleave proteins on cell membranes, releasing the products of this cleavage process into the extracellular space.
The alpha-secretase ADAM10 is a competitor of beta-secretase. It cleaves the amyloid precursor protein, preventing the synthesis of amyloid beta-peptides while there is a release in the growth factor APPs-alpha, which protects nerve cells.
The team of researchers hypothesized that an increase of a-secretase ADAM10 activity via acitretin would increase the CSF APPs-a levels in patients with AD. Moreover, researchers thought that a decrease of APPs-b levels would occur because of the stimulation of the nonamyloidogenic APP pathway via a-secretase activation by acitretin, with a consecutive reduction of Ab levels.
In this trial, twenty-one patients with mild to moderate AD received either acitretin (30 mg per day) or placebo for 4 weeks. The researchers examined the difference of CSF APPs-a ratios analyzed from the APPs-a levels, both at baseline and after the 4 weeks. Additionally, during the treatment, biomarkers such as b-amyloid 42 (Ab42) were examined.
Results from this class III trial revealed that the group that received acitretin had an increase in CSF APPs-a levels compared with the placebo group (difference 0.38, 95% confidence interval 0.03–0.72, p 5 0.035) within the 4 weeks of treatment.
The researchers indicate that although oral acitretin is able to increase the nonamyloidogenic APPs-a levels in patients with AD, the clinical mechanisms and outcomes of this process remain unclear. Further studies with larger AD samples and longer follow-up periods are necessary to evaluate acitretin as a new treatment option for AD.
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