Kurzfassung

The current pharmacological strategies of disease-modification in Alzheimer’s disease (AD) mainly focus on targets of the amyloidogenic pathway such as gamma-secretase-activity or immunization. It is commonly assumed that a down-regulation of the amyloidogenic pathway of APP-processing with the consequence of reduced accumulation of neurotoxic β-amyloid (Abeta) in the brain should attenuate the progression of the clinical symptoms of AD. Under normal conditions the non-amyloidogenic...The current pharmacological strategies of disease-modification in Alzheimer’s disease (AD) mainly focus on targets of the amyloidogenic pathway such as gamma-secretase-activity or immunization. It is commonly assumed that a down-regulation of the amyloidogenic pathway of APP-processing with the consequence of reduced accumulation of neurotoxic β-amyloid (Abeta) in the brain should attenuate the progression of the clinical symptoms of AD. Under normal conditions the non-amyloidogenic proteolytic cleavage of APP via α-secretase predominates and generates soluble APP fragments (APPsα), whereas in AD this pathway is reduced. APPsα-levels have been found to be reduced in CSF of patients with AD compared to age-matched controls. Disintegrin and metalloproteinase 10 (ADAM10) was identified as a major α-secretase that processes APP in vitro and in vivo. It has been shown that in an AD mouse model, overexpression of ADAM10 increased the generation of APPsα and inhibited the production of APPsβ and Abeta as well as the formation of plaque. As a consequence, moderate ADAM10 overexpression improved cognitive deficits in the AD mouse model. A strong enhancement of the non-amyloidogenic processing of APP by the vitamin A analogue acitretin could be shown recently.
The proposed multicenter randomized placebo-controlled parallel-group study aims to demonstrate an enhancement of the α-secretase activity as measured by increased CSF APPSα-levels under 30 days period acitretin therapy in 76 patients with mild to moderate AD. Second, the safety and tolerability of acitretin in AD patients should be proven. Acitretin (Neotigason®) is an already approved and established drug also used for treatment of elderly patients. Neotigason® is a well-tolerated drug in patients suffering from psoriasis. Once we have shown the mechanism of action of acitretin in AD patients a larger and longer lasting clinical trial has to be conducted to prove the clinical efficacy in terms of disease-modifying properties (e.g. deceleration of clinical progression). It can be assumed that the increased α-secretase (ADAM10) activity enhances APPSα-processing and reduces Abeta-formation. Thus, the clinical deterioration in AD that is partially due to Abeta accumulation and the toxicity of Abeta-oligomers will be probably attenuated by the potent ADAM10 activator acitretin.
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