Regulation of ADAM10 gene expression and neuroprotection

Coordinator:    Dr. Kristina Endres
Institution: Institut für Biochemie, Johannes-Gutenberg Universität Mainz
Alzheimer’s disease is a progressive neurodegenerative disease for which the underlying pathological cause is still unknown. Investigations regarding brain tissue of patients revealed that an altered processing of a distinct protein – the amyloid precursor protein APP – occurs under pathological conditions. This is based on a dysbalance of two proteases: the alpha-secretase ADAM10 is reduced in favor of the beta-secretase (BACE-1). The latter gives rise to toxic cleavage products of APP – the A-beta peptides (Figure 1).

The aim of our research is to understand what drives ADAM10 expression in neuronal cells and to steer this expression via activation of its promoter. The promoter of a gene represents a regulatory region that decides about the amount of a certain gene product. Promoters can be manipulated regarding their activity by exogenously added substances or endogenous cellular proteins (transcription factors, Figure 2). We screened a library of approved drugs as well as a library consisting of human transcription factors for their potential to activate the ADAM10 promoter and identified a number of candidates: for example the X-box binding protein 1 (XBP-1) enhanced ADAM10 amount in neuronal cells. XBP-1 is a sensor for stress within the cell that allows the cell to circumvent cell death under certain conditions. When this protein becomes activated, it stimulates ADAM10 synthesis and leads to increased APP processing via this enzyme. We were able to demonstrate that the amount and/ or activity of XBP-1 is altered along with pathological changes in Alzheimer model mice. In addition, analysis of cortical tissue from patients with Alzheimer’s disease revealed reduced XBP-1 activity which might contribute to disease progression.

By screening of the drug library we identified a synthetic retinoid as a potent ADAM10-activator. This retinoid is capable of enhancing ADAM10 activity within the brain of Alzheimer model mice which subsequently leads to reduction of A-beta peptides. In a clinical trial, which has been finished recently, we demonstrated the safety and efficacy of this drug in human patients. Further candidate drugs are currently being tested for their ability to overcome the blood-brain barrier to evaluate their therapeutic potential.

Figure 1:
ADAM10 and BACE-1: two enzymes competing for cleavage of the Alzheimer‘s disease relevant protein APP

The amyloid precursor protein (APP) is synthesized in neurons and anchored to the cell membrane. Following enzymatic cleavage, fragments of this protein are released from the cell surface. The cleavage of APP by the enzyme BACE-1 leads in combination with a second cleavage (not shown) to generation of toxic APP fragments (A-beta peptides) that are deposited in plaques and damage neurons. ADAM10 prevents the formation of these harmful cleavage products and produces an alternative APP fragment (APPs-alpha) which protects neurons and promotes their growth.

Figure 2: Regulation of ADAM10 amount via promoter activity
The amount of ADAM10 within cells is determined by the activity of the promoter within its gene sequence. This distinct stretch on the DNA responds to endogenous cellular proteins (transcription factors, TF) either directly or upon binding of an exogenously added ligand (L) to these proteins. This in consequence leads to enhanced production of ADAM10 and processing of APP by this protease.

Additional relevant Internet link:
Johannes Gutenberg-Universität Mainz
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