Extracellular targets for Alzheimer's Disease

The inhibition or downregulation of specific tetraspanin proteins can be used as a novel therapeutic approach for Alzheimer’s Disease. As these are extracellular proteins, an antibody-based approach can be anticipated.

Summary of the invention
γ-Secretase is a multiprotein complex consisting of presenilin (PS), nicastrin (NCT), Aph1 and Pen-2. It is responsible for the generation of the Aβ-peptide, the primary component of the amyloid plaques which are characteristic of AD brain. Although these 4 proteins are necessary and sufficient for Aβ generation, more proteins are likely involved in the regulation of this complex activity.

VIB researchers have now identified a series of extracellular proteins that transiently interact with γ-secretase and are associated with the tetraspanin web. Tetraspanin proteins form detergent-resistant, raft-like micro-domains and are extracellular proteins. Their inhibition via antibodies or down-regulation via siRNA results in decreased Aβ production and in KO-cell lines for these proteins, the substrates for γ-secretase cleavage accumulate, indicating decreased activity. These results indicate that these tetraspanin proteins can be used as novel therapeutic targets for AD.

 
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