Open drug discovery in Alzheimer\u27s disease.

Alzheimer\u27s disease (AD) drug discovery has focused on a set of highly studied therapeutic hypotheses, with limited success. The heterogeneous nature of AD processes suggests that a more diverse, systems-integrated strategy may identify new therapeutic hypotheses. Although many target hypotheses have arisen from systems-level modeling of human disease, in practice and for many reasons, it has proven challenging to translate them into drug discovery pipelines. First, many hypotheses implicate protein targets and/or biological mechanisms that are under-studied, meaning there is a paucity of evidence to inform experimental strategies as well as high-quality reagents to perform them. Second, systems-level targets are predicted to act in concert, requiring adaptations in how we characterize new drug targets. Here we posit that the development and open distribution of high-quality experimental reagents and informatic outputs-termed target enabling packages (TEPs)-will catalyze rapid evaluation of emerging systems-integrated targets in AD by enabling parallel, independent, and unencumbered research

Discovery of FERM domain protein-protein interaction inhibitors for MSN and CD44 as a potential therapeutic approach for Alzheimer\u27s disease.

Proteomic studies have identified moesin (MSN), a protein containing a four-point-one, ezrin, radixin, moesin (FERM) domain, and the receptor CD44 as hub proteins found within a coexpression module strongly linked to Alzheimer\u27s disease (AD) traits and microglia. These proteins are more abundant in Alzheimer\u27s patient brains, and their levels are positively correlated with cognitive decline, amyloid plaque deposition, and neurofibrillary tangle burden. The MSN FERM domain interacts with the phospholipid phosphatidylinositol 4,5-bisphosphate (PI

SFRP1: A Target Enabling Package

Secreted frizzled-related protein 1 (SFRP1) is a secreted glycoprotein with two major functional domains. The N-terminal cysteine rich domain CRD acts as an antagonist to the Wnt signalling pathway. The C-terminal netrin-like domain (NTR) binds and inhibits the activity of metalloprotease ADAM10. Both the Wnt pathway and ADAM10 activity have been implicated as regulators of AD pathology. Further study of the role of SFRP1 and development of research tools for SFRP1 could lead to a better understanding of AD. This TEP focuses on the development of these research tools

SFRP1: A Target Enabling Package

Secreted frizzled-related protein 1 (SFRP1) is a secreted glycoprotein with two major functional domains. The N-terminal cysteine rich domain CRD acts as an antagonist to the Wnt signalling pathway. The C-terminal netrin-like domain (NTR) binds and inhibits the activity of metalloprotease ADAM10. Both the Wnt pathway and ADAM10 activity have been implicated as regulators of AD pathology. Further study of the role of SFRP1 and development of research tools for SFRP1 could lead to a better understanding of AD. This TEP focuses on the development of these research tools

SFRP1: A Target Enabling Package

Secreted frizzled-related protein 1 (SFRP1) is a secreted glycoprotein with two major functional domains. The N-terminal cysteine rich domain CRD acts as an antagonist to the Wnt signalling pathway. The C-terminal netrin-like domain (NTR) binds and inhibits the activity of metalloprotease ADAM10. Both the Wnt pathway and ADAM10 activity have been implicated as regulators of AD pathology. Further study of the role of SFRP1 and development of research tools for SFRP1 could lead to a better understanding of AD. This TEP focuses on the development of these research tools

CNN3: A Target Enabling Package

Calponin-3 (CNN3) is a cytoskeletal associated factor that binds and regulates actin mediated transport. Despite both genetic and genomic linkage with AD, as discussed above, it’s potential role in AD is unknown. The role of CNN3 in synaptic formation in development (see below) suggests a role in synaptic stabilisation and transport regulation–consistent with the mapping of CNN3 to the Structural Stabilisation and Synapse biological domains. The CNN3 project is focused upon the development of key resources to study its role in AD pathophysiology bundled in a target enabling package (TEP). Purified protein and validated antibodies, along with informatics resources, are the core components of the CNN3 TEP