The role of metals in modulating metalloprotease activity in the AD brain

• Published in: European biophysics journal 2008-03, Vol.37 (3), p.315-321
• Main Authors: Filiz, Gulay, Price, Katherine A., Caragounis, Aphrodite, Du, Tai, Crouch, Peter J., White, Anthony R.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid - drug effects; Amyloid - metabolism; Amyloid beta-Peptides - metabolism; Animal models; Animals; Biochemistry; Biological and Medical Physics; Biomedical and Life Sciences; Biophysics; Brain - drug effects; Brain - enzymology; Brain - physiopathology; Cell Biology; Cell Culture Techniques; Chelating Agents - pharmacology; Chelating Agents - therapeutic use; Clioquinol - therapeutic use; Cognitive ability; Copper; Copper - chemistry; Copper - metabolism; Copper - pharmacology; Disease Models, Animal; Egtazic Acid - analogs & derivatives; Egtazic Acid - therapeutic use; Enzyme Activation - drug effects; Humans; Intracellular Space - metabolism; Life Sciences; Matrix Metalloproteinases, Secreted - metabolism; Membrane Biology; Membranes; Metal complexes; Metals; Mitogen-Activated Protein Kinases - drug effects; Mitogen-Activated Protein Kinases - metabolism; Mode of action; Nanotechnology; Neurobiology; Neurology; Plaque, Amyloid - drug effects; Proline - analogs & derivatives; Proline - therapeutic use; Proteases; Pyrrolidine; Receptor, Epidermal Growth Factor - drug effects; Receptor, Epidermal Growth Factor - metabolism; Review; Thiocarbamates - therapeutic use; Trace Elements - metabolism; Zinc - metabolism
• ISSN: 0175-7571; 1432-1017
• DOI: 10.1007/s00249-007-0244-1

Biometals such as copper and zinc have an important role in Alzheimer’s disease (AD). Accumulating evidence indicates that copper homeostasis is altered in AD brain with elevated extracellular and low intracellular copper levels. Studies in animals and cell cultures have suggested that increasing intracellular copper can ameliorate AD-like pathology including amyloid deposition and tau phosphorylation. Modulating copper homeostasis can also improve cognitive function in animal models of AD. Treatments are now being developed that may result in redistribution of copper within the brain. Metal ligands such as clioquinol (CQ), DP-109 or pyrrolidine dithiocarbamate (PDTC) have shown promising results in animal models of AD, however, the actual mode of action in vivo has not been fully determined. We previously reported that CQ-metal complexes were able to increase intracellular copper levels in vitro. This resulted in stimulation of phosphoinositol-3-kinase activity and mitogen activated protein kinases (MAPK). Increased kinase activity resulted in up-regulated matrix metalloprotease (MMP2 and MMP3) activity resulting in enhanced degradation of secreted Aβ. These findings are consistent with previous studies reporting metal-mediated activation of MAPKs and MMPs. How this activation occurs is unknown but evidence suggests that copper may be able to activate membrane receptors such as the epidermal growth factor receptor (EGFR) and result in downstream activation of MAPK pathways. This has been supported by studies showing metal-mediated activation of EGFR through ligand-independent processes in a number of cell-types. Our initial studies reveal that copper complexes can in fact activate EGFR. However, further studies are necessary to determine if metal complexes such as CQ-copper induce up-regulation of Aβ-degrading MMP activity through this mechanism. Elucidation of this pathway may have important implications for the development of metal ligand based therapeutics for treatment of AD and other neurodegenerative disorders.