Affiliations: Centre for Experimental Therapeutics, William Harvey Research Institute, John Vane Science Centre, Bart's and the London Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1 6BQ, UK. Tel.: +44 (0)20 7882 6032; Fax: +44 (0)20 7882 6037; E-mail: alanandjill@lineone.net | [x] Department of Biochemistry, M.V. Lomonosov Moscow State University, Moscow, Russia | [y] Department of Biomedical Sciences, Ohio University, Athens, OH, USA
Abstract: Reactive oxygen species, reactive nitrogen species, copper and zinc ions, glycating agents and reactive aldehydes, protein cross-linking and proteolytic dysfunction may all contribute to Alzheimer's disease (AD). Carnosine (β-alanyl-L-histidine) is a naturally-occurring, pluripotent, homeostatic agent. The olfactory lobe is normally enriched in carnosine and zinc. Loss of olfactory function and oxidative damage to olfactory tissue are early symptoms of AD. Amyloid peptide aggregates in AD brain are enriched in zinc ions. Carnosine can chelate zinc ions. Protein oxidation and glycation are integral components of the AD pathophysiology. Carnosine can suppress amyloid-β peptide toxicity, inhibit production of oxygen free-radicals, scavenge hydroxyl radicals and reactive aldehydes, and suppresses protein glycation. Glycated protein accumulates in the cerebrospinal fluid (CSF) of AD patients. Homocarnosine levels in human CSF dramatically decline with age. CSF composition and turnover is controlled by the choroid plexus which possesses a specific transporter for carnosine and homocarnosine. Carnosine reacts with protein carbonyls and suppress the reactivity of glycated proteins. Carbonic anhydrase (CA) activity is diminished in AD patient brains. Administration of CA activators improves learning in animals. Carnosine is a CA activator. Protein cross-links (γ-glutamyl-ε-amino) are present in neurofibrillary tangles in AD brain. γ-Glutamyl-carnosine has been isolated from biological tissue. Carnosine stimulates vimentin expression in cultured human fibroblasts. The protease oxidised-protein-hydrolase is co-expressed with vimentin. Carnosine stimulates proteolysis in cultured myocytes and senescent cultured fibroblasts. These observations suggest that carnosine and related structures should be explored for therapeutic potential towards AD and other neurodegenerative disorders.
