A NEW HYPOTHESIS FOR THE ETIOPATHOGENESIS OF THE ALZHEIMERS SYNDROME - ADVANCED GLYCATION ENDPRODUCTS (AGES)

Despite intense efforts, it has not yet been possible to clarify the e tiopathogenesis of Alzheimer's dementia. There are, however, hypothese s which focus on certain aspects of this type of dementia, characteriz ed by particular neuropathological alterations and clinical correlates . Recently, evidence has accumulated that advanced glycation endproduc ts (AGEs) could play an important role in the etiology of the Alzheime r's syndrome. AGEs are generated by an irreversible reaction through t he non-enzymatic, long-term glycosylation of proteins. They are strong ly resistent to proteolytic processes and induce protein crosslinking. They could thus inhibit the physiological functions of many proteins. Moreover, it is suggested that they contribute to the transformation of the soluble form of beta-amyloid into its unsoluble version. AGEs a re also demonstrable in neurofibrillary tangles (NFTs). A further mech anism by which AGEs might be pathogenic is via their induction of oxid ative stress. AGEs probably exert their pathological effects not only directly because of their chemical properties, but also by indirect re ceptor-mediated mechanisms. Further investigation of AGE-mediated mech anisms should reveal their role in the etiopathogenesis of the Alzheim er's syndrome and, finally, lead to the development of new pharmacolog ical strategies aimed at inhibiting protein crosslinking.