BRAIN INSULIN AND INSULIN-RECEPTORS IN AGING AND SPORADIC ALZHEIMERS-DISEASE

The search for the causes of neurodegenerative disorders is a major th eme in brain research. Acquired disturbances of several aspects of cel lular metabolism appear pathologically important in sporadic Alzheimer 's disease (SDAT). Among these brain glucose utilisation is reduced in the early stages of the disease and the regulatory enzymes important for glucose metabolism are reduced. In the brain, insulin, insulin-lik e growth factors and their receptors regulate glucose metabolism and p romote neuronal growth. To detect changes in the functional activity o f the brain insulin neuromodulatory system of SDAT patients, we determ ined the concentrations of insulin and c-peptide as well as insulin re ceptor binding and IGF-I receptor binding in several regions of postmo rtem brain cortex during aging and Alzheimer's disease. Additionally, we performed immunohistochemical staining with antibodies against insu lin in neocortical brain areas in SDAT and controls. We show for the f irst time that insulin and c-peptide concentration in the brain are co rrelated and decrease with aging, as do brain insulin receptor densiti es. Weak insulin-immunoreactivity could be demonstrated histochemicall y in pyramidal neurons of controls, whereas in SDAT a stronger insulin -immunoreactivity was found. On a biochemical level, insulin and c-pep tide levels were reduced compared to middle-aged controls, but were un changed compared to age-matched controls. Brain insulin receptor densi ties in SDAT were decreased compared to middle-aged controls, but incr eased in comparison to age-matched controls. IGF-I receptor densities were unchanged in aging and in SDAT. Tyrosine kinase activity, a signa l transduction mechanism common to both receptor systems, was reduced in SDAT in comparison to middle-aged and age-matched control groups. T hese data are consistent with a neurotrophic role of insulin in the hu man brain and a disturbance of insulin signal transduction in SDAT bra in and favor the hypothesis that insulin dependent functions may be of pathogenetic relevance in sporadic SDAT.