The search for the causes of neurodegenerative disorders is a major theme in brain research. Acquired disturbances of several aspects of cellular 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-like growth factors and their receptors regulate glucose metabolism and promote neuronal growth. To detect changes in the functional activity of the brain insulin neuromodulatory system of SDAT patients, we determined the concentrations of insulin and c-peptide as well as insulin receptor binding and IGF-I receptor binding in several regions of postmortem brain cortex during aging and Alzheimer's disease. Additionally, we performed immunohistochemical staining with antibodies against insulin in neocortical brain areas in SDAT and controls. We show for the first time that insulin and c-peptide concentration in the brain are correlated and decrease with aging, as do brain insulin receptor densities. Weak insulin-immunoreactivity could be demonstrated histochemically in pyramidal neurons of controls, whereas in SDAT a stronger insulin-immunoreactivity was found. On a biochemical level, insulin and c-peptide levels were reduced compared to middle-aged controls, but were unchanged compared to age-matched controls. Brain insulin receptor densities in SDAT were decreased compared to middle-aged controls, but increased in comparison to age-matched controls. IGF-I receptor densities were unchanged in aging and in SDAT. Tyrosine kinase activity, a signal transduction mechanism common to both receptor systems, was reduced in SDAT in comparison to middle-aged and age-matched control groups. These data are consistent with a neurotrophic role of insulin in the human brain and a disturbance of insulin signal transduction in SDAT brain and favor the hypothesis that insulin dependent functions may be of pathogenetic relevance in sporadic SDAT.

Drastic abnormalities have been demonstrated to occur in cerebral glucose and energy metabolism in sporadic Alzheimer's disease, pointing to a primary disturbance in neuronal insulin and insulin receptor signal transduction and contributing to the causation of dementia. The compound streptozotocin (STZ) is known to inhibit insulin receptor function. The study was designed to investigate whether intracerebroventricularly (icv) applied STZ would inhibit neuronal insulin receptor function and would induce changes in both behavior and neuronal energy metabolism. Adult rats with icv-injected STZ developed long-term and progressive deficits in learning, memory, and cognitive behavior, indicated by decreases in working and reference memory in the holeboard task and the passive avoidance paradigm, along with a permanent and ongoing cerebral energy deficit. This animal model may be appropriate for investigations related to sporadic Alzheimer's dementia.

No abstract

The intracerebroventricular (icv) application of streptozotocin (STZ) in low dosage was used in 3-month-old rats to explore brain insulin system dysfunction. Three months following STZ icv treatment, the expression of insulin-1 and -2 mRNA was significantly reduced to 11% in hippocampus and to 28% in frontoparietal cerebral cortex, respectively. Insulin receptor (IR) mRNA expression decreased significantly in frontoparietal cerebral cortex and hippocampus (16% and 33% of control). At the protein/activity level, different abnormalities of protein tyrosine kinase activity (increase in hippocampus), total IR b-subunit (decrease in hypothalamus) and phosphorylated IR tyrosine residues (increase) became apparent. The STZ-induced disturbance in learning and memory capacities was not abolished by icv application of glucose transport inhibitors known to prevent STZ-induced diabetes mellitus.The discrepancy between reduced IR gene expression and increase in both phosphorylated IR tyrosine residues/protein tyrosine kinase activity may indicate imbalance between phosphorylation/dephosphorylation of the IR b-subunit causing its dysfunction. These abnormalities may point to a complex brain insulin system dysfunction after STZ icv application, which may lead to an increase in hyperphosphorylated tauprotein concentration. Brain insulin system dysfunction is discussed as possible pathological core in the generation of hyperphosphorylated tau protein as a morphological marker of sporadic Alzheimer's disease.

The insulin-resistant brain state is related to late-onset sporadic Alzheimer's disease, and alterations in the insulin receptor (IR) and its downstream phosphatidylinositol-3 kinase signalling pathway have been found in human brain. These findings have not been confirmed in an experimental model related to sporadic Alzheimer's disease, for example rats showing a neuronal IR deficit subsequent to intracerebroventricular (i.c.v.) treatment with streptozotocin (STZ). In this study, western blot analysis performed 1 month after i.c.v. injection of STZ showed an increase of 63% in the level of phosphorylated glycogen synthase kinase-3a/b (pGSK-3a/b) protein in the rat hippocampus, whereas the levels of the unphosphorylated form (GSK-3a/b) and protein kinase B (Akt/ PKB) remained unchanged. Three months after STZ treatment, pGSK-3a/b and Akt/PKB levels tended to decrease (by 8 and 9% respectively). The changes were region specific, as a different pattern was found in frontal cortex. Structural alterations were also found, characterized by b-amyloid peptide-like aggregates in brain capillaries of rats treated with STZ. Similar neurochemical changes and cognitive deficits were recorded in rats treated with i.c.v. 5-thio-D-glucose, a blocker of glucose transporter (GLUT)2, a transporter that is probably involved in brain glucose sensing. The IR signalling cascade alteration and its consequences in rats treated with STZ are similar to those found in humans with sporadic Alzheimer's disease, and our results suggest a role for GLUT2 in Alzheimer's pathophysiology. Keywords: Alzheimer's disease; glucose transporter 2; glycogen synthase kinase-3, hippocampus, protein kinase B, streptozotocin. Research into the brain insulin system has intensified in the past decade, particularly regarding its pathophysiology. There is a growing interest in determining the role of neuronal insulin and its receptor in the brain, and particularly in Alzheimer's disease. Recent data indicate that brain insulin deficiency and the insulin-resistant brain state are related to late-onset sporadic Alzheimer's disease (Fulop et al. 2003;Hoyer 2004;De la Monte and Wands 2005;Hoyer and Frölich 2005). The late-onset type of Alzheimer's disease is associated with glucose utilization abnormalities all over the cerebral cortex, and particularly in structures with both high glucose demands and high insulin sensitivity (Henneberg and Hoyer 1995). Neuronal glucose metabolism is under the regulation of neuronal insulin, and abnormalities in brain glucose metabolism found in Alzheimer's disease have been suggested to be induced at the level of insulin signal transduction (Hoyer 2002;Hoyer and Frölich 2005).