Siegfried Hoyer

Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease

Summary. 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 Alzheimers 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 Alzheimers 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.

Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein

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 β‐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 β‐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 tau‐protein 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.

Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis

Summary. The hypothesis is forwarded that sporadic late-onset Alzheimer disease is caused by non-insulin dependent diabetes mellitus which is confined to the brain. This hypothesis is based on the findings of Frölich and coworkers (this volume) who clearly demonstrate a perturbation of the neuronal insulin/insulin receptor signal transduction pathway which is considered to be the pathobiochemical basis for the drastic reduction in glucose/energy metabolism in Alzheimer brain. As a consequence of this abnormality, advanced glycation end products are formed. Münch et al. (this volume) evaluate the impacts of the latter related to oxidative stress and the formation of β-amyloid and neurofibrillary tangles.

Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type?

SummaryGlobal cerebral blood flow, oxidative brain metabolism, and the cerebral arteriovenous differences of amino acids and ammonia were studied in 20 clinically diagnosed patients with early-onset dementia of Alzheimer type (DAT). Eleven healthy age-matched subjects and 15 healthy young volunteers served as controls. The most prominent abnormality in patients with early-onset DAT was a 44% reduction in the cerebral metabolic rate of glucose and a fourfold increase of lactate production, whereas cerebral blood flow and the cerebral metabolic rate of oxygen were found not to be altered. The cerebral amino-N balance substantially changed in patients with early-onset DAT, showing a massive loss of amino acids and ammonia from the brain, which was indicative of excess protein catabolism due to cell degeneration in the acutely diseased brain. The abnormality found in glucose metabolism may suggest a perturbed control of glycolytic breakdown of glucose and its first oxidation step at the pyruvate dehydrogenase complex level, this thus being of pivotal significance in early-onset DAT.

Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway

The insulin‐resistant brain state is related to late‐onset sporadic Alzheimers 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 Alzheimers 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‐3α/β (pGSK‐3α/β) protein in the rat hippocampus, whereas the levels of the unphosphorylated form (GSK‐3α/β) and protein kinase B (Akt/PKB) remained unchanged. Three months after STZ treatment, pGSK‐3α/β 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 β‐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 Alzheimers disease, and our results suggest a role for GLUT2 in Alzheimers pathophysiology.

Predominant abnormality in cerebral glucose utilization in late-onset dementia of the Alzheimer type: A cross-sectional comparison against advanced late-onset and incipient early-onset cases

SummaryGlobal cerebral blood flow and the cerebral metabolic rates of oxygen, CO2, glucose and lactate were studied in 11 patients aged 61–78 years who had been clinically diagnosed as suffering from incipient late-onset dementia of the Alzheimer type (DAT), and in 7 patients aged 66–83 years, in whom advanced late-onset DAT had been diagnosed, using the Kety-Schmidt technique. In incipient late-onset DAT, the predominant abnormality was a 45% reduction in cerebral glucose utilization, whereas cerebral blood flow and the cerebral metabolic rate of oxygen were diminished by only 17% and 18%, respectively. A severe imbalance between oxygen utilization and glucose utilization thus became obvious. In contrast, in advanced stages of late-onset DAT, this imbalance between oxygen and glucose utilization rates in the brain became smaller and smaller, and cerebral blood flow diminished markedly; these biological brain parameters finally all settled down at between 55% and 65% of the corresponding control values. The predominant abnormality in brain glucose utilization in incipient late-onset DAT may be associated with an impairment of its control mechanism(s), which are assumed to be either an influence of brain insulin action, or brain insulin receptor function, or both.

Action of the diabetogenic drug streptozotocin on glycolytic and glycogenolytic metabolism in adult rat brain cortex and hippocampus.

In sporadic Alzheimers disease (AD), a number of metabolic alterations to the brain have been observed soon after the onset of the initial clinical symptoms. In particular, impairments of glucose utilization and related metabolic pathways are prominent and well‐established findings in incipient AD, resembling metabolic abnormalities such as have been found in noninsulin‐dependent diabetes mellitus. To mimic these abnormalities, we administered an intracerebroventricular (icv) injection of streptozotocin (STZ) to rats and studied the effects on glucose and glycogen metabolism in the cerebral cortex and hippocampus compared with controls. The enzymatic activities studied dropped significantly by 10–30% in brain cortex (cort.) and hippocampus (hc) 3 and 6 weeks after icv STZ injection: hexokinase (15% 3 weeks cort.; 14% 6 weeks cort.; 12% 3 weeks hc; 28% 6 weeks hc), phosphofructokinase (15%; 15%; 24%; 15%), glyceraldehyde‐3‐phosphate dehydrogenase (10%; 12%; 30%; 19%), pyruvate kinase (22%; 13%; 22%; 28%), glucose‐6‐phosphatase (10%; 23%; 14%; 19%) and phosphorylase a (22%; 11%; 30%; 15%).

The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update

Summary. Nosologically, Alzheimer disease may not be considered to be a single disorder in spite of a common clinical phenotype. Only a small proportion of about 5% to 10% of all Alzheimer cases is due to genetic mutations (type I) whereas the great majority of patients was found to be sporadic in origin. It may be assumed that susceptibility genes along with lifestyle risk factors contribute to the causation of the age-related sporadic Alzheimer disease (type II). In this context, the desensitization of the neuronal insulin receptor similar to not-insulin dependent diabetes mellitus may be of pivotal significance. This abnormality along with a reduction in brain insulin concentration is assumed to induce a cascade-like process of disturbances including cellular glucose, acetylcholine, cholesterol, and ATP associated with abnormalities in membrane pathology and the formation of both amyloidogenic derivatives and hyperphosphorylated tau protein. Sporadic Alzheimer disease may, thus, be considered to be the brain type of diabetes mellitus II. Experimental evidence is provided and discussed.

Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach

A growing body of evidence implicates impairments in brain insulin signaling in early sporadic Alzheimer disease (sAD) pathology. However, the most widely accepted hypothesis for AD aetiology stipulates that pathological aggregations of the amyloid beta (Abeta) peptide are the cause of all forms of Alzheimers disease. Streptozotocin-intracerebroventricularly (STZ-icv) treated rats are proposed as a probable experimental model of sAD. The current work reviews evidence obtained from this model indicating that central STZ administration induces brain pathology and behavioural alterations resembling those in sAD patients. Recently, alterations of the brain insulin system resembling those in sAD have been found in the STZ-icv rat model and are associated with tau protein hyperphosphorylation and Abeta-like aggregations in meningeal vessels. In line with these findings the hypothesis has been proposed that insulin resistance in the brain might be the primary event which precedes the Abeta pathology in sAD.

Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats

Interactions of glucose and cognitive function have been reported both in the presence of elevated arterial blood glucose levels and with decreased cerebral glucose metabolism. In order to test the peripheral vs. central effects of this phenomenon, we induced irreversible hyperglycemia and depression of cerebral glucose metabolism in separate designs by means of either intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of streptozotocin (STZ), which is known to damage insulin-producing cells. Behavioral functions, such as locomotor activity, learning, and memory, were investigated under these different conditions. IP treatment with STZ decreased locomotor activity and increased initial step-through latencies on the passive avoidance test. No effects of elevated arterial blood glucose levels on retention of passive avoidance learning checked at 24 h and 144 h after training were observed. I.c.v. treatment of STZ increased the rate of locomotor activity and impaired retention in the passive avoidance test at 24 h, without further forgetfulness at 144 h. This finding may indicate disturbed acquisition and/or consolidation of memory, which may remain impaired but at a constant level, without further deterioration. Enhanced motor activity and impaired acquisition of passive avoidance learning without further impairment have also been reported as a characteristical behavioral pattern after disruption of the cholinergic system. It is therefore postulated that the observed behavioral abnormalities consequent on an impairment of cerebral glucose metabolism may be suggestive of cholinergic dysfunction.