Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease

Converging evidence has identified a potential association among Alzheimer's disease, glucose metabolism, insulin activity, and memory. Notably, type 2 diabetes, which is characterized by insulin resistance, may modulate the risk of Alzheimer's disease, and patients with Alzheimer's disease may have a greater risk for glucoregulatory impairments than do healthy older adults. In animal studies, it has been shown that raising blood glucose levels acutely can facilitate memory, in part, by increasing cholinergic activity, which is greatly diminished in patients with Alzheimer's disease. Other studies have confirmed that glucose administration can facilitate memory in healthy humans and in patients with Alzheimer's disease. Interestingly, glucose effects on memory appear to be modulated by insulin sensitivity (efficiency of insulin-mediated glucose disposal). Of course, the acute effects of glucose administration should be distinguished from the effects of chronic hyperglycemia (diabetes), which has been associated with cognitive impairments, at least in older adults. The relationship of insulin and memory has been more difficult to characterize. In animals, systemic insulin administration has been associated with memory deficits, likely due, in part, to hypoglycemia that occurs when exogenous insulin is not supplemented with glucose to maintain euglycemia. In healthy adults and patients with Alzheimer's disease, raising plasma insulin levels while maintaining euglycemia can improve memory; however, raising plasma glucose while suppressing endogenous insulin secretion may not improve memory, suggesting that adequate levels of insulin and glucose are necessary for memory facilitation. Clinical studies have corroborated findings that patients with Alzheimer's disease are more likely than healthy older adults to have reduced insulin sensitivity, and further suggest that apolipoprotein E genotype may modulate the effects of insulin on glucose disposal, memory facilitation, and amyloid precursor protein processing. Collectively, these findings support an association among Alzheimer's disease, impaired glucose metabolism, and reduced insulin sensitivity.     

Protein quality control in Alzheimer's disease: a fatal saviour

Aggregation of Abeta plays a key role in the pathogenesis of Alzheimer's disease. Although the highly structured Abeta aggregates (fibrils) have long been thought to be the toxic form of Abeta, recent evidence suggests that smaller, soluble intermediates in Abeta aggregation are the real culprit. Because these oligomeric aggregates are already formed in the secretory pathway, this raises another issue: Is intra- or extracellular Abeta involved in the pathogenic cascade? Because aggregated proteins are very toxic, cells have developed quality control responses to deal with such proteins. A prime site for quality culum. Here, aberrant proteins are recognized and can be targeted for degradation to the cytosolic quality control system. In addition, there is accumulating evidence for quality control in other subcellular compartments in the cell. All quality control mechanisms are initially protective, but will become destructive after prolonged accumulation of aggregated proteins. This is enhanced by decreased efficiency of these systems during aging and therefore, these responses may play an important role in the pathogenesis of Alzheimer's disease. In this review, we will discuss the role of protein quality control in the neurotoxicity of Abeta.     

Therapeutic treatments for Alzheimer's disease based on metal bioavailability

The amyloid beta peptide (Abeta) has been widely implicated as a significant causative agent in Alzheimer's disease, although the common mechanistic links between Abeta and other critical elements of Alzheimer's disease, such as advancing age and oxidative stress, are still poorly understood. Here we review data indicating that biometal dyshomeostasis plays a role in these aspects of Alzheimer's disease. Although strong evidence has been published demonstrating a role for iron and zinc in Alzheimer's disease, we have here limited our discussion to data on the role of copper. We also describe how the development of therapeutic agents designed to modulate metal bioavailability has provided promising results in the treatment of Alzheimer's disease. The metal ligand clioquinol has been used successfully in vitro, as well as in animal models and small clinical trials, and a new generation of metal ligand-based therapeutics is under development.     

Diabetes, sugar-coated but harmful to the brain

Type 2 diabetes mellitus appears to directly impair cognition and brain function, independent of its associated cardiovascular disease. This is supported by the presence of similar findings among adults with insulin resistance (pre-diabetes) and obese children with type 2 diabetes, years before overt cardiovascular disease. Hippocampal based memory performance is impaired early in the disease, although deficits in executive function, attention, and psychomotor speed are also seen in more chronic disease and/or poorer disease control, particularly in the presence of co-morbidities such as hypertension. Although there has been some speculation as to possible links between diabetes and Alzheimer's Disease based on associations found in population studies, no convincing empirical evidence has been put forth and brain autopsy studies, the gold standard of Alzheimer's diagnosis, have not supported such a link. Future studies should focus on understanding the mechanisms for the cognitive impairments associated with type 2 diabetes. We propose that insulin resistance-associated impairments in vascular reactivity and endothelial function are possible candidates as they may impact substrate delivery across the blood-brain-barrier. These are important issues given the obesity epidemic and the associated rising prevalence of insulin resistance and type 2 diabetes.     

The development of anti-amyloid therapy for Alzheimer's disease : from secretase modulators to polymerisation inhibitors

The leading hypothesis of the pathophysiology of Alzheimer's disease holds that the pivotal event is cleavage of the amyloid precursor protein to release intact the 42-amino-acid amyloid-beta peptide (Abeta); this hypothesis best explains the known genetic causes of Alzheimer's disease. If this theory is correct, optimal strategies for altering the disease process should be directed toward modifying the generation, clearance and/or toxicity of Abeta. Abeta is highly aggregable, spontaneously assuming a beta-sheet conformation and polymerising into oligomers, protofibrils, fibrils and plaques. The relative contribution of the various forms of Abeta to neuronal dysfunction in Alzheimer's disease remains uncertain; however, recent evidence implicates diffusible oligomeric species.This article reviews the range of strategies that have been investigated to target Abeta to slow the progression of Alzheimer's disease, from secretase modulators to anti-polymerisation agents. One amyloid-binding drug, tramiprosate (3-amino-1-propanesulfonic acid; Alzhemed), which is effective in reducing polymerisation in vitro and plaque deposition in animals, has now reached phase III clinical trials. Thus, it is plausible that an effective anti-amyloid strategy will become available for the treatment of Alzheimer's disease within the next few years.     

Effect of HMG-CoA reductase inhibitors on beta-amyloid peptide levels: implications for Alzheimer's disease

To date, a number of hypotheses of the cause of Alzheimer's disease, the most common form of dementia, have been postulated. The beta-amyloid peptide (Abeta) is the major constituent of senile plaques, which together with atrophy and neurofibrillary tangles, is the main neuropathological finding in Alzheimer's disease. It is a widely accepted theory that aggregation of Abeta into plaques is an initial event in the pathogenesis of Alzheimer's disease, driving neurodegeneration. The cholesterol hypothesis, primarily based on in vitro and animal studies, states that increased levels of cholesterol promote the production of Abeta. Furthermore, treating animals with HMG-CoA reductase inhibitors ('statins'; cholesterol-lowering agents), or adding these agents to cell culture, results in decreased production of Abeta. This 'positive' effect of statin treatment has further been verified by some, but not all, longitudinal studies where a reduced prevalence of Alzheimer's disease is seen among patients taking statins. These findings have together been interpreted to indicate that statins act via a cholesterol-dependent mechanism, reducing the production of Abeta and, hence, the risk of developing Alzheimer's disease.This review focuses on the cholesterol hypothesis of Alzheimer's disease and investigations into its validity in the clinical setting, i.e. the outcome of clinical trials where the effect of statin treatment on Abeta production has been studied. To date, the cholesterol hypothesis has not been shown to be valid in clinical trials. We hypothesise that the vascular contributions in Alzheimer's disease may be one possible mechanism for statins to interfere with the disease process and reduce the prevalence of Alzheimer's disease. We also suggest that statins may act through the inflammatory pathway. Both of these mechanistic suggestions are good candidates, supported by the literature, for the underlying mechanistic link between statin treatment and a reduced prevalence for Alzheimer's disease.     

Links between Alzheimer's disease and diabetes

The existence of links between Alzheimer's disease and diabetes is an important topic currently under active debate. Establishing such links if they exist and defining their common pathogenesis and pathophysiological mechanisms may lead to new concepts and research directions for the pharmacological treatment of Alzheimer's disease and diabetes. Alzheimer's disease is associated with peripheral and central insulin abnormalities. Cognitive capacities are often impaired in patients with diabetes. There are many mechanisms by which insulin-signaling abnormalities may affect clinical and pathological outcome of Alzheimer's disease. Insulin resistance and dysregulation of the degradation of neurotoxic amyloid and insulin appear at the core of the links between Alzheimer's disease and diabetes. Functions and expression of insulysin, an enzyme involved in the degradation of neurotoxic amyloid peptides and insulin, are usually impaired or reduced in Alzheimer's disease and diabetes. The increased occurrence of insulin resistance in Alzheimer's disease suggests that improving insulin effectiveness and insulysin activity may have therapeutic value in Alzheimer's disease patients and therefore is worth intensive investigation.     

Tramiprosate

Current treatment options for patients with Alzheimer's disease are limited to providing symptomatic relief, with no effects on the underlying pathophysiology. However, a greater understanding of the importance of beta-amyloid peptides (Abeta) in the pathogenesis of this disease has led to the investigation of a number of potential antiamyloid therapies, of which tramiprosate (Neurochem Inc.) is in the most advanced stage of development. Tramiprosate is a glycosaminoglycan (GAG) mimetic designed to interfere with the actions of Abeta early in the cascade of amyloidogenic events. Preclinical data have shown that tramiprosate reduces brain and plasma levels of Abeta, prevents fibril formation and exerts cytoprotective effects in the brain. The pharmacological effects have also been demonstrated in clinical trials of patients with mild to moderate Alzheimer's disease. Promising findings for the efficacy of tramiprosate, indicated by improvement or stabilization of cognitive function, have been shown in phase II clinical trials and open-label extensions of these studies. Furthermore, tramiprosate appears to be well tolerated with no reports of safety concerns. This article reviews the unique mode of action of tramiprosate and summarizes the available clinical information on the effects of tramiprosate in patients with Alzheimer's disease.     

Peptidases,proteases and amyloid beta-peptide catabolism

The formation of senile plaques containing amyloid beta peptides (Abeta peptides) as a major constituent plays a significant role in development of Alzheimer's disease. The concentration of Abeta peptides in the brain is determined by a combination of their rate of synthesis and their rate of clearance. Considerable effort has been expended in producing inhibitors of the beta and gamma secretases involved in the synthesis of the Abeta peptides. More recently interest in the mechanism of clearance of the Abeta peptides has emerged, as promoting Abeta peptide clearance represents an alternative therapeutic approach. It now appears that cleavage of Abeta peptide by peptidases and proteases represents the major mechanism of clearance. This review describes those peptidases and proteases implicated in Abeta peptide clearance, the evidence that these enzymes function in vivo, and how they may represent new therapeutic targets.     

Genetically modified mice models for Alzheimer's disease

Transgenic mice models for Alzheimer's disease (AD) are essential to the understanding of disease pathophysiology, develop robust behavioral models and predict outcomes from pharmacological interventions. In the last 10 years, numerous mice models have been developed particularly focusing on the amyloid precursor protein-processing pathway and Tau pathology since brain amyloid deposits and Tau tangles are some of the primary neuropathological consequences of AD. Current views on the amyloid hypothesis and mice models relating to the role of soluble Abeta oligomers and intracellular Abeta in AD pathophysiology will be reviewed. Several novel transgenic mice models that have recently been developed and their potential impact on understanding disease pathogenesis will also be summarized.     

Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans

Deposition of the beta-amyloid peptide (Abeta) in the brain occurs during normal ageing and is substantially accelerated in patients with Alzheimer's disease. Since Abeta is continuously produced in the brain, it has been suggested that a clearance mechanism should exist to prevent its accumulation and subsequent aggregation. Until now, little attention has been paid to the possible role of P-glycoprotein (P-gp), a member of the ATP binding cassette superfamily of transporter proteins, in the pathogenesis of Alzheimer's disease. A recent study demonstrated that Abeta40 and Abeta42 interact directly with P-gp. We therefore hypothesized that Abeta accumulation in the brain would correlate inversely with the degree of vascular P-gp expression. To study early pathogenetic factors that influence the deposition of Abeta, at routine autopsies, brain tissue samples were taken from 243 non-demented subjects who died between the ages of 50 and 91 years. Vascular P-gp expression and the number of Abeta40- and Abeta42-positive senile plaques were assessed immunohistochemically in the medial temporal lobe. In addition, the apolipoprotein E (apoE) genotypes, as well as multiple drug resistance gene 1 ( ) polymorphisms (exon 2, G-1A; exon 21, G2677T/A; exon 26, C3436T), were also determined for each case. P-gp expression was not correlated with genotypes, but we found a significant inverse correlation between P-gp expression and the deposition of both Abeta40 and Abeta42 in the medial temporal lobe. Our results provide the first evidence in human brain tissue that the accumulation of Abeta may be influenced by the expression of P-gp in blood vessels, and suggest that P-gp may influence the elimination of Abeta from brain.     

Low density lipoprotein receptor-related proteins (LRPs), Alzheimer's and cognition

This review will focus primarily on the role of the low density lipoprotein receptor-related protein (LRP-1) in neuronal synapse formation and function in Alzheimer's Disease (AD). We review the role that its ligands may have in cognition or AD: apolipoprotein E (ApoE), alpha2-macroglobulin, Transforming Growth Factor-Beta (TGFbeta, Tissue Plasminogen Activator (tPA), insulin growth factor binding protein-3 (IGFBP-3), which all bind LRP-1 and apolipoprotein J (ApoJ), which is a ligand for LRP-2. After reviewing its role as a signaling receptor, we discuss the connection between LRP and the NMDA glutamate receptor via the post synaptic density 95 (PSD-95) neuronal scaffold protein and the implications it may have for memory and cognition. Finally, we discuss the evidence supporting a role for LRP in AD. Although the evidence for LRP as a genetic risk factor is weak, many of its ligands impose genetic risk, and have been implicated in AD pathogenic cascades. We discuss the role of LRP in amyloid precursor protein (APP) processing and production of beta-amyloid (Abeta. We identify LRP ligands that accelerate aggregation of toxic Abeta species. LRP mediates crucial pathways in AD pathogenesis such as Abeta clearance, Abeta uptake, intraneuronal Abeta accumulation and Abeta-associated neuron death. Interestingly, the TGFbeta -V receptor is LRP-1. Data show that one critical ligand TGFbeta2, associated with neurodegeneration in amyloid diseases, induces LRP expression in PC12 cells. Data from rodent infusion models demonstrate the impact of TGFbeta2 in modifying Abeta- induced Long Term Potentiation (LTP) responses, presynaptic proteins, lipid peroxidation, gliosis and staining for neuronal nuclei. The evidence supports a complex and significant role of LRP in cognition and AD.     

Rosiglitazone attenuates the cognitive deficits induced by high fat diet feeding in rats

The present study was designed to test the hypothesis that insulin resistance plays a role in high fat diet feeding induced cognitive deficits. Rats consuming the high fat diet exhibited characteristic features of insulin resistance viz. mild hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and hyperinsulinemia. Further, these rats showed a severe deficit in learning and memory. In contrast, rosiglitazone at the dose of 5 mg/kg, p.o. for 7 days prior to biochemical and behavioral testing significantly lowered the plasma glucose, triglycerides, cholesterol, and insulin levels. These animals also performed better on Morris water maze task, suggesting improved spatial memory. Our data demonstrate that the insulin sensitizers can overcome the cognitive deficits arising from high fat diet feeding, which may be in part mediated through the development of peripheral insulin resistance.     

Insulin resistance as a proinflammatory state: mechanisms,mediators, and therapeutic interventions

Insulin resistance has been recognized as an inflammatory disease based on the scientific evidence collected over the last decade. Inflammatory markers like CRP, PAI-1, IL-6 are present in higher concentrations in insulin resistant people than in normal people. Mechanisms, linking inflammation to insulin resistance are being explored and progress has been made in this direction. TNFalpha has been shown to be responsible for insulin resistance in obese subjects. Macronutrient intake may also induce inflammation whereas fasting has anti-inflammatory effects. Insulin itself has been found to be anti-inflammatory and this action may be useful in many disease states. Thiazolidinediones, such as rosiglitazone that act primarily as insulin sensitisers, have a profound anti-inflammatory and potentially antiatherosclerotic activity. These effects may be of considerable clinical significance if sustained during long-term therapy, given the morbidity and mortality associated with atherosclerosis, the major complication of insulin resistance.     

Spatial memory impairment without apoptosis induced by the combination of beta-amyloid oligomers and cerebral ischemia is related to decreased acetylcholine release in rats

The purpose of the present study was to examine the effect of beta-amyloid (Abeta) oligomers, not the fibrils that make up Abeta plaques, on spatial memory and the cholinergic system in rats. Recently, several researchers have suggested that small assemblies of Abeta, Abeta oligomers, caused memory loss during the early stages of Alzheimer's disease without showing cell death. In the present study, the combination of Abeta oligomers and cerebral ischemia, but not cerebral ischemia alone, significantly impaired spatial memory without apoptosis in the CA1 region of the hippocampus. Donepezil, an acetylcholinesterase inhibitor, ameliorated this memory impairment. Therefore we examined acetylcholine (ACh) release from the dorsal hippocampus. A microdialysis study showed that spontaneous release of ACh was not significantly decreased by the combination of Abeta oligomers and cerebral ischemia; however, high K(+)-evoked ACh release was decreased. These results suggest that a combination of Abeta oligomers and cerebral ischemia induces memory impairment by cholinergic synapse dysfunction without apoptosis. This model may be useful for developing new drugs for the treatment of early-phase Alzheimer's disease.     

Neuroprotective effects of estrogens: cross-talk between estrogen and intracellular insulin signalling

The incidence of neurodegenerative diseases is higher in postmenopausal women that young women. In this sense, Alzheimer's and Parkinson's diseases, ischemic brain injury and memory or cognitive dysfunction increase dramatically when the ovarian function declines. On the other hand, insulin resistance represents an independent factor in the etiology of age-associated coronary and cerebrovascular disease. Therefore, depression, neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and memory or cognitive dysfunction should be considered, in some cases, a result of metabolic syndrome, and that postmenopausal women are more vulnerable that young women to these diseases Several studies have suggested that the molecular mechanism by which estradiol exerts its neuroprotective effects involves activation of the PI3-k signalling pathway, which is activated by insulin and IGF-1. Therefore, it seems possible that ERalpha can interact with these signalling pathways, mainly with PI3-k and IRS-1, to promote neuroprotective effects in the brain. In particular, IGF-I seems to be particularly important in the process of neuroprotection; it can reverse age-related effects and attenuate the age-related decrease in cerebral glucose utilization. Moreover, gonadal hormones have been found to regulate IGF-I receptor. Therefore, it seems clear that the interaction of both systems plays a role in the prevention of neuronal age-related effects. These findings suggest that by interacting with some components of the IGF-I signalling pathway, ERalpha affects the actions of IGF-I in the brain and suggest future avenues of research. The relationship between insulin resistance states associated with aging in females, and the cross-talk between estradiol and proteins includes in the IRS-1/PI3-k/Akt and IGF-1-IR signalling pathways, will lead to a more complete understanding of the precise mechanism underlying estradiol-mediated neuroprotection. Numerous clinical studies have demonstrated that the incidence of neurodegenerative diseases in higher in postmenopausal women that young women. In this sense, Alzheimer's and Parkinson's disease, ischemic brain injury and memory or cognitive dysfunction increase dramatically when the ovarian function declines. Moreover, estrogen replacement therapy seems to be a good element in order to decrease the risk and/or severity of neurodegenerative conditions, and it would be able to improve some aspects related to memory and learning process.     

The inhibition of gamma-secretase as a therapeutic approach to Alzheimer's disease

Alzheimer's disease is a dementing neurodegenerative disorder for which there is no effective treatment at present. Genetic and biological studies provide evidence that the production and deposition of amyloid-beta peptides (Abeta contribute to the etiology of Alzheimer's disease. gamma-Secretase is the pivotal enzyme in generating the C terminus of Abeta which determines its aggregability and speed of deposition. Drugs that regulate the production of Abeta by inhibiting gamma-secretase activity could provide an effective therapy for Alzheimer's disease, although recent studies suggest that gamma-secretase plays important roles in cellular signaling. This review focuses on studies of the gamma-secretase biology and provides the direction for developing effective and selective gamma-secretase inhibitors as drugs for the treatment of Alzheimer's disease.     

Abeta immunotherapy and other means to remove amyloid

The amyloid cascade hypothesis postulates that accumulation of beta-amyloid (Abeta) plays a key role in the development of Alzheimer's disease (AD). Accordingly, much effort has gone into reducing the amyloid burden, especially in transgenic mice expressing mutations in human amyloid precursor protein. Such mice develop amyloid plaques but not neurofibrillary tangles. Immunization with Abeta and other inflammatory stimuli, inhibitors of Abeta formation, cholesterol lowering agents, beta-sheet breaker peptides, antioxidants and various miscellaneous agents have been found to reduce the more soluble Abeta in such transgenic mice. Whether they would affect the more consolidated, cross-linked Abeta of AD and, if they did, whether that would really prove an effective treatment for the disease remains for future research to determine.