The modulation of metal bio-availability as a therapeutic strategy for the treatment of Alzheimer's disease

The postmortem Alzheimer's disease brain is characterized histochemically by the presence of extracellular amyloid plaques and neurofibrillary tangles. Also consistent with the disease is evidence for chronic oxidative damage within the brain. Considerable research data indicates that these three critical aspects of Alzheimer's disease are interdependent, raising the possibility that they share some commonality with respect to the ever elusive initial factor(s) that triggers the development of Alzheimer's disease. Here, we discuss reports that show a loss of metal homeostasis is also an important event in Alzheimer's disease, and we identify how metal dyshomeostasis may contribute to development of the amyloid-beta, tau and oxidative stress biology of Alzheimer's disease. We propose that therapeutic agents designed to modulate metal bio-availability have the potential to ameliorate several of the dysfunctional events characteristic of Alzheimer's disease. Metal-based therapeutics have already provided promising results for the treatment of Alzheimer's disease, and new generations of pharmaceuticals are being developed. In this review, we focus on copper dyshomeostasis in Alzheimer's disease, but we also discuss zinc and iron.     

Immunology and immunotherapy of Alzheimer's disease

Although Alzheimer's disease is considered to be a degenerative brain disease, it is clear that the immune system has an important role in the disease process. As discussed in this Review, immune-based therapies that are designed to remove amyloid-beta peptide from the brain have produced positive results in animal models of the disease and are being tested in humans with Alzheimer's disease. Although immunotherapy holds great promise for the treatment of Alzheimer's disease, clinical trials of active amyloid-beta vaccination of patients with Alzheimer's disease were discontinued after some patients developed meningoencephalitis. New immunotherapies using humoral and cell-based approaches are currently being investigated for the treatment and prevention of Alzheimer's disease.     

Akt/GSK3beta serine/threonine kinases: evidence for a signalling pathway mediated by familial Alzheimer's disease mutations

Although Alzheimer's disease pathologically affects the brain, familial Alzheimer's disease associated mutations of beta-amyloid precursor protein and presenilin are ubiquitously expressed and therefore aberrant intracellular signals, separate from but similar to, the brain may be expected. Here, we report selective down regulation of the serine/threonine kinase, Akt/PKB, concurrent with elevated endogenous GSK3beta kinase activity in familial Alzheimer's disease beta-amyloid precursor protein expressing human embryonic kidney (HEK) and familial Alzheimer's disease presenilin lymphoblast cells. Further, familial Alzheimer's disease presenilin in the human lymphoblast was associated with beta-catenin destabilization. Moreover, limited immunohistochemistry analysis reveals Akt/PKB in a subset of neurofibrillary tangles where GSK3beta and tau have been reported to co-localize, suggesting a possible Akt/GSK3beta and tau interaction in vivo. Our data suggest that familial Alzheimer's disease mutants of beta-amyloid precursor protein and presenilin signal, at least in part, through the Akt/GSKbeta pathway and that Akt/GSK3beta-mediated signalling may contribute to the underlying Alzheimer's disease pathogenesis induced by familial Alzheimer's disease mutants.     

Proteoglycans and the acute-phase response in Alzheimer's disease brain

Alzheimer's disease is a dementing disorder affecting increasingly large numbers of individuals in the aging population. The characteristic neuropathologic changes of Alzheimer's disease are the deposition of extracellular is the major constituent of senile plaques. In addition to the A4 peptide, senile plaques contain a variety of molecular species, including proteoglycans and inflammatory components. The presence of proteoglycans in the amyloid deposits of Alzheimer's disease and of systemic amyloidoses suggests that these molecules play an active role in the pathogenesis of amyloidosis. However, the molecular mechanisms that lead to the codeposition of amyloid peptide with proteoglycans is still unknown. Recent evidence suggests that the metabolism of proteoglycans is altered in Alzheimer's disease patients. The acute-phase response observed in the brain of patients affected by Alzheimer's disease may be responsible for this effect. In this article, we discuss the role of proteoglycans in Alzheimer's disease, and the possible interactions between factors involved in brain inflammatory mechanisms and proteoglycans in the pathogenesis of Alzheimer's disease     

Is hypercholesterolemia a risk factor for alzheimer’s disease?

There is considerable attention being given to the association of Alzheimer's disease and cholesterol homeostasis. To that end, some have suggested that elevated cholesterol levels are a risk factor for Alzheimer's disease. If elevated cholesterol is a risk factor for Alzheimer's disease, then it would be expected that patients with Alzheimer's disease would have elevated serum and brain cholesterol levels. Studies were reviewed that have examined cholesterol levels in Alzheimer's patients and control subjects, including prospective studies, and based on that review, the conclusion is reached that the majority of studies do not support elevated cholesterol levels in serum and brain as a risk factor for Alzheimer's disease. Alternative hypotheses are discussed, including cholesterol domains and subgroups of individuals with hypercholesteremia.     

Oxidative damage in cultured human olfactory neurons from Alzheimer's disease patients

Oxidative abnormalities precede clinical and pathological manifestations of Alzheimer's disease and are the earliest pathological changes reported in the disease. The olfactory pathways and mucosa also display the pathological features associated with Alzheimer's disease in the brain. Olfactory neurons are unique because they can undergo neurogenesis and are able to be readily maintained in cell culture. In this study, we examined neuronal cell cultures derived from olfactory mucosa of Alzheimer's disease and control patients for oxidative stress responses. Levels of lipid peroxidation (hydroxynonenal), N(epsilon)-(carboxymethyl)lysine (glycoxidative and lipid peroxidation), and oxidative stress response (heme oxygenase-1) were measured immunocytochemically. We found increased levels for all the oxidative stress markers examined in Alzheimer's disease neurons as compared to controls. Interestingly, in one case of Alzheimer's disease, we found hydroxynonenal adducts accumulated in cytoplasmic lysosome-like structures in about 20% of neurons cultured, but not in neurons from control patients. These lysosome-like structures are found in about 100% of the vulnerable neurons in brains of cases of Alzheimer's disease. This study suggests that manifestations of oxidative imbalance in Alzheimer's disease extend to cultured olfactory neurons. Primary culture of human olfactory neurons will be useful in understanding the mechanism of oxidative damage in Alzheimer's disease and can even be utilized in developing therapeutic strategies.     

Modeling of pathological traits in Alzheimer's disease based on systemic extracellular signaling proteome

The study of chronic brain diseases including Alzheimer's disease in patients is typically limited to brain imaging or psychometric testing. Given the epidemic rise and insufficient knowledge about pathological pathways in sporadic Alzheimer's disease, new tools are required to identify the molecular changes underlying this disease. We hypothesize that levels of specific secreted cellular signaling proteins in cerebrospinal fluid or plasma correlate with pathological changes in the Alzheimer's disease brain and can thus be used to discover signaling pathways altered in the disease. Here we measured 91 proteins of this subset of the cellular communication proteome in plasma or cerebrospinal fluid in patients with Alzheimer's disease and cognitively normal controls to mathematically model disease-specific molecular traits. We found small numbers of signaling proteins that were able to model key pathological markers of Alzheimer's disease, including levels of cerebrospinal fluid β-amyloid and tau, and classify disease in independent samples. Several of these factors had previously been implicated in Alzheimer's disease supporting the validity of our approach. Our study also points to proteins which were previously unknown to be associated with Alzheimer's disease thereby implicating novel signaling pathways in this disorder.     

Can statin therapy really reduce the risk of Alzheimer's disease and slow its progression?

PURPOSE OF REVIEW: Statins are the most used cholesterol-lowering agents worldwide. Earlier studies suggested that they may have preventive effects in Alzheimer's disease. However, prospective studies have questioned this hypothesis. RECENT FINDINGS: Statins regulate beta-amyloid metabolism and microglial activation. Pathologically, patients with Alzheimer's disease have more severe atherosclerosis in cerebral arteries than do controls. Such lesions may cause cerebral hypoperfusion, a risk factor for dementia and cognitive decline. Although most population-based studies have failed to show a beneficial effect of statins in Alzheimer's disease, two randomized controlled trials suggested that statins slow cognitive decline in mild to moderate Alzheimer's disease. SUMMARY: There is still some hope that statins reduce the incidence of Alzheimer's disease and slow its progression. Large-scale randomized controlled trials of simvastatin and atorvastatin for mild to moderate Alzheimer's disease are underway, which might provide more conclusive results than earlier studies.     

Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease

The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of a number of biologically active molecules. Among them, the neurotoxin quinolinic acid (QUIN), is considered to be involved in the pathogenesis of a number of inflammatory neurological diseases. Alzheimer's disease is the major dementing disorder of the elderly that affects over 20 million peoples world-wide. Most of the approaches to explain the pathogenesis of Alzheimer's disease focus on the accumulation of amyloid beta peptide (A beta), in the form of insoluble deposits leading to formation of senile plaques, and on the formation of neurofibrillary tangles composed of hyperphosphorylated Tau protein. Accumulation of A beta is believed to be an early and critical step in the neuropathogenesis of Alzheimer's disease. There is now evidence for the KP being associated with Alzheimer's disease. Disturbances of the KP have already been described in Alzheimer's disease. Recently, we demonstrated that A beta 1-42, a cleavage product of amyloid precursor protein, induces production of QUIN, in neurotoxic concentrations, by macrophages and, more importantly, microglia. Senile plaques in Alzheimer's disease are associated with evidence of chronic local inflammation (especially activated microglia) A major aspect of QUIN toxicity is lipid peroxidation and markers of lipid peroxidation are found in Alzheimer's disease. Together, these data imply that QUIN may be one of the critical factors in the pathogenesis of neuronal damage in Alzheimer's disease. This review describes the multiple correlations between the KP and the neuropathogenesis of Alzheimer's disease and highlights more particularly the aspects of QUIN neurotoxicity, emphasizing its roles in lipid peroxidation and the amplification of the local inflammation.     

Alzheimer disease: mercury as pathogenetic factor and apolipoprotein E as a moderator

The etiology of most cases of Alzheimer's disease (AD) is as yet unknown. Epidemiological studies suggest that environmental factors may be involved beside genetic risk factors. Some studies have shown higher mercury concentrations in brains of deceased and in blood of living patients with Alzheimer's disease. Experimental studies have found that even smallest amounts of mercury but no other metals in low concentrations were able to cause all nerve cell changes, which are typical for Alzheimer's disease. The most important genetic risk factor for sporadic Alzheimer's disease is the presence of the apolipoprotein Ee4 allele whereas the apolipoprotein Ee2 allele reduces the risk of developing Alzheimer's disease. Some investigators have suggested that apolipoprotein Ee4 has a reduced ability to bind metals like mercury and therefore explain the higher risk for Alzheimer's disease. Therapeutic approaches embrace pharmaceuticals which bind metals in the brain of patients with Alzheimer's disease. In sum, both the findings from epidemiological and demographical studies, the frequency of amalgam application in industrialized countries, clinical studies, experimental studies and the dental state of AD patients in comparison to controls suggest a decisive role for inorganic mercury in the etiology of AD.     

Amyloid beta-protein and lipid metabolism

Lipids play an important part as risk or protective factors for Alzheimer's disease. This review summarizes the current findings in which lipids influence Alzheimer's disease and introduces the molecular mechanism how these lipids are linked to amyloid production. Besides the pathological impact of amyloid in Alzheimer's disease, amyloid has a physiological function in regulating lipid homeostasis in return. The understanding of the resulting regulatory cycles between amyloid precursor protein processing and lipids provides a platform for the development of new causal therapeutic approaches for Alzheimer's disease.     

Cholesterol metabolism, apolipoprotein E, adenosine triphosphate-binding cassette transporters, and Alzheimer's disease

PURPOSE OF REVIEW: Recent evidence suggests that cholesterol metabolism participates in the pathogenesis of Alzheimer's disease. Apolipoprotein E is the main lipid carrier in the brain and the best-established risk factor for late-onset Alzheimer's disease. Intracellular cholesterol levels influence the generation of amyloid-beta peptides, the toxic species thought to be a primary cause of Alzheimer's disease. Finally, compounds that modulate cholesterol metabolism affect amyloid-beta generation. This review summarizes data linking apolipoprotein E and adenosine triphosphate-binding cassette transporters to aspects of cholesterol metabolism and Alzheimer's disease pathogenesis. RECENT FINDINGS: In vivo, the lipidation status of apolipoprotein E affects amyloid-beta burden in mice with Alzheimer's disease, which appears to caused by the modulation of amyloid-beta deposition or clearance rather than amyloid-beta production. State-of-the-art in-vivo assays reveal that amyloid-beta is cleared from the brain by multiple pathways. Members of the adenosine triphosphate-binding cassette superfamily of transporters regulate lipid homeostasis and apolipoprotein metabolism in the brain, and may affect Alzheimer's disease pathogenesis by modulating apolipoprotein E lipidation as well as intracellular sterol homeostasis. SUMMARY: Proteins involved in brain cholesterol metabolism may affect the pathogenesis of Alzheimer's disease. Compounds that modulate the expression of these proteins may be of therapeutic benefit in Alzheimer's disease.     

Amyloid beta-protein and lipid metabolism

Lipids play an important part as risk or protective factors for Alzheimer's disease. This review summarizes the current findings in which lipids influence Alzheimer's disease and introduces the molecular mechanism how these lipids are linked to amyloid production. Besides the pathological impact of amyloid in Alzheimer's disease, amyloid has a physiological function in regulating lipid homeostasis in return. The understanding of the resulting regulatory cycles between amyloid precursor protein processing and lipids provides a platform for the development of new causal therapeutic approaches for Alzheimer's disease.     

The Endosomal-Lysosomal System of Neurons in Alzheimer's Disease Pathogenesis: A Review

A prominent feature of brain pathology in Alzheimer's disease is a robust activation of the neuronal lysosomal system and major cellular pathways converging on the lysosome, namely, endocytosis and autophagy. Recent studies that identify a disturbance of the endocytic pathway as one of the earliest known manifestation of Alzheimer's disease provide insight into how beta-amyloidogenesis might be promoted in sporadic Alzheimer's disease, the most prevalent and least well understood form of the disease. Primary lysosomal dysfunction has historically been linked to neurodegeneration. New data now directly implicate cathepsins as proteases capable of initiating, as well as executing, cell death programs in certain pathologic states. These and other studies support the view that the progressive alterations of lysosomal function observed during aging and Alzheimer's disease contribute importantly to the neurodegenerative process in Alzheimer's disease.     

Changes of Activity and Isozyme Pattern of Phosphofructokinase in the Brains of Patients with Alzheimer's Disease

Abstract: A severe reduction of the in vivo cerebral glucose consumption rate is generally found in patients with Alzheimer's disease. In postmortem studies changes in the activities of key regulatory glycolytic enzymes, including 6-phosphofructokinase (PFK), have been reported in Alzheimer's disease brains, but the results obtained so far are inconsistent and controversial. We reevaluated the activity of PFK in brain tissue from clinically and neuropathologically confirmed cases of Alzheimer's disease using optimized tissue disintegration and assay methods and determined the PFK isozyme pattern. PFK activity in brains from patients with Alzheimer's disease was significantly increased in frontal and temporal cortex and unchanged in the other brain areas studied when compared with control brains. All three PFK isozymes were detected in each of the brain areas studied. In brains of Alzheimer's disease patients the level of the C-type PFK was slightly reduced at the expense of the M- and L-type subunits. The data presented do not support the results of other groups, which reported up to a 90% reduction of PFK activity in Alzheimer's disease. In contrast, the data presented clearly rule out the suggestion that changes of PFK activity might be one of the causes for the reduced glucose consumption in Alzheimer's disease brains.     

Alterations of selected enzymes of phospholipid metabolism in Alzheimer's disease brain tissue as compared to non-Alzheimer's demented controls

Previous studies have demonstrated elevated brain levels of phosphomonoesters in early stages of Alzheimer's disease and elevations of phosphodiesters later in the disease. In addition, preliminary quantitative analyses of the phospholipids of Alzheimer's brain reveals either decreases in some phospholipids or elevations followed by decreases in others. This study quantitated the activities of selected enzymes involved in phospholipid and choline metabolism and demonstrated elevated glycerol-3-phosphorylcholine phosphodiesterase and decreased choline kinase activities in Alzheimer's disease brain. The former could provide an enzymatic mechanism for the increased phosphorylcholine found in Alzheimer's disease brain.     

Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins

A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.     

Alzheimer''s disease: Transgenic models to test new chemicals and pharmaceuticals

Alzheimer's disease is the most common form of senile dementia and is predicted to become even more prevalent as the proportion of elderly in the population increases over the next few decades. As yet, there are no effective treatments for the disorder. A major limitation to identifying new drugs and therapeutic targets for Alzheimer's disease has been the absence of an animal model displaying typical Alzheimer's pathology. Transgenic technology is now providing a powerful new approach for the development of animal models of Alzheimer's disease.     

Wheat germ agglutinin-binding glycoproteins are decreased in Alzheimer's disease cerebrospinal fluid

A number of biomarkers (e.g. Abeta, tau) has been identified in Alzheimer's disease CSF. However, none fulfils the criteria of sensitivity and specificity (> 80%) needed for the development of an accurate diagnostic test. The lack of a suitable marker has prompted the search for new CSF biomarkers. In this study, the glycosylation of CSF proteins was examined using lectin blotting. Lumbar CSF was collected ante mortem from 22 non-Alzheimer's disease and 12 probable Alzheimer's disease cases and ventricular CSF collected post mortem from 7 non-Alzheimer's disease and 16 Alzheimer's disease cases confirmed by pathologic examination. When CSF glycoproteins were stained with wheat germ agglutinin (WGA), the staining intensity was found to be significantly lower in the Alzheimer's disease group. No difference in staining was found using other lectins (Canavalia ensiformis agglutinin, Ricinus communis agglutinin, Lens culinaris agglutinin). The measurement of WGA-reactive glycoproteins in CSF may be a useful biomarker for diagnosis of Alzheimer's disease.     

Neuropeptides in Alzheimer's disease: a postmortem study

The concentration of 5 neuropeptides, neurotensin (NT), somatostatin (SRIF), corticotropin-releasing factor (CRF), bombesin and thyrotropin-releasing hormone (TRH) was measured in 3 cerebrocortical areas and several subcortical regions in post-mortem brains obtained from patients with histologically verified Alzheimer's disease and from controls without neurological or psychiatric disorders using sensitive and specific radioimmunoassay procedures. In Alzheimer's disease, reductions in the concentration of SRIF and CRF were observed in frontal and temporal cortex. In addition, in Alzheimer's disease, SRIF was also reduced in concentration in the hypothalamus, whereas CRF concentrations were reduced in the caudate nucleus. Neurotensin was reduced in concentration in the amygdala in Alzheimer's disease. No alterations in TRH or bombesin/gastrin-releasing peptide were found. These findings provide further evidence for the pathological involvement of certain neuropeptide-containing neurons in Alzheimer's disease.