Blocking substance P signaling reduces musculotendinous and dermal fibrosis and sensorimotor declines in a rat model of overuse injury.

Purpose/Aim: Substance P-NK-1R signaling has been implicated in fibrotic tendinopathies and myositis. Blocking this signaling with a neurokinin 1 receptor antagonist (NK1RA) has been proposed as a therapeutic target for their treatment.Materials and Methods: Using a rodent model of overuse injury, we pharmacologically blocked Substance P using a specific NK1RA with the hopes of reducing forelimb tendon, muscle and dermal fibrogenic changes and associated pain-related behaviors. Young adult rats learned to pull at high force levels across a 5-week period, before performing a high repetition high force (HRHF) task for 3 weeks (2 h/day, 3 days/week). HRHF rats were untreated or treated in task weeks 2 and 3 with the NK1RA, i.p. Control rats received vehicle or NK1RA treatments.Results: Grip strength declined in untreated HRHF rats, and mechanical sensitivity and temperature aversion increased compared to controls; these changes were improved by NK1RA treatment (L-732,138). NK1RA treatment also reduced HRHF-induced thickening in flexor digitorum epitendons, and HRHF-induced increases of TGFbeta1, CCN2/CTGF, and collagen type 1 in flexor digitorum muscles. In the forepaw upper dermis, task-induced increases in collagen deposition were reduced by NK1RA treatment.Conclusions: Our findings indicate that Substance P plays a role in the development of fibrogenic responses and subsequent discomfort in forelimb tissues involved in performing a high demand repetitive forceful task.

Olfactory cell cultures to investigate health effects of air pollution exposure: Implications for neurodegeneration.

Air pollution is a major, global public health concern. A growing body of evidence shows that exposure to air pollutants may impair the brain. Living in highly polluted areas has been linked to several neurodegenerative diseases, where exposure to complex mixtures of air pollutants in urban environments may have harmful effects on brain function. These harmful effects are thought to originate from elevated inflammation and oxidative stress. The olfactory epithelium is a key entry site of air pollutants into the brain as the particles are deposited in the upper airways and the nasal region. A potential source of patient-derived cells for study of air pollutant effects is the olfactory mucosa, which constitutes a central part of the olfactory epithelium. This review first summarizes the current literature on the available in vitro models of the olfactory epithelium. It then describes how alterations of the olfactory mucosa are linked to neurodegeneration and discusses potential therapeutic applications of these cells for neurodegenerative diseases. Finally, it reviews the research performed on the effects of air pollutant exposure in cells of the olfactory epithelium. Patient-derived olfactory epithelial models hold great promise for not only elucidating the molecular and cellular pathophysiology of neurodegenerative disorders, but for providing key understanding about air pollutant particle entry and effects at this key brain entry site.

Alteration of in vivo cellulose ribbon assembly by carboxymethylcellulose and other cellulose derivatives.

In vivo cellulose ribbon assembly by the Gram-negative bacterium Acetobacter xylinum can be altered by incubation in carboxymethylcellulose (CMC), a negatively charged water-soluble cellulose derivative, and also by incubation in a variety of neutral, water-soluble cellulose derivatives. In the presence of all of these substituted celluloses, normal fasciation of microfibril bundles to form the typical twisting ribbon is prevented. Alteration of ribbon assembly is most extensive in the presence of CMC, which often induces synthesis of separate, intertwining bundles of microfibrils. Freeze-etch preparations of the bacterial outer membrane suggest that particles that are thought to be associated with cellulose synthesis or extrusion may be specifically organized to mediate synthesis of microfibril bundles. These data support the previous hypothesis that the cellulose ribbon of A. xylinum is formed by a hierarchical, cell-directed, self-assembly process. The relationship of these results to the regulation of cellulose microfibril size and wall extensibility in plant cell walls is discussed.

Diminished gastric prokinetic response to ghrelin in a rat model of spinal cord injury.

BACKGROUND: Patients with cervical or high-thoracic spinal cord injury (SCI) often present reduced gastric emptying and early satiety. Ghrelin provokes motility via gastric vagal neurocircuitry and ghrelin receptor agonists offer a therapeutic option for gastroparesis. We have previously shown that experimental high-thoracic injury (T3-SCI) diminishes sensitivity to another gastrointestinal peptide, cholecystokinin. This study tests the hypothesis that T3-SCI impairs the vagally mediated response to ghrelin. METHODS: We investigated ghrelin sensitivity in control and T3-SCI rats at 3-days or 3-weeks after injury utilizing: (i) acute (3-day post-injury) fasting and post-prandial serum levels of ghrelin; (ii) in vivo gastric reflex recording following intravenous or central brainstem ghrelin; and (iii) in vitro whole cell recording of neurons within the dorsal motor nucleus of the vagus (DMV). KEY RESULTS: The 2-day food intake of T3-SCI rats was reduced while fasting serum ghrelin levels were higher than in controls. Intravenous and fourth ventricle ghrelin increased in vivo gastric motility in fasted 3-day control rats but not fasted T3-SCI rats. In vitro recording of DMV neurons from 3-day T3-SCI rats were insensitive to exogenous ghrelin. For each measure, vagal responses returned after 3-weeks. CONCLUSIONS AND INFERENCES: Hypophagia accompanying T3-SCI produces a significant and physiologically appropriate elevation in serum ghrelin levels. However, higher ghrelin levels did not translate into increased gastric motility in the acute stage of T3-SCI. We propose that this may reflect diminished sensitivity of peripheral vagal afferents to ghrelin or a reduction in the responsiveness of medullary gastric vagal neurocircuitry following T3-SCI.

Acupuncture and related interventions for smoking cessation.

BACKGROUND: Acupuncture and related techniques are promoted as a treatment for smoking cessation in the belief that they may reduce nicotine withdrawal symptoms. OBJECTIVES: The objectives of this review are to determine the effectiveness of acupuncture and the related interventions of acupressure, laser therapy and electrostimulation, in smoking cessation in comparison with no intervention, sham treatment, or other interventions. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group specialized register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, BIOSIS Previews, PsycINFO, Science and Social Sciences Citation Index, AMED and CISCOM. Date of last search January 2005. SELECTION CRITERIA: Randomized trials comparing a form of acupuncture, acupressure, laser therapy or electrostimulation with either no intervention, sham treatment or another intervention for smoking cessation. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of smokers recruited, the nature of the acupuncture and control procedures, the outcome measures, method of randomization, and completeness of follow up. We assessed abstinence from smoking at the earliest time-point (before six weeks), and at the last measurement point between six months and one year. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Those lost to follow up were counted as continuing smokers. Where appropriate, we performed meta-analysis using a fixed-effect model. MAIN RESULTS: We identified 24 reports of studies. The only comparison for which there were sufficient studies to combine meaningfully was acupuncture compared with sham acupuncture. The fixed-effect odds ratio (OR) for the short-term effect was 1.36 (95% confidence interval 1.07 to 1.72), but the studies are heterogeneous and the result is strongly influenced by one individual positive study. The significant short-term effect was lost with the random-effects model for pooling, or by removing the outlying study that led to heterogeneity. The long-term result shows no effect of acupuncture compared with sham acupuncture. There was no consistent evidence that acupuncture is superior to no treatment, and no evidence that the effect of acupuncture was different from that of other anti-smoking interventions, or that any particular acupuncture technique is superior to other techniques. AUTHORS' CONCLUSIONS: There is no consistent evidence that acupuncture, acupressure, laser therapy or electrostimulation are effective for smoking cessation, but methodological problems mean that no firm conclusions can be drawn. Further research using frequent or continuous stimulation is justified.

Autogenic training for tension type headaches: a systematic review of controlled trials.

OBJECTIVE: To determine from the published evidence whether autogenic training as sole therapy is effective for prevention of tension-type headaches in adults. METHOD: Systematic review of controlled trials. Literature searches were performed in January 2005 in six major databases, specifically Medline, EMBASE, AMED, CENTRAL, PsychInfo and CINAHL and information was extracted and evaluated in a pre-defined manner. RESULTS: Seven controlled clinical trials were included in the review. The methodological quality of these studies was low. Patient samples were generally representative of the more severely affected cases. None of the studies show autogenic training to be convincingly superior to other interventions care. Some trials suggested that the effect of autogenic training is no different from hypnosis and inferior to biofeedback. CONCLUSION: There is no consistent evidence to suggest that autogenic training is superior to other interventions for prevention of tension headaches, or different from other forms of relaxation. Further studies should investigate the use of standard autogenic training in patients with moderate headache.

Endogenous Cu in the central nervous system fails to satiate the elevated requirement for Cu in a mutant SOD1 mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, a fatal degenerative disorder in which motor neurons in the central nervous system (CNS) progressively deteriorate. Most cases of ALS are sporadic, but 10% are familial and mutations affecting the copper (Cu)-dependent antioxidant Cu/Zn-superoxide dismutase (SOD1) are the most common familial cause. Cu malfunction is evident in CNS tissue from transgenic mice that over-express mutant SOD1 and modulating Cu bioavailability in the CNS provides positive therapeutic outcomes. In the present study we assessed levels of Cu and Zn, SOD activity, and SOD1 protein levels in CNS and non-CNS tissue from transgenic mutant SOD1 mice (SOD1(G37R)) and non-transgenic controls. Physiological SOD1 binds one structural Zn and one catalytic Cu per subunit. Due to over-expression of the transgene, SOD activity and SOD1 protein levels are elevated in all tissues examined from the SOD1(G37R) mice and a commensurate increase in Zn is evident. There is a comparable increase in Cu in non-CNS tissue, but the increase in Cu in the SOD1(G37R) mouse brain is limited and there is no increase in Cu in the spinal cord. The limited change in CNS Cu is associated with a strong disparity between SOD1 protein and SOD activity in the brain and spinal cord. We hypothesise that the limited capacity for CNS tissue to respond to an increased requirement for bioavailable Cu contributes to CNS vulnerability in ALS.

Restoration of intestinal function in an MPTP model of Parkinson's Disease.

Patients with Parkinson's disease often experience non-motor symptoms including constipation, which manifest prior to the onset of debilitating motor signs. Understanding the causes of these non-motor deficits and developing disease modifying therapeutic strategies has the potential to prevent disease progression. Specific neuronal subpopulations were reduced within the myenteric plexus of mice 21 days after intoxication by the intraperitoneal administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and was associated with a reduction in stool frequency, indicative of intestinal dysfunction. Oral administration of the divalent copper complex, Cu(II)(atsm), which has been shown to be neuroprotective and restore motor performance to MPTP lesioned mice, improved stool frequency and was correlated with restoration of neuronal subpopulations in the myenteric plexus of MPTP lesioned mice. Restoration of intestinal function was associated with reduced enteric glial cell reactivity and reduction of markers of inflammation. Therapeutics that have been shown to be neuroprotective in the central nervous system, such as Cu(II)(atsm), therefore also provide symptom relief and are disease modifying in the intestinal tract, suggesting that there is a common cause of Parkinson's disease pathogenesis in the enteric nervous system and central nervous system.

The Alzheimer's disease amyloid precursor protein modulates copper-induced toxicity and oxidative stress in primary neuronal cultures.

The amyloid precursor protein (APP) of Alzheimer's disease can reduce copper (II) to copper (I) in a cell-free system potentially leading to increased oxidative stress in neurons. We used neuronal cultures derived from APP knock-out (APP(-/-)) and wild-type (WT) mice to examine the role of APP in copper neurotoxicity. WT cortical, cerebellar, and hippocampal neurons were significantly more susceptible than their respective APP(-/-) neurons to toxicity induced by physiological concentrations of copper but not by zinc or iron. There was no difference in copper toxicity between APLP2(-/-) and WT neurons, demonstrating specificity for APP-associated copper toxicity. Copper uptake was the same in WT and APP(-/-) neurons, suggesting APP may interact with copper to induce a localized increase in oxidative stress through copper (I) production. This was supported by significantly higher levels of copper-induced lipid peroxidation in WT neurons. Treatment of neuronal cultures with a peptide corresponding to the human APP copper-binding domain (APP142-166) potentiated copper but not iron or zinc toxicity. Incubation of APP142-166 with low-density lipoprotein (LDL) and copper resulted in significantly increased lipid peroxidation compared to copper and LDL alone. Substitution of the copper coordinating histidine residues with asparagines (APP142-166(H147N, H149N, H151N)) abrogated the toxic effects. A peptide corresponding to the zinc-binding domain (APP181-208) failed to induce copper or zinc toxicity in neuronal cultures. These data support a role for the APP copper-binding domain in APP-mediated copper (I) generation and toxicity in primary neurons, a process that has important implications for Alzheimer's disease and other neurodegenerative disorders.

The evolution of oscillatory behavior in age-structured species.

A major challenge in ecology is to explain why so many species show oscillatory population dynamics and why the oscillations commonly occur with particular periods. The background environment, through noise or seasonality, is one possible driver of these oscillations, as are the components of the trophic web with which the species interacts. However, the oscillation may also be intrinsic, generated by density-dependent effects on the life history. Models of structured single-species systems indicate that a much broader range of oscillatory behavior than that seen in nature is theoretically possible. We test the hypothesis that it is selection that acts to constrain the range of periods. We analyze a nonlinear single-species matrix model with density dependence affecting reproduction and with trade-offs between reproduction and survival. We show that the evolutionarily stable state is oscillatory and has a period roughly twice the time to maturation, in line with observed patterns of periodicity. The robustness of this result to variations in trade-off function and density dependence is tested.

Acupuncture for back pain: a meta-analysis of randomized controlled trials.

BACKGROUND: Acupuncture is commonly used to treat back pain, but there is no published meta-analysis of trials of its effectiveness for this condition. OBJECTIVE: To perform a meta-analysis of trials of acupuncture for the treatment of back pain. METHODS: A systematic literature search was conducted to retrieve all randomized controlled trials of any form of acupuncture for any type of back pain in humans. The adequacy of the acupuncture treatment was assessed by consulting 6 experienced acupuncturists. The main outcome measure for the meta-analysis was numbers of patients whose symptoms were improved at the end of treatment. RESULTS: Twelve studies were included, of which 9 presented data suitable for meta-analysis. The odds ratio of improvement with acupuncture compared with control intervention was 2.30 (95% confidence interval, 1.28-4.13). For sham-controlled, evaluator-blinded studies, the odds ratio was 1.37 (95% confidence interval, 0.84-2.25). CONCLUSION: Acupuncture was shown to be superior to various control interventions, although there is insufficient evidence to state whether it is superior to placebo.

Randomized trial of acupuncture for nicotine withdrawal symptoms.

BACKGROUND: Acupuncture is frequently used for smoking cessation. Positive results from uncontrolled studies have not been supported by meta-analysis of controlled trials. One possible reason for this is that the optimal acupuncture technique was not applied or that the technique was not repeated sufficiently often. METHODS: A randomized, sham-controlled trial was performed with 2 parallel treatment arms; the participant and the evaluator were unaware of which treatment was received. Seventy-six adults who wanted to stop smoking received either 100-Hz electroacupuncture with needles inserted into the appropriate point in each ear or a sham control procedure over the mastoid bone. Interventions were given on days 1, 3, and 7 of smoking cessation. Nicotine withdrawal symptoms were measured by visual analog scale scores recorded in a daily diary for 14 days; smoking cessation was confirmed objectively. RESULTS: There was no significant difference between the mean reduction of withdrawal symptom scores of the 2 groups from day 1 to day 14. Fifteen participants (39%) who received electroacupuncture and 16 participants (42%) who received a sham procedure were abstinent on day 14. CONCLUSION: This form of electroacupuncture is no more effective than placebo in reducing nicotine withdrawal symptoms.

Complementary medicine. What physicians think of it: a meta-analysis.

BACKGROUND: Complementary (or alternative) medicine has become a prevalent phenomenon in most industrialized countries. At present the evidence from randomized controlled trials investigating its effectiveness is fragmentary and therefore inconclusive. OBJECTIVE: To assess whether physicians perceive complementary medicine as useful and/or effective. METHOD: A literature search was performed to retrieve all relevant articles. Twelve surveys addressing this question were found and analyzed by evaluating perceived usefulness and/or effectiveness. RESULTS: The results show a remarkable variability between surveys. On average physicians perceive complementary medicine as moderately effective--the rating was 46 +/- 18 on a scale of 0 to 100 points. Young physicians seem to judge complementary medicine more optimistically than their more seasoned colleagues. There is no trend to suggest that complementary medicine is increasingly perceived as useful and/or effective. The data do not answer the question whether physicians view complementary medicine as a nonspecific powerful placebo or as specifically effective. CONCLUSION: Complementary medicine may be useful; however, the notion urgently needs to be tested in randomized controlled trials.

Amyloid beta.

Amyloid beta (A beta) is a 39-43 residue amyloidogenic peptide that is deposited into the extracellular amyloid plaques which characterize an Alzheimer's disease (AD) brain. A beta is derived from the amyloid precursor protein (APP) and undergoes a toxic conformational change (gain of toxic function). The length of the A beta peptide dramatically influences its properties with the longer 42 and 43 residue species being more amyloidogenic. The genetics of familial AD (FAD) supports a central role for A beta in AD since mutations in the FAD causing genes APP and the presenilins (PS1 and PS2) increase the formation of A beta 42,43. Considerable activity is directed towards A beta as a therapeutic target. These strategies aim to inhibit A beta synthesis, A beta fibril formation, its toxic actions on cells or promote its clearance from the brain.

Prospective studies of the safety of acupuncture: a systematic review.

PURPOSE: The objective of this review was to determine the incidence of adverse events associated with acupuncture. SUBJECTS AND METHODS: A search for prospective surveys of the safety of acupuncture was conducted using computerized databases (Medline, Embase, the Cochrane Library, and CISCOM), inquiries to acupuncture organizations, and our own files. Data on sample, size, types of patients duration of study, types of acupuncture, definition of adverse events, method of evaluation, and findings were extracted systematically from the retrieved reports. RESULTS: Nine surveys were located and included in the review. Their results were not uniform. The most common adverse events were needle pain (1% to 45%) from treatments, tiredness (2% to 41%), and bleeding (0.03% to 38%). Feelings of faintness and syncope were uncommon, with an incidence of 0% to 0.3%. Feelings of relaxation were reported by as many as 86% of patients. Pneumothorax was rare, occurring only twice in nearly a quarter of a million treatments. CONCLUSIONS: Although the incidence of minor adverse events associated with acupuncture may be considerable, serious adverse events are rare. Those responsible for establishing competence in acupuncture should consider how to reduce these risks.

Antibacterial activity of ticarcillin in the presence of clavulanate potassium.

The antibacterial effects produced by ticarcillin disodium plus clavulanate potassium, a combination of the broad-spectrum penicillin ticarcillin, and the beta-lactamase inhibitor clavulanic acid as the potassium salt, have been measured in vitro and in experimental infection studies. The presence of clavulanic acid resulted in a significant enhancement of the activity of ticarcillin against a wide range of beta-lactamase-producing bacteria. These included ticarcillin-resistant strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, P. vulgaris, Yersinia enterocolitica, and the anaerobe Bacteroides fragilis. In addition, beta-lactamase-producing isolates of Hemophilus influenzae, Branhamella catarrhalis, Neisseria gonorrhoeae, and Staphylococcus aureus were susceptible to ticarcillin and clavulanate. Clavulanic acid did not influence the activity of ticarcillin against ticarcillin-susceptible bacteria. The bactericidal effects of the antibiotic combination were measured in an in vitro kinetic model in which the drug concentrations were varied to simulate those measured in humans after intravenous dosing with ticarcillin (3.0 g) and clavulanate potassium (100 mg clavulanic acid). In these tests, ticarcillin plus clavulanic acid had pronounced bactericidal activity against ticarcillin-resistant bacteria. The protection of ticarcillin by clavulanic acid from inactivation by bacterial beta-lactamases in vivo was demonstrated in experimental infection models in which the efficacy of the ticarcillin plus clavulanic acid combination against infections caused by beta-lactamase-producing bacteria was correlated with the presence of effective concentrations of both antibiotic and inhibitor at the site of infection.

Autogenic training reduces anxiety after coronary angioplasty: a randomized clinical trial.

OBJECTIVES: Autogenic training (AT) is a method of autosuggestion with some potential for reducing anxiety. This study tests whether AT lowers anxiety levels experienced by patients undergoing coronary angioplasty. METHODS: Fifty-nine patients were randomly assigned to receive regular AT or no such therapy as an adjunct to standard care for 5 months. The primary outcome measure was State Anxiety at 2 months. Qualitative information was generated by face-to-face interviews. RESULTS: State Anxiety showed a significant intergroup difference both at 2 and 5 months. This finding was corroborated by secondary outcome measures, for example, quality of life, and by qualitative information about patients' experiences. The results do not allow us to determine whether the observed effects are specific to AT or of a nonspecific nature. CONCLUSIONS: Our results suggest that AT may have a role in reducing anxiety of patients undergoing coronary angioplasty.

Temocillin. In vitro antibacterial activity.

Temocillin, a 6-alpha-methoxy penicillin derivative, was tested in vitro against 516 recent clinical isolates of Enterobacteriaceae. The compound exhibited good antibacterial activity, with 95% of isolates inhibited by a range 2 to 16 mg/L. Further studies, against selected isolates resistant to ticarcillin, piperacillin and cefuroxime (Klebsiella oxytoca, 25; Enterobacter species, 34; and Citrobacter species, 5), showed about half of the isolates of K. oxytoca (11/25) to be resistant to aztreonam (MIC range 16-greater than or equal to 128 mg/L), but susceptible to temocillin, cefotaxime and latamoxef. In general, the resistant strains of Enterobacter species tested were not susceptible to cefotaxime (MIC range 16-128 mg/L), or aztreonam (MIC range 1.0-64 mg/L), and many exhibited reduced susceptibility to latamoxef (MIC range 2-128 mg/L). In contrast, all the strains were susceptible to temocillin (MIC range 4-16 mg/L). The bactericidal activity of temocillin was confirmed against selected aztreonam-resistant strains of K. oxytoca and Enterobacter cloacae by conventional time-kill studies, and against a strain of E. cloacae in an in vitro model system designed to simulate the temocillin concentration profiles attained in extravascular fluid such as peripheral lymph. In the time-kill studies, temocillin concentrations of 16 and 32 mg/L were shown to effectively reduce the numbers of viable bacteria by 99 and 99.9%, respectively, within 12 hours. In the in vitro model system the numbers of bacteria were reduced 99.9% over the initial 4-hour period. In combination with aminoglycoside antibiotics, temocillin exerted a synergistic or partially synergistic effect (sigma FIC less than or equal to 0.75) against the majority of strains of Pseudomonas aeruginosa tested. When combined with piperacillin, cefotaxime or latamoxef, temocillin, unlike cefoxitin, exhibited no antagonism against strains of Enterobacteriaceae producing inducible cephalosporinases.

Human pharmacokinetics and antimicrobial activities of the temocillin epimers.

The pharmacokinetics of the epimers of temocillin were investigated in 4 healthy male subjects following intravenous administration of 1g of temocillin disodium (free acid) which contains a R : S epimer ratio of approximately 65 : 35. The R epimer had a 2-fold greater total plasma clearance, a 23% larger volume of distribution and a shorter beta half-life than the S epimer. Intermediate values were obtained for total temocillin (R + S) from high pressure liquid chromatography (HPLC) data. In each plasma sample, the unbound fraction of the R epimer was generally 2-fold higher than that of the S epimer, which is suggested as the reason for the differences in the pharmacokinetic properties of the epimers. The temocillin pharmacokinetic parameters obtained from the microbiological assay data reflect most closely those for the R epimer derived from HPLC data. The resolved R epimer exhibited twice the potency of the S epimer against the microbiological assay organism Pseudomonas aeruginosa NCTC 10701. However, in tests for antibacterial susceptibility, for instance minimum inhibitory concentration (MIC) determinations involving prolonged incubation, there was little difference in the inhibitory activities of the resolved R and S epimers compared with temocillin (R + S), presumably as a consequence of the epimerization of the individual epimers. In contrast, in rapid tests for bactericidal activity, which minimise the effect of epimerization, the R epimer exhibited greater bactericidal activity than the S epimer.

Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice.

The pathological process in Alzheimer's disease (AD) involves amyloid beta (Abeta) deposition and neuronal cell degeneration. The neurotoxic Abeta peptide is derived from the amyloid precursor protein (APP), a member of a larger gene family including the amyloid precursor-like proteins, APLP1 and APLP2. The APP and APLP2 molecules contain metal binding sites for copper and zinc. The zinc binding domain (ZnBD) is believed to have a structural rather than a catalytic role. The activity of the copper binding domain (CuBD) is unknown, however, APP reduces copper (II) to copper (I) and this activity could promote copper-mediated neurotoxicity. The expression of APP and APLP2 in the brain suggests they could have an important direct or indirect role in neuronal metal homeostasis. To examine this, we measured copper, zinc and iron levels in the cerebral cortex, cerebellum and selected non-neuronal tissues from APP (APP(-/-)) and APLP2 (APLP2(-/-)) knockout mice using atomic absorption spectrophotometry. Compared with matched wild-type (WT) mice, copper levels were significantly elevated in both APP(-/-) and APLP2(-/-) cerebral cortex (40% and 16%, respectively) and liver (80% and 36%, respectively). Copper levels were not significantly different between knockout and WT cerebellum, spleen or serum samples. There were no significant differences observed between APP(-/-), APLP2(-/-) and WT mice zinc or iron levels in any tissue examined. These findings indicate APP and APLP2 expression specifically modulates copper homeostasis in the liver and cerebral cortex, the latter being a region of the brain particularly involved in AD. Perturbations to APP metabolism and in particular, its secretion or release from neurons may alter copper homeostasis resulting in increased Abeta accumulation and free radical generation. These data support a novel mechanism in the APP/Abeta pathway which leads to AD.