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Metal/mineral dyshomeostasis has been implicated in the development of Alzheimer’s disease (AD). The aim of the study was to investigate the difference in absolute and percentage levels of plasma phosphorus, calcium, iron, zinc, copper, selenium in cognitively normal (CN) and AD subjects. Total reflection X-ray fluorescence (TXRF) spectroscopy was used to detect plasma metals/minerals in CN and AD subjects (n = 44 per group). TXRF detected significantly increased plasma levels of phosphorus (p = 1.33 × 10−12) and calcium (p = 0.025) in AD compared to CN subjects, with higher phosphorus/calcium (p = 2.55 × 10−14) ratio in the former. Percentage concentrations calculated for phosphorus, calcium, iron, zinc, copper, selenium by dividing the concentration of each element by the total concentration of these elements and multiplying by 100%, demonstrated phosphorus was higher in AD compared to CN subjects, while calcium, iron, zinc, copper and selenium were lower in AD subjects, with area under the curves as high as 0.937 (p = 6 × 10−5) computed from receiver operating curves. With exclusion of high levels of phosphorus and calcium from percentage calculations, iron levels remained low in AD whereas zinc was higher in AD, and copper and selenium levels were similar. We demonstrate altered distribution of elements in the plasma of AD subjects with high interdependencies between elemental levels and propose the potential of TXRF measurements for disease monitoring.

Brain iron dyshomeostasis is a feature of Alzheimer's disease. Conventionally, research has focused on non-heme iron although degradation of heme from hemoglobin subunits can generate iron to augment the redox-active iron pool. Hemopexin both detoxifies heme to maintain iron homeostasis and bolsters antioxidant capacity via catabolic products, biliverdin and carbon monoxide to combat iron-mediated lipid peroxidation. The aim of the present study was to examine the association of cerebrospinal fluid levels (CSF) hemopexin and hemoglobin subunits (α and β) to Alzheimer's pathological proteins (amyloid and tau), hippocampal volume and metabolism, and cognitive performance. We analyzed baseline CSF heme/iron proteins (multiplexed mass spectrometry-based assay), amyloid and tau (Luminex platform), baseline/longitudinal neuroimaging (MRI, FDG-PET) and cognitive outcomes in 86 cognitively normal, 135 mild-cognitive impairment and 66 Alzheimer's participants from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1) cohort. Multivariate regression analysis was performed to delineate differences in CSF proteins between diagnosis groups and evaluated their association to amyloid and tau, neuroimaging and cognition. A p-value ≤ 0.05 was considered significant. Higher hemopexin was associated with higher CSF amyloid (implying decreased brain amyloid deposition), improved hippocampal metabolism and cognitive performance. Meanwhile, hemoglobin subunits were associated with increased CSF tau (implying increased brain tau deposition). When dichotomizing individuals with mild-cognitive impairment into stable and converters to Alzheimer's disease, significantly higher baseline hemoglobin subunits were observed in the converters compared to non-converters. Heme/iron dyshomeostasis is an early and crucial event in AD pathophysiology, which warrants further investigation as a potential therapeutic target.

Alzheimer’s disease is an emerging global epidemic that is becoming increasingly unsustainable. Most of the clinical trials have been centered around targeting β-amyloid and have met with limited success. There is a great impetus to identify alternative drug targets. Iron appears to be the common theme prevalent across neurodegenerative diseases. Iron has been shown to promote aggregation and pathogenicity of the characteristic aberrant proteins, β-amyloid, tau, α-synuclein, and TDP43, in these diseases. Further support for the involvement of iron in pathogenesis is provided by the recent discovery of a new form of cell death, ferroptosis. Arising from iron-dependent lipid peroxidation, ferroptosis is augmented in conditions of cysteine deficiency and glutathione peroxidase-4 inactivation. Here, we review clinical trials that provide the rationale for targeting ferroptosis to delay the pathogenesis of Alzheimer’s disease (AD), potentially of relevance to other neurodegenerative diseases.

Background Heme and iron homeostasis is perturbed in Alzheimer’s disease (AD); therefore, the aim of the study was to examine the levels and association of heme with iron-binding plasma proteins in cognitively normal (CN), mild cognitive impairment (MCI), and AD individuals from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohorts. Methods Non-targeted proteomic analysis by high-resolution mass spectrometry was performed to quantify relative protein abundances in plasma samples from 144 CN individuals from the AIBL and 94 CN from KARVIAH cohorts and 21 MCI and 25 AD from AIBL cohort. ANCOVA models were utilized to assess the differences in plasma proteins implicated in heme/iron metabolism, while multiple regression modeling (and partial correlation) was performed to examine the association between heme and iron proteins, structural neuroimaging, and cognitive measures. Results Of the plasma proteins implicated in iron and heme metabolism, hemoglobin subunit β (p = 0.001) was significantly increased in AD compared to CN individuals. Multiple regression modeling adjusted for age, sex, APOEε4 genotype, and disease status in the AIBL cohort revealed lower levels of transferrin but higher levels of hemopexin associated with augmented brain amyloid deposition. Meanwhile, transferrin was positively associated with hippocampal volume and MMSE performance, and hemopexin was negatively associated with CDR scores. Partial correlation analysis revealed lack of significant associations between heme/iron proteins in the CN individuals progressing to cognitive impairment. Conclusions In conclusion, heme and iron dyshomeostasis appears to be a feature of AD. The causal relationship between heme/iron metabolism and AD warrants further investigation.

Microglia and astrocytes can quench metal toxicity to maintain tissue homeostasis, but with age, increasing glial dystrophy alongside metal dyshomeostasis may predispose the aged brain to acquire neurodegenerative diseases. The aim of the present study was to investigate age-related changes in brain metal deposition along with glial distribution in normal C57Bl/6J mice aged 2-, 6-, 19- and 27-months (n = 4/age). Using synchrotron-based X-ray fluorescence elemental mapping, we demonstrated age-related increases in iron, copper, and zinc in the basal ganglia (p < 0.05). Qualitative assessments revealed age-associated increases in iron, particularly in the basal ganglia and zinc in the white matter tracts, while copper showed overt enrichment in the choroid plexus/ventricles. Immunohistochemical staining showed augmented numbers of microglia and astrocytes, as a function of aging, in the basal ganglia (p < 0.05). Moreover, qualitative analysis of the glial immunostaining at the level of the fimbria and ventral commissure, revealed increments in the number of microglia but decrements in astroglia, in older aged mice. Upon morphological evaluation, aged microglia and astroglia displayed enlarged soma and thickened processes, reminiscent of dystrophy. Since glial cells have major roles in metal metabolism, we performed linear regression analysis and found a positive association between iron (R 2 = 0.57, p = 0.0008), copper (R 2 = 0.43, p = 0.0057), and zinc (R 2 = 0.37, p = 0.0132) with microglia in the basal ganglia. Also, higher levels of iron (R 2 = 0.49, p = 0.0025) and zinc (R 2 = 0.27, p = 0.040) were correlated to higher astroglia numbers. Aging was accompanied by a dissociation between metal and glial levels, as we found through the formulation of metal to glia ratios, with regions of basal ganglia being differentially affected. For example, iron to astroglia ratio showed age-related increases in the substantia nigra and globus pallidus, while the ratio was decreased in the striatum. Meanwhile, copper and zinc to astroglia ratios showed a similar regional decline. Our findings suggest that inflammation at the choroid plexus, part of the blood-cerebrospinal-fluid barrier, prompts accumulation of, particularly, copper and iron in the ventricles, implying a compromised barrier system. Moreover, age-related glial dystrophy/senescence appears to disrupt metal homeostasis, likely due to induced oxidative stress, and hence increase the risk of neurodegenerative diseases.

Metal/mineral dyshomeostasis has been implicated in the development of Alzheimer's disease (AD). The aim of the study was to investigate the difference in absolute and percentage levels of plasma phosphorus, calcium, iron, zinc, copper, selenium in cognitively normal (CN) and AD subjects. Total reflection X-ray fluorescence (TXRF) spectroscopy was used to detect plasma metals/minerals in CN and AD subjects (n = 44 per group). TXRF detected significantly increased plasma levels of phosphorus (p = 1.33 × 10

The disruption of iron metabolism and iron transport proteins have been implicated in the pathogenesis of Alzheimer's disease (AD). Serum melanotransferrin (MTf), a transferrin homolog capable of reversibly binding iron, has been proposed as a biochemical marker of AD. MTf has also been shown to be elevated in iron-rich reactive microglia near amyloid plaques in AD. We examined the association of CSF MTf to hippocampal volumes and cognitive tests in 86 cognitively normal, 135 mild cognitive impairment (MCI) and 66 AD subjects. CSF was collected at baseline for MTf, Aβ, total-tau and phosphorylated-tau measurements. Serial cognitive testing with ADAS-Cog13, Rey's auditory visual learning test (RAVLT), mini-mental state examination (MMSE) were performed alongside hippocampal MRI volumetric analysis for up to 10 years after baseline measurements. High levels of baseline CSF MTf were positively associated with baseline hippocampal volume (R 2 = 22%, β = 0.202, and p = 0.017) and RAVLT scores (R 2 = 7.30%, β = -0.178, and p = 0.043) and negatively correlated to ADAS-Cog13 (R 2 = 17.3%, β = 0.247, and p = 0.003) scores in MCI subjects. Interestingly, MCI subjects that converted to AD demonstrated significantly lower levels of CSF MTf (p = 0.020) compared to MCI non-converters at baseline. We suggest the diminished CSF MTf observed in MCI-converters to AD may arise from impaired transport of MTf from blood into the brain tissue/CSF and/or increased MTf export from the CSF into the blood arising from attenuated competition with reduced levels of CSF Aβ. Further investigations are required to determine the source of CSF MTf and how brain MTf is regulated by cellular barriers, Aβ and activated microglia that surround plaques in AD pathophysiology. In conclusion, low CSF MTf may identify those MCI individuals at risk of converting to AD.

Alzheimer's disease (AD) is associated with amyloid accumulation that takes place decades before symptoms appear. Cognitive impairment in AD is associated with reduced glucose metabolism. However, neuronal plasticity/compensatory mechanisms might come into play before the onset of dementia. The aim of this study was to determine whether there is evidence of cortical hypermetabolism as a compensatory mechanism before amyloid deposition takes place in subjects with amnestic mild cognitive impairment (aMCI).Nine AD subjects and ten aMCI subjects had both [(11)C]PIB and [(18)F]FDG PET scans with arterial input in order to quantify the amyloid deposition and glucose metabolism in vivo in comparison with healthy control subjects who underwent either [(11)C]PIB or [(18)F]FDG PET scans. The [(11)C]PIB PET scans were quantified using [(11)C]PIB target region to cerebellum uptake ratio images created by integrating the activity collected from 60 to 90 min, and regional cerebral glucose metabolism was quantified using spectral analysis.In MCI subjects, cortical hypermetabolism was observed in four amyloid-negative subjects and one amyloid-positive subject, while hypometabolism was seen in five other MCI subjects with high amyloid load. Subjects with hypermetabolism and low amyloid did not convert to AD during clinical follow-up for 18 months in contrast to four amyloid-positive hypometabolic subjects who did convert to AD.This preliminary study suggests that compensatory hypermetabolism can occur in aMCI subjects, particularly in those who are amyloid-negative. The increase in metabolic rate in different cortical regions with predominance in the occipital cortex may be a compensatory response to the neuronal damage occurring early in the disease process. It may also reflect recruitment of relatively minimally affected cortical regions to compensate for reduced function in the temporoparietal cortical association areas.

Schwann cell dedifferentiation from a myelinating to a progenitor-like cell underlies the remarkable ability of peripheral nerves to regenerate following injury. However, the molecular identity of the differentiated and dedifferentiated states in vivo has been elusive. Here, we profiled Schwann cells acutely purified from intact nerves and from the wound and distal regions of severed nerves. Our analysis reveals novel facets of the dedifferentiation response, including acquisition of mesenchymal traits and a Myc module. Furthermore, wound and distal dedifferentiated Schwann cells constitute different populations, with wound cells displaying increased mesenchymal character induced by localized TGFβ signaling. TGFβ promotes invasion and crosstalks with Eph signaling via N-cadherin to drive collective migration of the Schwann cells across the wound. Consistently, Tgfbr2 deletion in Schwann cells resulted in misdirected and delayed reinnervation. Thus, the wound microenvironment is a key determinant of Schwann cell identity, and it promotes nerve repair through integration of multiple concerted signals. VIDEO ABSTRACT.

Glioblastomas (GBM) are aggressive and therapy-resistant brain tumours, which contain a subpopulation of tumour-propagating glioblastoma stem-like cells (GSC) thought to drive progression and recurrence. Diffuse invasion of the brain parenchyma, including along preexisting blood vessels, is a leading cause of therapeutic resistance, but the mechanisms remain unclear. Here, we show that ephrin-B2 mediates GSC perivascular invasion. Intravital imaging, coupled with mechanistic studies in murine GBM models and patient-derived GSC, revealed that endothelial ephrin-B2 compartmentalises non-tumourigenic cells. In contrast, upregulation of the same ephrin-B2 ligand in GSC enabled perivascular migration through homotypic forward signalling. Surprisingly, ephrin-B2 reverse signalling also promoted tumourigenesis cell-autonomously, by mediating anchorage-independent cytokinesis via RhoA. In human GSC-derived orthotopic xenografts, EFNB2 knock-down blocked tumour initiation and treatment of established tumours with ephrin-B2-blocking antibodies suppressed progression. Thus, our results indicate that targeting ephrin-B2 may be an effective strategy for the simultaneous inhibition of invasion and proliferation in GBM. DOI: http://dx.doi.org/10.7554/eLife.14845.001, eLife digest Glioblastoma is the most common and deadly type of brain cancer. On average, patients with glioblastoma only survive 15 months even with aggressive treatment. One of the main reasons that therapy fails is the strong tendency of the tumor cells in this form of cancer to spread into the normal brain tissue. This makes it impossible for surgeons to completely remove the tumor, which means that the disease will almost always recur. Within the brain, invading glioblastoma tumor cells spread along pre-existing structures, like blood vessels. When the tumors use blood vessels as a highway to the rest of the brain it is called “perivascular invasion”. Scientists do not know exactly how glioblastoma cells move along the blood vessels. Learning more about this type of tumor cell movement could help scientists develop treatments to stop the tumor cells from spreading. Now, Krusche et al. show that the glioblastoma tumor cells highjack the system that normally helps keep brain cells in place. Experiments with mouse and human tumor cells grown in the laboratory and injected in mice to produce glioblastoma tumors showed that a family of proteins called ephrins determines whether perivascular invasion occurs. Ephrins are found on the surface of both tumor cells and blood vessels. Normally, the blood vessels use these proteins to block the spread of normal brain cells. However, tumor cells override this normal anti-tumor mechanism and become able to spread along the blood vessels. Specifically, Krusche et al. showed that an increase in the levels of ephrin-B2 in tumor cells allows them to move along the blood vessels. Ephrin-B2 was also found to drive the multiplication of the tumor cells independently of the protein’s interactions with the blood vessels. Using antibodies to block ephrin-B2 in tumors greatly reduced tumor size and extended survival in mice with glioblastoma tumors. The experiments suggest the blocking ephrin-B2 might be a therapy that both stops the glioblastoma cells from spreading and prevents the tumor cells from multiplying. DOI: http://dx.doi.org/10.7554/eLife.14845.002

SummaryA major advancement in the field of medicine has been the timely advent of amyloid imaging, which has allowed critical evaluation of the complex relationship between amyloid β peptide (Aβ) aggregation and Alzheimer's disease in vivo. Most importantly, amyloid imaging has the potential to detect Aβ in mildly affected as well as asymptomatic individuals, when the therapeutic window of opportunity might still be open to pharmacological intervention. It also shows significant promise in differential diagnosis of mild cognitive impairment or atypical dementias. Amyloid imaging studies support a model in which amyloid aggregation is considered an early event on the path of dementia, beginning insidiously in cognitively healthy individuals being accompanied by subtle cognitive, functional and structural brain alterations suggestive of incipient AD. As individuals progress to dementia, clinical decline and neurodegeneration accelerate and might proceed independently of amyloid accumulation. In this review we focus on amyloid imaging with particular emphasis on [11C]PIB in AD, mild cognitive impairment and other dementias, and discuss the advances made in this perplexing field.

There is an emerging evidence that growth factors may have a potential beneficial use in the treatment of Alzheimer's disease (AD) because of their neuroprotective properties and effects on neuronal proliferation. Basic fibroblast growth factor or fibroblast growth factor-2 (FGF2) is an anti-inflammatory, angiogenic, and neurotrophic factor that is expressed in many cell types, including neurons and glial cells. Here, we explored whether subcutaneous administration of FGF2 could have therapeutic effects in the APP 23 transgenic mouse, a model of amyloid pathology. FGF2 treatment attenuated spatial memory deficits, reduced amyloid-β (Aβ) and tau pathologies, decreased inducible nitric oxide synthase expression, and increased the number of astrocytes in the dentate gyrus in APP 23 mice compared with the vehicle-treated controls. The decrease in Aβ deposition was associated with a reduction in the expression of BACE1, the main enzyme responsible for Aβ generation. These results were confirmed in a neuroblastoma cell line, which demonstrated that incubation with FGF2 regulates BACE1 transcription. In addition, and in contrast with what has been previously published, the levels of FGF2 were reduced in postmortem brains from AD patients compared with controls. These data, therefore, suggest that systemic administration of FGF2 could have a potential therapeutic application in AD.