Changes in brain transcripts related to alzheimer's disease in a model of HFE hemochromatosis are not consistent with increased alzheimer's disease risk

Iron abnormalities are observed in the brains of Alzheimer's disease (AD) patients, but it is unclear whether common disorders of systemic iron overload such as hemochromatosis alter risks of AD. We used microarrays and real-time reverse transcription-PCR to investigate changes in the brain transcriptome of adult Hfe-/- mice, a model of hemochromatosis, relative to age- and gender-matched wildtype controls. Classification by functional pathway analysis revealed transcript changes for various genes important in AD. There were decreases of up to 9-fold in transcripts for amyloid-β protein precursor, tau, apolipoprotein E, presenilin 1, and various other γ-secretase components, as well as Notch signaling pathway molecules. This included decreased transcripts for 'hairy and enhancer of split' Hes1 and Hes5, downstream targets of Notch canonical signaling. The reductions in Hes1 and Hes5 transcripts provide evidence that the changes in levels of transcripts for γ-secretase components and Notch signaling genes have functional consequences. The effects appeared relatively specific for AD in that few genes pertaining to other important neurodegenerative diseases, notably Parkinson's disease and Huntington's disease, or to inflammation, oxidative stress, or apoptosis, showed altered transcript levels. The observed effects on AD-related gene transcripts do not appear to be consistent with increased AD risk in HFE hemochromatosis and might, if anything, be predicted to protect against AD to some extent. As Hfe-/- mice did not have higher brain iron levels than wildtype controls, these studies highlight the need for further research in models of more severe hemochromatosis with brain iron loading

Relationship between brain R2 and liver and serum Iron concentrations in elderly men

Studies of iron overload in humans and animals suggest that brain iron concentrations may be related in a regionally specific way to body iron status. However, few quantitative studies have investigated the associations between peripheral and regional brain iron in a normal elderly cohort. To examine these relationships, we used MRI to measure the proton transverse relaxation rate (R2) in 13 gray and white matter brain regions in 18 elderly men (average age, 75.5 years) with normal cognition. Brain R2 values were compared with liver iron concentrations measured using the FerriScan® MRI technique and serum iron indices. R2 values in high-iron gray matter regions were significantly correlated (positively) with liver iron concentrations (globus pallidus, ventral pallidum) and serum transferrin saturation (caudate nucleus, globus pallidus, putamen) measured concurrently with brain R2, and with serum iron concentrations (caudate nucleus, globus pallidus) measured three years before the current study. Our results suggest that iron levels in specific gray matter brain regions are influenced by systemic iron status in elderly men

A Cross-Sectional community study of serum iron measures and cognitive status in older adults

The relationship of iron status with cognition and dementia risk in older people is contentious. We have examined the longitudinal relationship between serum ferritin and cognition in 800 community-dwelling Australians 60 years or older. Iron studies (serum iron, transferrin saturation, serum ferritin) were performed in 1994/5 and 2003/4 and clinical and cognitive assessments were conducted in 2003/4 for 800 participants of the Busselton Health Study. All participants completed the Cambridge Cognitive test (CAMCOG). Those with CAMCOG scores 0.05). In participants without dementia (n=749), neither serum ferritin in 1994/5 or 2003/4 nor change in serum ferritin between these times was related to total CAMCOG or executive function scores, with or without adjustment for gender, age, National Adult reading test, or stroke history (all p> 0.05). No relationships were observed between ferritin and cognition for participants with possible or probable dementia (n=51). All participants identified as HFE C282Y homozygous or with serum ferritin >1,000 ng/ml had normal CAMCOG scores. We conclude abnormal body iron stores (low or high) are unlikely to have clinically significant effects on cognition or dementia risk in community-dwelling older people

Noncitrus fruits as novel dietary environmental modifiers of iron stores in people with or without HFE gene mutations

OBJECTIVE To investigate whether citrus fruit, noncitrus fruit, and other dietary factors act as environmental modifiers of iron status in the absence or presence of hemochromatotic HFE gene mutations. PARTICIPANTS AND METHODS Iron studies, HFE genotypic analyses, and dietary data from a survey conducted from March 21, 1994, through December 15, 1995, were analyzed for a group of 2232 residents (1105 men, 1127 women) aged 20 to 79 years recruited from the community electoral roll of Busselton in Western Australia. Data were analyzed by linear regression analysis and analysis of covariance. RESULTS Higher levels of fresh fruit intake (excluding citrus fruits and citrus juices) had a significant protective effect (P=.002) against high body iron status as gauged by ferritin levels in men, irrespective of HFE genotype. Consumption of 2 or more pieces of fruit per day on average reduced mean serum ferritin levels by 20% compared with average consumption of less than 1 piece of fruit per day. This effect was not observed in women. Consumption of citrus fruits and citrus juices had no significant effects in either sex. No protective effects were observed for tea consumption or any other dietary factors studied. Red meat and alcohol consumption correlated with high body iron stores (P.05). CONCLUSION Noncitrus fruits are environmental modifiers of iron status independent of HFE genotype. This could have important implications for the provision of evidence-based dietary advice to patients with other iron-storage disorders

Brain transcriptome perturbations in the Hfe−/− mouse model of genetic iron loading

Severe disruption of brain iron homeostasis can cause fatal neurodegenerative disease, however debate surrounds the neurologic effects of milder, more common iron loading disorders such as hereditary hemochromatosis, which is usually caused by loss-of-function polymorphisms in the HFE gene. There is evidence from both human and animal studies that HFE gene variants may affect brain function and modify risks of brain disease. To investigate how disruption of HFE influences brain transcript levels, we used microarray and real-time reverse transcription polymerase chain reaction to assess the brain transcriptome in Hfe−/− mice relative to wildtype AKR controls (age 10 weeks, n ≥ 4/group). The Hfe−/− mouse brain showed numerous significant changes in transcript levels (p < 0.05) although few of these related to proteins directly involved in iron homeostasis. There were robust changes of at least 2-fold in levels of transcripts for prominent genes relating to transcriptional regulation (FBJ osteosarcoma oncogene Fos, early growth response genes), neurotransmission (glutamate NMDA receptor Grin1, GABA receptor Gabbr1) and synaptic plasticity and memory (calcium/calmodulin-dependent protein kinase IIα Camk2a). As previously reported for dietary iron-supplemented mice, there were altered levels of transcripts for genes linked to neuronal ceroid lipofuscinosis, a disease characterized by excessive lipofuscin deposition. Labile iron is known to enhance lipofuscin generation which may accelerate brain aging. The findings provide evidence that iron loading disorders can considerably perturb levels of transcripts for genes essential for normal brain function and may help explain some of the neurologic signs and symptoms reported in hemochromatosis patients

Passifloraceae na Serra Negra, Minas Gerais, Brasil

Neste trabalho são apresentadas as espécies de Passifloraceae da Serra Negra, parte da Serra da Mantiqueira localizada no sul da Zona da Mata de Minas Gerais, nas coordenadas 21º58'11"S e 43º53'21"W. A vegetação é representada por um mosaico de campos rupestres e florestas semidecíduas e ombrófilas. A família está representada por 12 espécies pertencentes ao gênero Passiflora: P. alata Curtis, P. amethystina J.C.Mikan, P. campanulata Mast., P. capsularis L., P. edulis Sims, P. haematostigma Mart. ex Mast., P. marginata Mast., P. mediterranea Vell., P. porophylla Vell., P. sidifolia M.Roem., P. speciosa Gardner e uma espécie ainda não identificada, possivelmente tratando-se de um novo táxon. Para reconhecimento das espécies são apresentadas chave de identificação, descrições, ilustrações, distribuição geográfica e comentários taxonômicos das espécies

Brain transcriptome perturbations in the transferrin receptor 2 mutant mouse support the case for brain changes in iron loading disorders, including effects relating to long-term depression and long-term potentiation

Iron abnormalities within the brain are associated with several rare but severe neurodegenerative conditions. There is growing evidence that more common systemic iron loading disorders such as hemochromatosis can also have important effects on the brain. To identify features that are common across different forms of hemochromatosis, we used microarray and real-time reverse transcription polymerase chain reaction (RT-PCR) to assess brain transcriptome profiles of transferrin receptor 2 mutant mice (Tfr2mut), a model of a rare type of hereditary hemochromatosis, relative to wildtype control mice. The results were compared with our previous findings in dietary iron-supplemented wildtype mice and Hfe-/- mice, a model of a common type of hereditary hemochromatosis. For transcripts showing significant changes relative to controls across all three models, there was perfect (100%) directional concordance (i.e. transcripts were increased in all models or decreased in all models). Comparison of the two models of hereditary hemochromatosis, which showed more pronounced changes than the dietary iron-supplemented mice, revealed numerous common molecular effects. Pathway analyses highlighted changes for genes relating to long-term depression (6.8-fold enrichment, p=5.4×10-7) and, to a lesser extent, long-term potentiation (3.7-fold enrichment, p=0.01), with generalized reductions in transcription of key genes from these pathways, which are involved in modulating synaptic strength and efficacy and are essential for memory and learning. The agreement across the models suggests the findings are robust and strengthens previous evidence that iron loading disorders affect the brain. Perturbations of brain phenomena such as long-term depression and long-term potentiation might partly explain neurologic symptoms reported for some hemochromatosis patients