A novel approach to the identification and quantitative elemental analysis of amyloid deposits—Insights into the pathology of Alzheimer’s disease

Rajendran, Reshmi; Ren, Mingchun; Ynsa, M.D.; Casadesús, Gemma; Smith, Mark A.; Perry, George; Halliwell, Barry; Watt, F.

doi:10.1016/j.bbrc.2009.02.136

Cited by 98 publications

(83 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Fifth, although we observed a significant effect of HFE and TfC2 genes on brain iron levels (Bartzokis et al, 2010) and the basal ganglia-working memory association, these genes likely account for a minority of the variance, much of the genetic influence on iron levels remains unknown (Njajou et al, 2006;Whitfield et al, 2000), and future studies may identify additional genetic influences on brain iron and its impact on cognitive performance. Finally, although reproducible (Bartzokis et al, 1994;Bartzokis et al, 2000) and very highly correlated with postmortem iron levels (Bartzokis et al, 2007c), the FDRI measure specifically quantifies ferritin iron load that may be only indirectly related to the amount of free iron or other transition metals that may be more directly associated with toxicity (Lavados et al, 2008;Rajendran et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

Bartzokis

Tingus

et al. 2011

Neuropsychopharmacol

View full text Add to dashboard Cite

Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer's disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON + ) vs noncarrier (IRONÀ) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON + vs IRONÀ status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r ¼ À0.50, p ¼ 0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRONÀ group (r ¼ À0.49, p ¼ 0.005) but not in the IRON + group. Between-group interactions (p ¼ 0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.

show abstract

Section: Discussionmentioning

confidence: 99%

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

Bartzokis

Tingus

et al. 2011

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…At the level of grey matter homogenates, there is no agreement that any particular metal ion is specifically elevated or lowered in AD brain. Most techniques have detected elevations in Cu, Zn, or Fe in AD amyloid plaques, either in situ or after their purification (see, for example, Rajendran et al 2009), but such analytical approaches have never been entirely convincing. The observations that both APP and Ab have sequences consistent with metal-binding motifs and metallo-complexing activities add a new dimension to this line of enquiry (Faller 2009;Duce et al 2010).…”

Section: Metal Ionsmentioning

confidence: 99%

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

Masters

Selkoe²

2012

Cold Spring Harbor Perspectives in Medicine

492

405

View full text Add to dashboard Cite

“…Aβ, αS, and PrP also complex metal ions, such as FeII and CuI, that strongly catalyze ROS formation [40,41]. Concentrations of CuI and FeII are in amyloid plaques are about twice as high as in surrounding tissues [42].…”

Section: Toxicity and Amyloid Formationmentioning

confidence: 99%

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Bieschke

2013

Neurotherapeutics

View full text Add to dashboard Cite

Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

show abstract

A novel approach to the identification and quantitative elemental analysis of amyloid deposits—Insights into the pathology of Alzheimer’s disease

Cited by 98 publications

References 38 publications

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Contact Info

Product

Resources

About