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J Neurochem
The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.
Published: February 2025
Brain iron (Fe) dyshomeostasis is implicated in neurodegenerative diseases. Genome-wide association studies (GWAS) have identified plausible loci correlated with peripheral levels of Fe. Systemic organs and the brain share several Fe regulatory proteins but there likely exist different homeostatic pathways. We performed the first GWAS of inductively coupled plasma mass spectrometry measures of postmortem brain Fe from 635 Rush Memory and Aging Project (MAP) participants. Sixteen single nucleotide polymorphisms (SNPs) associated with Fe in at least one of four brain regions were measured (p < 5 × 10). Promising SNPs (p < 5 × 10) were followed up for replication in published GWAS of blood, spleen, and brain imaging Fe traits and mapped to candidate genes for targeted cortical transcriptomic and epigenetic analysis of postmortem Fe in MAP. Results for SNPs previously associated with other Fe traits were also examined. Ninety-eight SNPs associated with postmortem brain Fe were at least nominally (p < 0.05) associated with one or more related Fe traits. Most novel loci identified had no direct links to Fe regulatory pathways but rather endoplasmic reticulum-Golgi trafficking (SORL1, SORCS2, MARCH1, CLTC), heparan sulfate (HS3ST4, HS3ST1), and coenzyme A (SLC5A6, PANK3); supported by nearest gene function and omic analyses. We replicated (p < 0.05) several previously published Fe loci mapping to candidate genes in cellular and systemic Fe regulation. Finally, novel loci (BMAL, COQ5, SLC25A11) and replication of prior loci (PINK1, PPIF, LONP1) lend support to the role of circadian rhythms and mitochondria function in Fe regulation more generally. In summary, we provide support for novel loci linked to pathways that may have greater relevance to brain Fe accumulation; some of which are implicated in neurodegeneration. However, replication of a subset of prior loci for blood Fe suggests that genetic determinants or biological pathways underlying Fe accumulation in the brain are not completely distinct from those of Fe circulating in the periphery.
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http://dx.doi.org/10.1111/jnc.16309 | DOI Listing |
Neurobiol Aging
March 2025
Department of Neurology, Mayo Clinic, Rochester, MN, USA. Electronic address:
Transactive response DNA-binding protein 43 kDa (TDP-43) deposition is linked to regional brain atrophy in Alzheimer's disease (AD), but diffusion changes associated with AD-related TDP-43 proteinopathy remain underexplored. This study evaluates the potential of diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) as in vivo markers for detecting TDP-43 proteinopathy in AD. We analyzed DTI and NODDI metrics in 49 cases with AD neuropathologic changes, categorized by postmortem TDP-43 status.
View Article and Find Full Text PDFMol Neurodegener
March 2025
Department of Neurosciences, Laboratory for Molecular Neurobiomarker Research, Leuven Brain Institute, KU Leuven, Leuven, Belgium.
Alzheimer's disease (AD) is neuropathologically characterized by the extracellular deposition of the amyloid-β peptide (Aβ) and the intraneuronal accumulation of abnormal phosphorylated tau (τ)-protein (p-τ). Most frequently, these hallmark lesions are accompanied by other co-pathologies in the brain that may contribute to cognitive impairment, such as vascular lesions, intraneuronal accumulation of phosphorylated transactive-response DNA-binding protein 43 (TDP-43), and/or α-synuclein (αSyn) aggregates. To estimate the extent of these AD and co-pathologies in patients, several biomarkers have been developed.
View Article and Find Full Text PDFNat Neurosci
March 2025
Center for Vascular Biology, University of Connecticut Medical School, Farmington, CT, USA.
Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal degeneration.
View Article and Find Full Text PDFActa Neuropathol
March 2025
Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA.
Recent developments in tau positron emission tomography (PET) radiotracers have enhanced the visualization of tau aggregates in Alzheimer's disease (AD). The maturity level of neurofibrillary tangles can affect its recognition by biomarkers. Early detection of tau aggregates regarding tangle pathology is of interest in early diagnosis and comparison of tau radiotracers in this aspect is important.
View Article and Find Full Text PDFJ Neuropathol Exp Neurol
March 2025
Department of Clinical Sciences Lund, Neurosurgery, Lund University, Lund, Sweden.
White matter (WM) disruption and atrophy is a consequence of traumatic brain injury (TBI) and contributes to persisting cognitive impairment. An increased expression of the myelin-associated axonal outgrowth inhibitor Nogo-A and oligodendrocyte pathology might be negatively associated with postinjury WM changes. Here, we analyzed brain tissue from severe TBI patients, obtained by surgical decompression in the early postinjury phase and postmortem brain tissue of long-term TBI survivors and observed an increased number of Nogo-A+ cells in WM tracts such as the corpus callosum (CC).
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