Biology subjects

Forman, H. J.

Publications and source records attributed to Forman, H. J..

3 recordsLinked to original sources

bioRxiv2026

Induction of ferroptotic and amyloidogenic signatures linked to Alzheimers disease by chemically distinct air pollutants

Air pollution (AirP) exposure is associated with increased Alzheimers disease (AD) risk, yet AirP is chemically heterogeneous, complicating identification of shared pathogenic drivers. We examined acute cortical responses to two metal-rich AirP sources, diesel exhaust particles (DEP) and World Trade Center (WTC) dust, and compared them to woodsmoke (WS), a particulate exposure with low metal content. DEP and WTC elicited highly convergent transcriptional responses, sharing over 1200 differentially expressed genes linked to inflammation, ferroptosis, neuronal remodeling, and amyloid processing. These changes were accompanied by impaired antioxidant activity and increased lipid peroxidation within lipid rafts, a membrane microdomain critical for amyloid processing, resulting in increased A{beta} generation. In contrast, WS produced a distinct transcriptional signature and failed to induce ferroptotic priming or lipid peroxidation, consistent with its low metal composition. Together, these findings implicate metals as a shared driver linking diverse AirP exposures to amyloidogenic vulnerability and elevated AD risk. Graphical AbstractAcute AirP exposure converges on ferroptotic priming, amyloidogenic processing, and white-matter vulnerability. Acute exposure to metal-rich AirP, such as DEP or WTC introduces redox-active metals and particulate matter that promote lipid peroxidation, amyloidogenesis, and altered transcriptional regulation in the brain. AirP exposure engages xenobiotic metabolism pathways (AhR/ARNT), activates iron and heme handling through ferritinophagy (NCOA4) and heme oxygenase activity (HMOX1), and blunts lipid peroxide detoxification systems, including glutathione peroxidase 4 (GPx4), ferroptosis suppressor protein 1 (FSP1), and glutathione (GSH) synthesis. These changes promote ferroptotic priming and lipid raft oxidation, facilitating amyloid precursor protein (APP) processing by secretases (ADAM10, BACE1, {gamma}-secretase) and increasing amyloid-{beta} (A{beta}) generation. In parallel, transcriptional and cell-state remodeling involving neuronal and oligodendrocyte responses contribute to selective white-matter vulnerability, particularly within the corpus callosum. Together, these pathways provide a mechanistic framework linking acute AirP exposure to convergent oxidative, amyloidogenic, and microstructural changes relevant to Alzheimers disease pathology. O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/696601v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@3a22dcorg.highwire.dtl.DTLVardef@c6ae26org.highwire.dtl.DTLVardef@1d3412forg.highwire.dtl.DTLVardef@5cb011_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Down syndrome with Alzheimers disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis

INTRODUCTIONCerebral microbleeds (MB) are associated with sporadic Alzheimers Disease (AD) and Down Syndrome with AD (DSAD). Higher MB iron may cause iron mediated lipid peroxidation. We hypothesize that amyloid deposition is linked to MB iron and that amyloid precursor protein (APP) triplication increases iron load and lipid peroxidation. METHODSPrefrontal cortex and cerebellum of cognitively normal (CTL), AD and DSAD ApoE3,3 carriers were examined for proteins that mediated iron metabolism, antioxidant response, and amyloid processing in lipid rafts. RESULTSIron was 2-fold higher in DSAD than CTL and AD. Iron storage proteins and lipid peroxidation were increased in prefrontal cortex, but not in the cerebellum. The glutathione synthesis protein GCLM was decreased by 50% in both AD and DSAD. Activity of lipid raft GPx4, responsible for membrane repair, was decreased by at least 30% in AD and DSAD. DISCUSSIONDSAD shows greater lipid peroxidation than AD consistent with greater MBs and iron load. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/636731v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@fd0d2aorg.highwire.dtl.DTLVardef@16b65d5org.highwire.dtl.DTLVardef@1eab2ddorg.highwire.dtl.DTLVardef@184e6d2_HPS_FORMAT_FIGEXP M_FIG C_FIG Cerebral microbleeds result in increased brain iron and lipid peroxidation in DSAD consistent with ferroptosis as reported for Alzheimers disease. A{beta}; beta-amyloid peptides, APP; amyloid precursor protein, GCLC; glutathione cysteine ligase catalytic subunit, GCLM; glutathione cysteine modifier subunit, GPx4; glutathione peroxidase 4, HNE; 4-hydroxynonenal. RESEARCH IN CONTEXTO_LISystematic Review: DS is associated with increased microbleeds and brain iron that may be mediated by increased APP from Trisomy 21. To assess potential links between amyloid and iron levels, we examined sporadic and DS with AD brains for amyloid processing and antioxidant enzyme defense in lipid rafts. We further compared DSAD with rare variants of DS: partial and mosaic T21. C_LIO_LIInterpretation: DSAD brains showed greater oxidation of lipid rafts where APP is processed than sporadic AD. Corresponding decreases in lipid raft antioxidant enzymes, despite increased total levels of these antioxidant enzymes, present a new mechanism for aberrant amyloid processing during AD. C_LIO_LIFuture Directions: Iron chelation therapies in combination with amyloid monoclonals may benefit DSAD. C_LI

neuroscience↗

bioRxiv2023

Alzheimer's Disease associations of ferritin and glutathione with oxidative damage and neuronal loss

ABSTRACTIron-mediated cell death (ferroptosis) is a proposed mechanism of Alzheimers disease (AD) pathology. While iron is essential for basic biological functions, its reactivity generates oxidants which contribute to cell damage and death. To further resolve mechanisms of iron-mediated toxicity in AD, we analyzed postmortem human brain and ApoEFAD mice. AD brains had decreased antioxidant enzymes, including those mediated by glutathione (GSH). Subcellular analyses of AD brains showed greater oxidative damage and lower antioxidant enzymes in lipid rafts, the site of amyloid processing, than in the non-raft membrane fraction. ApoE4 carriers had lower lipid raft yield with greater membrane oxidation. The hypothesized role of iron to AD pathology was tested in ApoEFAD mice by iron chelation with deferoxamine, which decreased fibrillar amyloid and lipid peroxidation, together with increased GSH-mediated antioxidants. These novel molecular pathways in iron mediated damage during AD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/534324v3_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1a28ddborg.highwire.dtl.DTLVardef@10f57f7org.highwire.dtl.DTLVardef@583c8corg.highwire.dtl.DTLVardef@ef45f9_HPS_FORMAT_FIGEXP M_FIG C_FIG Hypothesis: AD brain lipid peroxidation is driven by increased brain iron and decreased antioxidant defenses. Schema shows proteins that mediate iron metabolism in relation to lipid peroxidation (HNE) and antioxidant defenses in prefrontal cortex. AD-associated increase (red), decrease (blue), or no change (grey), relative to cognitively normal elderly controls. A{beta}; amyloid beta, ALDH2; alcohol dehydrogenase, APP; amyloid precursor protein, DMT1; divalent metal transporter 1; FPN, ferroportin; FSP1, ferroptosis suppressor protein 1, which requires the quinol cycle to attenuate lipid peroxidation; FTH1, ferritin heavy chain; FTL; ferritin light chain; GCLC, glutathione cysteine ligase catalytic subunit; GCLM, glutathione cysteine ligase modulator; GPx4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; GSTA4, glutathione S-transferase A4; HMOX; heme oxygenase; IRP, iron regulatory protein; LAT1, large neutral amino acid transporter 1; LOOH, Lipid hydroperoxides; Nrf2, Nuclear factor erythroid 2-related factor 2; Prdx6, peroxiredoxin 6; TF, transferrin, TfR; Transferrin receptor; xCT, cysteine-glutamate antiporter.

neuroscience↗