Biology subjects

Finch, C. E.

Publications and source records attributed to Finch, C. E..

3 recordsLinked to original sources

bioRxiv2025

Chimpanzee and human ApoE isoforms differ in the stimulation of neurite differentiation consistent with structural predictions with relevance to brain development and aging

BackgroundAmong anthropoids, humans uniquely possess ApoE isoforms that modulate Alzheimers disease (AD) risk and brain aging. While chimpanzee and human ApoE4 share R112 and R158, chimps do not exhibit advanced AD. A key difference is T61 in chimps versus R61 in humans, structurally resembling ApoE3. ObjectiveWe examined how astrocyte-derived ApoE isoforms impact neuronal morphology and used structural modeling to explore functional divergence. MethodsNeonatal rat hippocampal neurons were cultured with astrocyte-conditioned media (ACM) from mice expressing human ApoE3, ApoE4, or chimpanzee ApoE. Neuronal outgrowth was quantified after 72 hours. ResultsChimpanzee ACM increased neurite number by 30% over human ApoE isoforms. However, chimpanzee ACM resembled ApoE4 functionally, producing 40% shorter neurites and spines. Structural modeling supported greater similarity to ApoE4. ConclusionsChimpanzee ApoE is structurally and functionally more similar to ApoE4 than ApoE3, revealing evolutionary distinctions relevant to AD risk and neurodevelopment.

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↗