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Apolipoprotein E ( APOE- gene; apoE- protein) is the strongest genetic modulator of late-onset Alzheimer’s disease (AD), with its three major isoforms conferring risk for disease ε2 < ε3 < ε4. Emerging protective gene variants, such as APOE Christchurch and the COLBOS variant of REELIN , an alternative target of certain apoE receptors, offer novel insights into resilience against AD. In recent years, the role of apoE has been shown to extend beyond its primary function in lipid transport, influencing multiple biological processes, including amyloid-β (Aβ) aggregation, tau pathology, neuroinflammation, autophagy, cerebrovascular integrity and protection from lipid peroxidation and the resulting ferroptotic cell death. While the detrimental influence of apoE ε4 on these and other processes has been well described, the molecular mechanisms underpinning this disadvantage require further enunciation, particularly to realize therapeutic opportunities related to apoE. This review explores the multifaceted roles of apoE in AD pathogenesis, emphasizing recent discoveries and translational approaches to target apoE-mediated pathways. These findings underscore the potential for apoE-based therapeutic strategies to prevent or mitigate AD in genetically at-risk populations.

Allelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer’s disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron-dependent regulated cell death pathway. Here, we report that apoE is a potent inhibitor of ferroptosis (EC 50  ≈ 10 nM; N27 neurons). We demonstrate that apoE signals to activate the PI3K/AKT pathway that then inhibits the autophagic degradation of ferritin (ferritinophagy), thus averting iron-dependent lipid peroxidation. Using postmortem inferior temporal brain cortex tissue from deceased subjects from the Rush Memory and Aging Project (MAP) ( N  = 608), we found that the association of iron with pathologically confirmed clinical Alzheimer’s disease was stronger among those with the adverse APOE -ε4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of ε4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the ε4 allele’s heighted risk of AD. These data support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD.

Rampant phospholipid peroxidation initiated by iron causes ferroptosis unless this is restrained by cellular defences. Ferroptosis is increasingly implicated in a host of diseases, and unlike other cell death programs the physiological initiation of ferroptosis is conceived to occur not by an endogenous executioner, but by the withdrawal of cellular guardians that otherwise constantly oppose ferroptosis induction. Here, we profile key ferroptotic defence strategies including iron regulation, phospholipid modulation and enzymes and metabolite systems: glutathione reductase (GR), Ferroptosis suppressor protein 1 (FSP1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Dihydrofolate reductase (DHFR), retinal reductases and retinal dehydrogenases (RDH) and thioredoxin reductases (TR). A common thread uniting all key enzymes and metabolites that combat lipid peroxidation during ferroptosis is a dependence on a key cellular reductant, nicotinamide adenine dinucleotide phosphate (NADPH). We will outline how cells control central carbon metabolism to produce NADPH and necessary precursors to defend against ferroptosis. Subsequently we will discuss evidence for ferroptosis and NADPH dysregulation in different disease contexts including glucose-6-phosphate dehydrogenase deficiency, cancer and neurodegeneration. Finally, we discuss several anti-ferroptosis therapeutic strategies spanning the use of radical trapping agents, iron modulation and glutathione dependent redox support and highlight the current landscape of clinical trials focusing on ferroptosis.

Key Points The development of new imaging tools and transgenic animals has greatly improved our understanding of the physiological and pathophysiological role of Zn 2+ in brain functioning. Neurons have numerous homeostatic systems to maintain extracellular and intracellular Zn 2+ concentrations at levels that are non-toxic. Major systems involved in Zn 2+ homeostasis include Zn 2+ transporters, Zn 2+ -importing proteins, metallothioneins, lysosomes and mitochondria. Zn 2+ has a major role in controlling synaptic excitability as it can greatly modulate both glutamatergic and GABA (γ-aminobutyric acid)-ergic neurotransmission. Zn 2+ is also potently neurotoxic and has an important role in triggering neuronal death in transient global ischaemia and brain trauma. Zn 2+ is also instrumental in the development of amyloid plaques in Alzheimer's disease. Pharmacological interventions aimed at restoring Zn 2+ homeostasis in the brain are yielding promising results in the treatment of patients with Alzheimer's disease. An important role for zinc homeostasis in brain function has recently emerged. Sensi and colleagues review the evidence pointing to the physiological role of zinc in the regulation of synaptic excitability and to its pathophysiological role in brain trauma and Alzheimer's disease. The past few years have witnessed dramatic progress on all frontiers of zinc neurobiology. The recent development of powerful tools, including zinc-sensitive fluorescent probes, selective chelators and genetically modified animal models, has brought a deeper understanding of the roles of this cation as a crucial intra- and intercellular signalling ion of the CNS, and hence of the neurophysiological importance of zinc-dependent pathways and the injurious effects of zinc dyshomeostasis. The development of some innovative therapeutic strategies is aimed at controlling and preventing the damaging effects of this cation in neurological conditions such as stroke and Alzheimer's disease.

The emergence of ferroptosis as a cell death pathway associated with brain disorders including stroke and neurodegenerative diseases emphasizes the need to develop therapeutics able to target the brain and to protect neurons from ferroptotic death. Selenium plays an essential role in reducing lipid peroxidation generated during ferroptosis through its incorporation into the catalytic site of glutathione peroxidase 4. Here, we compared the anti-ferroptotic activity of several organic and inorganic selenium compounds: methylselenocysteine, selenocystine, selenomethionine, selenocystamine, ebselen, sodium selenite, and sodium selenate. All were effective against erastin- and RSL3-induced ferroptosis in vitro. We characterized the ability of the selenium compounds to release selenium and boost glutathione peroxidase expression and activity. Based on our results, we selected organic selenium compounds of similar characteristics and investigated their effectiveness in protecting against neuronal death in vivo using the cerebral ischemia–reperfusion injury mouse model. We found that pretreatment with methylselenocysteine or selenocystamine provided protection from ischemia–reperfusion neuronal damage in vivo. These data support the use of ferroptosis inhibitors for treatment and select selenium compounds for prevention of neuronal damage in ischemic stroke and other diseases of the brain where ferroptosis is implicated.

Mutations in presenilin 1 and 2 (PS1 and PS2) cause autosomal dominant familial Alzheimer’s disease (FAD). Ferroptosis has been implicated as a mechanism of neurodegeneration in AD since neocortical iron burden predicts Alzheimer’s disease (AD) progression. We found that loss of the presenilins dramatically sensitizes multiple cell types to ferroptosis, but not apoptosis. FAD causal mutations of presenilins similarly sensitizes cells to ferroptosis. The presenilins promote the expression of GPX4, the selenoprotein checkpoint enzyme that blocks ferroptosis by quenching the membrane propagation of lethal hydroperoxyl radicals. Presenilin γ-secretase activity cleaves Notch-1 to signal LRP8 expression, which then controls GPX4 expression by regulating the supply of selenium into the cell since LRP8 is the uptake receptor for selenoprotein P. Selenium uptake is thus disrupted by presenilin FAD mutations, suppressing GPX4 expression. Therefore, presenilin mutations may promote neurodegeneration by derepressing ferroptosis, which has implications for disease-modifying therapeutics.

Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.

Alzheimer's disease is the most common form of dementia in the elderly, and it is characterized by elevated brain iron levels and accumulation of copper and zinc in cerebral β-amyloid deposits (e.g., senile plaques). Both ionic zinc and copper are able to accelerate the aggregation of Aβ, the principle component of β-amyloid deposits. Copper (and iron) can also promote the neurotoxic redox activity of Aβ and induce oxidative cross-linking of the peptide into stable oligomers. Recent reports have documented the release of Aβ together with ionic zinc and copper in cortical glutamatergic synapses after excitation. This, in turn, leads to the formation of Aβ oligomers, which, in turn, modulates long-term potentiation by controlling synaptic levels of the NMDA receptor. The excessive accumulation of Aβ oligomers in the synaptic cleft would then be predicted to adversely affect synaptic neurotransmission. Based on these findings, we have proposed the “Metal Hypothesis of Alzheimer's Disease,” which stipulates that the neuropathogenic effects of Aβ in Alzheimer's disease are promoted by (and possibly even dependent on) Aβ-metal interactions. Increasingly sophisticated pharmaceutical approaches are now being implemented to attenuate abnormal Aβ-metal interactions without causing systemic disturbance of essential metals. Small molecules targeting Aβ-metal interactions (e.g., PBT2) are currently advancing through clinical trials and show increasing promise as disease-modifying agents for Alzheimer's disease based on the “metal hypothesis.”

The blood–brain barrier (BBB) is a highly specialized neurovascular unit, initially described as an intact barrier to prevent toxins, pathogens, and potentially harmful substances from entering the brain. An intact BBB is also critical for the maintenance of normal neuronal function. In cerebral vascular diseases and neurological disorders, the BBB can be disrupted, contributing to disease progression. While restoration of BBB integrity serves as a robust biomarker of better clinical outcomes, the restrictive nature of the intact BBB presents a major hurdle for delivery of therapeutics into the brain. Recent studies show that the BBB is actively engaged in crosstalk between neuronal and the circulatory systems, which defines another important role of the BBB: as an interfacing conduit that mediates communication between two sides of the BBB. This role has been subject to extensive investigation for brain‐targeted drug delivery and shows promising results. The dual roles of the BBB make it a unique target for drug development. Here, recent developments and novel strategies to target the BBB for therapeutic purposes are reviewed, from both barrier and carrier perspectives. Blood–brain barrier (BBB), which separates the blood and the brain, plays a critical protective role in brain homeostasis. However, it is also a formidable barrier for brain‐targeted drug delivery. This review summarizes the key strategies to restore BBB integrity and to penetrate the BBB for drug delivery, in particular, under neuroinflammation conditions.

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in Caenorhabditis elegans. Here, we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant aging rate. Because excess age-related iron elevation in somatic tissue, particularly in brain, is thought to contribute to degenerative disease, post-developmental interventions to limit ferroptosis may promote healthy aging.