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Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), have important roles in human nutrition and brain health by promoting neuronal functions, maintaining inflammatory homeostasis, and providing structural integrity. As Alzheimer's disease (AD) pathology progresses, DHA metabolism in the brain becomes dysregulated, the timing and extent of which may be influenced by the apolipoprotein E ε4 (APOE4) allele. Here, we discuss how maintaining adequate DHA intake early in life may slow the progression to AD dementia in cognitively normal individuals with APOE4, how recent advances in DHA brain imaging could offer insights leading to more personalized preventive strategies, and how alternative strategies targeting PUFA metabolism pathways may be more effective in mitigating disease progression in patients with existing AD dementia., Competing Interests: Declarations of interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer's disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC. Plasma and cerebrospinal fluid (CSF) lipidomic measurements were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA supplementation (n = 10) versus placebo (n = 12) for six months in nondemented older adults stratified by APOE4 status. Wild-type C57B6/J mice were fed a high or low DHA diet for 6 months followed by plasma and brain lipidomic analysis. Levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increases in CSF following supplementation (P < 0.001). DHA within triglyceride (TG) lipids in CSF strongly correlated with corresponding plasma TG lipids, and differed by APOE4, with carriers having a lower increase than noncarriers. Changes in plasma PC DHA had the strongest association with changes in EC thickness in millimeters, independent of APOE4 status (P = 0.007). In mice, a high DHA diet increased PUFAs within brain lipids. Our findings demonstrate an exchange of DHA at the CSF-blood barrier and into the brain within all lipid species with APOE having the strongest effect on DHA-containing TGs. The correlation of PC DHA with EC suggests a functional consequence of DHA accretion in high density lipoprotein for the brain., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic neuroinflammation is one of the hallmarks of late-onset Alzheimer's disease (AD) dementia pathogenesis. Carrying the apolipoprotein ε4 (APOE4) allele has been associated with an accentuated response to brain inflammation and increases the risk of AD dementia progression. Among inflammation signaling pathways, aberrant eicosanoid activation plays a prominent role in neurodegeneration., Methods: Using brains from the Religious Order Study (ROS), this study compared measures of brain eicosanoid lipidome in older persons with AD dementia to age-matched controls with no cognitive impairment (NCI), stratified by APOE genotype., Results: Lipidomic analysis of the dorsolateral prefrontal cortex demonstrated lower levels of omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and DHA-derived neuroprotectin D1 (NPD-1) in persons with AD dementia, all of which associated with lower measures of cognitive function. A significant interaction was observed between carrying the APOE4 allele and higher levels of both pro-inflammatory lipids and pro-resolving eicosanoid lipids on measures of cognitive performance and on neuritic plaque burden. Furthermore, analysis of lipid metabolism pathways implicated activation of calcium-dependent phospholipase A2 (cPLA2), 5-lipoxygenase (5-LOX), and soluble epoxide hydrolase (sEH) enzymes., Conclusion: These findings implicate activation of the eicosanoid lipidome in the chronic unresolved state of inflammation in AD dementia, which is increased in carriers of the APOE4 allele, and identify potential therapeutic targets for resolving this chronic inflammatory state., (© 2022. The Author(s).)

Purpose of Review: To highlight recent developments in studying mechanisms by which the apolipoprotein E4 (APOE4) allele affects the metabolism of brain lipids and predisposes the brain to inflammation and Alzheimer's disease (AD) dementia., Recent Findings: APOE4 activates Ca2+ dependent phospholipase A2 (cPLA2) leading to changes in arachidonic acid (AA), eicosapentaenoic acid and docosahexaenoic acid signaling cascades in the brain. Among these changes, the increased conversion of AA to eicosanoids associates with sustained and unresolved chronic brain inflammation. The effects of APOE4 on the brain differ by age, disease stage, nutritional status and can be uncovered by brain imaging studies of brain fatty acid uptake. Reducing cPLA2 expression in the dementia brain presents a viable strategy that awaits to be tested., Summary: Fatty acid brain imaging techniques can clarify how changes to brain polyunsaturated fatty acid metabolism during the various phases of AD and guide the development of small molecules to mitigate brain inflammation., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Sensorineural hearing loss is irreversible and is associated with the loss of spiral ganglion neurons (SGNs) and sensory hair cells within the inner ear. Improving spiral ganglion neuron (SGN) survival, neurite outgrowth, and synaptogenesis could lead to significant gains for hearing-impaired patients. There has therefore been intense interest in the use of neurotrophic factors in the inner ear to promote both survival of SGNs and re-wiring of sensory hair cells by surviving SGNs. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) represent the primary neurotrophins in the inner ear during development and throughout adulthood, and have demonstrated potential for SGN survival and neurite outgrowth. We have pioneered a hybrid molecule approach to maximize SGN stimulation in vivo , in which small molecule analogues of neurotrophins are linked to bisphosphonates, which in turn bind to cochlear bone. We have previously shown that a small molecule BDNF analogue coupled to risedronate binds to bone matrix and promotes SGN neurite outgrowth and synaptogenesis in vitro . Because NT-3 has been shown in a variety of contexts to have a greater regenerative capacity in the cochlea than BDNF, we sought to develop a similar approach for NT-3. 1Aa is a small molecule analogue of NT-3 that has been shown to activate cells through TrkC, the NT-3 receptor, although its activity on SGNs has not previously been described. Herein we describe the design and synthesis of 1Aa and a covalent conjugate of 1Aa with risedronate, Ris-1Aa. We demonstrate that both 1Aa and Ris-1Aa stimulate neurite outgrowth in SGN cultures at a significantly higher level compared to controls. Ris-1Aa maintained its neurotrophic activity when bound to hydroxyapatite, the primary mineral component of bone. Both 1Aa and Ris-1Aa promote significant synaptic regeneration in cochlear explant cultures, and both 1Aa and Ris-1Aa appear to act at least partly through TrkC. Our results provide the first evidence that a small molecule analogue of NT-3 can stimulate SGNs and promote regeneration of synapses between SGNs and inner hair cells. Our findings support the promise of hydroxyapatite-targeting bisphosphonate conjugation as a novel strategy to deliver neurotrophic agents to SGNs encased within cochlear bone., Competing Interests: DJ receives compensation and stock options as a consultant for Akouos. Akouos is a participant in the Department of Defense Grant listed under Funding, but was not involved in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kempfle, Duro, Zhang, Amador, Kuang, Lu, Kashemirov, Edge, McKenna and Jung.)