Our understanding of lipid peroxidation in biology and medicine is rapidly evolving, as it is increasingly implicated in various diseases but also recognized as a key part of normal cell function, signaling, and death (ferroptosis). Not surprisingly, the root and consequences of lipid peroxidation have garnered increasing attention from multiple disciplines in recent years. Here we “connect the dots” between the fundamental chemistry underpinning the cascade reactions of lipid peroxidation (enzymatic or free radical), the reactive nature of the products formed (lipid-derived electrophiles), and the biological targets and mechanisms associated with these products that culminate in cellular responses. We additionally bring light to the use of highly sensitive, fluorescence-based methodologies. Stemming from the foundational concepts in chemistry and biology, these methodologies enable visualizing and quantifying each reaction in the cascade in a cellular and ultimately tissue context, toward deciphering the connections between the chemistry and physiology of lipid peroxidation. The review offers a platform in which the chemistry and biomedical research communities can access a comprehensive summary of fundamental concepts regarding lipid peroxidation, experimental tools for the study of such processes, as well as the recent discoveries by leading investigators with an emphasis on significant open questions.

Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer's disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has disease-modifying effects in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis at pre-plaque stages, before frank amyloid-␤ (A␤) plaque deposition, during which A␤ is primarily intraneuronal. Here, we are interested in determining whether the positive effects of microdose lithium extend into early A␤ post-plaque stages. We administered NP03 (40 g Li/kg; 1 ml/kg body weight) to McGill-R-Thy1-APP transgenic rats for 12 weeks spanning the transition phase from plaque-free to plaque-bearing. The effect of NP03 on remote working memory was assessed using the novel object recognition task. Levels of human A␤ 38 , A␤ 40 , and A␤ 42 as well as levels of pro-inflammatory mediators were measured in brain-extracts and plasma using electrochemiluminescent assays. Mature A␤ plaques were visualized with a thioflavin-S staining. Vesicular acetylcholine transporter (VAChT) bouton density and levels of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), and 4-hydroxynonenal (4-HNE) were probed using quantitative immunohistochemistry. During the early A␤ post-plaque stage, we find that NP03 rescues functional deficits in object recognition, reduces loss of cholinergic boutons in the hippocampus, reduces levels of soluble and insoluble cortical A␤ 42 and reduces hippocampal A␤ plaque number. In addition, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of A␤ plaques.

No abstract

These results suggest that NP03 may function to slow the AD-like pathology in part by modifying oxidative/nitrosative damage and neuroinflammation, raising the possibility that low doses of microencapsulated lithium might be of therapeutic-preventive value during very early or preclinical AD.

Basal forebrain cholinergic neurons (BFCNs) represent the main source of cholinergic innervation to the cortex and hippocampus and degenerate early in Alzheimer's disease (AD) progression. Phenotypic maintenance of BFCNs depends on levels of mature nerve growth factor (mNGF) and mature brain-derived neurotrophic factor (mBDNF), produced by target neurons and retrogradely transported to the cell body.