Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species.

Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer's disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors.

Objective: To determine whether the high potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans.

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor.

The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity.

Site-specific, intramolecular cross-linking of Pin1 active site residues by the lipid electrophile 4-oxo-2-nonenal.

Products of oxidative damage to lipids include 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE), both of which are cytotoxic electrophiles. ONE reacts more rapidly with nucleophilic amino acid side chains, resulting in covalent protein adducts, including residue-residue cross-links. Previously, we demonstrated that peptidylprolyl cis/trans isomerase A1 (Pin1) was highly susceptible to adduction by HNE and that the catalytic cysteine (Cys113) was the preferential site of modification.

Peptidyl-prolyl cis/trans-isomerase A1 (Pin1) is a target for modification by lipid electrophiles.

Oxidation of membrane phospholipids is associated with inflammation, neurodegenerative disease, and cancer. Oxyradical damage to phospholipids results in the production of reactive aldehydes that adduct proteins and modulate their function. 4-Hydroxynonenal (HNE), a common product of oxidative damage to lipids, adducts proteins at exposed Cys, His, or Lys residues.

2-Mercaptoethane sulfonate prevents doxorubicin-induced plasma protein oxidation and TNF-α release: implications for the reactive oxygen species-mediated mechanisms of chemobrain.

Doxorubicin (DOX), an anthracycline used to treat a variety of cancers, is known to generate intracellular reactive oxygen species. Moreover, many patients who have undergone chemotherapy complain of cognitive dysfunction often lasting years after cessation of the chemotherapy. Previously, we reported that intraperitoneal administration of DOX led to elevated TNF-α and oxidative stress in the plasma and brain of mice.

Redox proteomics analysis of brains from subjects with amnestic mild cognitive impairment compared to brains from subjects with preclinical Alzheimer's disease: insights into memory loss in MCI.

Alzheimer's disease (AD) is a central nervous system disorder pathologically characterized by senile plaques, neurofibrillary tangles, and synapse loss. A small percentage of individuals with normal antemortem psychometric scores, after adjustments for age and education, meet the neuropathological criteria for amnestic mild cognitive impairment (MCI) or AD; these individuals have been termed 'preclinical' or 'asymptomatic' AD (PCAD). In this study, we employed the immunochemical slot-blot method and two-dimensional gel-based redox proteomics to observe differences in protein levels and oxidative modifications between groups with equal levels of AD pathology who differ in regards to clinical symptoms of memory impairment.

Oxidative modification to LDL receptor-related protein 1 in hippocampus from subjects with Alzheimer disease: implications for Aβ accumulation in AD brain.

Alzheimer disease (AD) is a neurodegenerative disorder characterized histopathologically by the presence of senile plaques (SPs), neurofibrillary tangles, and synapse loss. The main component of SPs is amyloid-β peptide (Aβ), which has been associated with increased oxidative stress, leading to oxidative modification of proteins and consequently to neurotoxicity and neurodegeneration. Low-density lipoprotein receptor-related protein 1 (LRP1) is the primary moiety responsible for the efflux of Aβ from the brain to the blood across the blood-brain barrier.

Chemo brain (chemo fog) as a potential side effect of doxorubicin administration: role of cytokine-induced, oxidative/nitrosative stress in cognitive dysfunction.

Doxorubicin (ADRIAMYCIN, RUBEX) is a chemotherapeutic agent that is commonly administered to breast cancer patients in standard chemotherapy regimens. As true of all such therapeutic cytotoxic agents, it can damage normal, noncancerous cells and might affect biochemical processes in a manner that might lead to, or contribute to, chemotherapy-induced cognitive deficits when administered either alone or in combination with other agents.

Potential in vivo amelioration by N-acetyl-L-cysteine of oxidative stress in brain in human double mutant APP/PS-1 knock-in mice: toward therapeutic modulation of mild cognitive impairment.

Alzheimer's disease (AD) is the most prevalent form of dementia among the elderly. Although the underlying cause has yet to be established, numerous data have shown that oxidative stress is implicated in AD as well as in preclinical stages of AD, such as mild cognitive impairment (MCI). The oxidative stress observed in brains of subjects with AD and MCI may be due, either fully or in part, to increased free radicals mediated by amyloid-beta peptide (Abeta).

Preclinical Alzheimer disease: brain oxidative stress, Abeta peptide and proteomics.

Alzheimer disease (AD) is a neurodegenerative disorder characterized clinically by progressive memory loss and subsequent dementia and neuropathologically by senile plaques, neurofibrillary tangles, and synapse loss. Interestingly, a small percentage of individuals with normal antemortem psychometric scores meet the neuropathological criteria for AD (termed 'preclinical' AD (PCAD)). In this study, inferior parietal lobule (IPL) from PCAD and control subjects was compared for oxidative stress markers by immunochemistry, amyloid beta peptide by ELISA, and identification of protein expression differences by proteomics.

In vivo amelioration of adriamycin induced oxidative stress in plasma by gamma-glutamylcysteine ethyl ester (GCEE).

Adriamycin (ADR) is a common chemotherapeutic known to generate significant amounts of reactive oxygen species (ROS). Although ROS generation is one of several means by which ADR attacks cancerous tissues, oxidative stress-related toxicity has been documented in several non-targeted organs as a result of anthracycline chemotherapy. Oxidative damage to tissues has been shown in the past to be minimized with co-administration of various antioxidants.

Peptides and proteins in plasma and cerebrospinal fluid as biomarkers for the prediction, diagnosis, and monitoring of therapeutic efficacy of Alzheimer's disease.

Alzheimer's disease (AD) affects millions of persons worldwide. Earlier detection and/or diagnosis of AD would permit earlier intervention, which conceivably could delay progression of this dementing disorder. In order to accomplish this goal, reliable and specific biomarkers are needed.