ObjectivePro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1–5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.MethodsWe studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants.ResultsIn cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.ConclusionsSetmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.

The apolipoprotein E (APOE)-ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease, likely increasing risk by altering amyloid-β (Aβ) accumulation. We recently demonstrated that the low-density lipoprotein receptor (LDLR) is a major apoE receptor in the brain that strongly regulates amyloid plaque deposition. In the current study, we sought to understand the mechanism by which LDLR regulates Aβ accumulation by altering Aβ clearance from brain interstitial fluid. We hypothesized that increasing LDLR levels enhances blood-brain barrier-mediated Aβ clearance, thus leading to reduced Aβ accumulation. Using the brain Aβ efflux index method, we found that blood-brain barriermediated clearance of exogenously administered Aβ is enhanced with LDLR overexpression. We next developed a method to directly assess the elimination of centrally derived, endogenous Aβ into the plasma of mice using an anti-Aβ antibody that prevents degradation of plasma Aβ, allowing its rate of appearance from the brain to be measured. Using this plasma Aβ accumulation technique, we found that LDLR overexpression enhances brain-toblood Aβ transport. Together, our results suggest a unique mechanism by which LDLR regulates brain-to-blood Aβ clearance, which may serve as a useful therapeutic avenue in targeting Aβ clearance from the brain.dementia | low-density lipoprotein-related protein 1 | peripheral | in vivo microdialysis | sequestration A ccumulation of soluble amyloid-β (Aβ) into toxic oligomers and amyloid plaques is widely hypothesized to initiate a pathogenic cascade leading to synaptic dysfunction, neuronal death, and, ultimately, loss of cognitive function (1-3). The factors that initiate or regulate risk and onset of Aβ accumulation in sporadic, late-onset Alzheimer's disease (AD) cases that account for the majority of total cases remain poorly understood. Emerging evidence suggests that faulty clearance from the brain accounts for Aβ accumulation in sporadic, lateonset AD (4). The strongest identified genetic risk factor for this disease is the APOE ε4 allele, which increases AD risk and decreases onset by 10-15 y in a dose-dependent fashion (reviewed in ref. 5). APOE status is hypothesized to modulate AD risk and age of onset by regulating the onset of amyloid deposition (6-11). Using a mouse model that develops human apoE isoform-dependent β-amyloidosis (12), we recently provided direct in vivo evidence that human apoE isoforms differentially regulate soluble Aβ clearance from brain interstitial fluid (ISF) (11), strongly suggesting that APOE's role in AD risk development is related to its regulation of Aβ clearance pathways.Aβ is eliminated from brain ISF through various routes, including cellular uptake and degradation, ISF bulk flow, and blood-brain barrier (BBB)-mediated transport. ApoE has been shown to impede the clearance of Aβ across the BBB (13-15), and various members of the low-density lipoprotein receptor (LDLR) family have been implicated in mediating apoE-independent or apoE-dependent...

BackgroundThe relationship between the pathogenic amyloid β-peptide species Aβ1–42 and tau pathology has been well studied and suggests that Aβ1–42 can accelerate tau pathology in vitro and in vivo. The manners if any in which Aβ1–40 interacts with tau remains poorly understood. In order to answer this question, we used cell-based system, transgenic fly and transgenic mice as models to study the interaction between Aβ1–42 and Aβ1–40.ResultsIn our established cellular model, live cell imaging (using confocal microscopy) combined with biochemical data showed that exposure to Aβ1–42 induced cleavage, phosphorylation and aggregation of wild-type/full length tau while exposure to Aβ1–40 didn’t. Functional studies with Aβ1–40 were carried out in tau-GFP transgenic flies and showed that Aβ1–42, as previously reported, disrupted cytoskeletal structure while Aβ1–40 had no effect at same dose. To further explore how Aβ1–40 affects tau pathology in vivo, P301S mice (tau transgenic mice) were injected intracerebrally with either Aβ1–42 or Aβ1–40. We found that treatment with Aβ1–42 induced tau phosphorylation, cleavage and aggregation of tau in P301S mice. By contrast, Aβ1–40 injection didn’t alter total tau, phospho-tau (recognized by PHF-1) or cleavage of tau, but interestingly, phosphorylation at Ser262 was shown to be significantly decreased after direct inject of Aβ1–40 into the entorhinal cortex of P301S mice.ConclusionsThese results demonstrate that Aβ1–40 plays different role in tau pathogenesis compared to Aβ1–42. Aβ1–40 may have a protective role in tau pathogenesis by reducing phosphorylation at Ser262, which has been shown to be neurotoxic.

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