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Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics.

Trafficking defects in retinal pigmented epithelial (RPE) cells contribute to RPE atrophy, a hallmark of geographic atrophy (GA) in dry age-related macular degeneration (AMD). Dry AMD pathogenesis is multifactorial, including amyloid-β (Aβ) accumulation and oxidative stress—common features of Alzheimer’s disease (AD). The Sigma-2 receptor (S2R) regulates lipid and protein trafficking, and S2R modulators reverse trafficking deficits in neurodegeneration in vitro models. Given overlapping mechanisms contributing to AD and AMD, S2R modulator effects on RPE function were investigated. The S2R modulator CT1812 is in clinical trials for AD, dementia with Lewy bodies, and GA. Leveraging AD trials testing CT1812, unbiased analyses of patient biofluid proteomes revealed that proteins altered by CT1812 associated with GA and macular degeneration disease ontologies and overlapped with proteins altered in dry AMD. Differential expression analysis of RPE transcripts from APP-Swedish/London mutant transgenic mice, a model featuring Aβ accumulation, revealed reversal of autophagy/trafficking transcripts in S2R modulator-treated animals versus vehicle toward healthy control levels. Photoreceptor outer segment (POS) trafficking in human RPE cells showed deficits in response to Aβ 1−42 or hydrogen peroxide compared to vehicle. S2R modulators normalized stressor-induced POS trafficking deficits, resembling healthy control. Taken together, S2R modulation may provide a novel therapeutic strategy for dry AMD.

A series of σ2R compounds containing benzimidazolone and diazacycloalkane cores was synthesized and evaluated in radioligand binding assays. Replacing the piperazine moiety in a lead compound with diazaspiroalkanes and the fused octahydropyrrolo[3,4-b] pyrrole ring system resulted in a loss in affinity for the σ2R. On the other hand, the bridged 2,5-diazabicyclo[2.2.1]heptane, 1,4-diazepine, and a 3-aminoazetidine analog possessed nanomolar affinities for the σ2R. Computational chemistry studies were also conducted with the recently published crystal structure of the σ2R/TMEM97 and revealed that hydrogen bond interactions with ASP29 and π-stacking interactions with TYR150 were largely responsible for the high binding affinity of small molecules to this protein.

Lipid and photoreceptor outer segment (POS) trafficking and digestion are important homeostatic functions of retinal pigment epithelial (RPE) cells, the primary cell type that degenerates in late-stage dry AMD preceded by extracellular drusen deposits of lipids and proteins. The sigma-2 receptor (S2R, TMEM97) interacts with proteins involved in lipid trafficking, such as low-density lipoprotein receptor (LDLR), which is the primary receptor for LDL-cholesterol uptake in the retina. Preclinical studies demonstrate the necessity of S2R in protecting the retina and other nervous system tissues, and loss of either S2R or LDLR has been shown to exacerbate RPE cell death and visual dysfunction. Targeting the regulatory receptors of lipid and protein trafficking functions in RPE cells represents a tractable therapeutic strategy for dry AMD. We previously demonstrated that small molecule modulators of S2R can rescue RPE POS trafficking deficits induced by exogenous stressors. Given that disruption in lipid homeostasis is a key factor in dry AMD pathogenesis and S2R interacts with LDLR, we hypothesized that LDLR-mediated lipid trafficking in RPE could be altered using S2R-targeting small molecules. In this study, RPE cells treated with S2R modulators increased LDL uptake, assessed using fluorescently-labeled LDL, compared to vehicle-treatment. Lentiviral shRNAs to reduce TMEM97 or LDLR expression, or a neutralizing blocking antibody against LDLR, reduced S2R modulator-mediated LDL uptake, confirming the requirement of TMEM97 and LDLR for S2R modulator effects. Together, these data elaborate on a potential mechanism that may underlie the favorable reduction in geographic atrophy lesion size found in participants treated with the S2R modulator zervimensine in the Ph2 clinical trial MAGNIFY in patients with geographic atrophy (COG2201, NCT05893537). Retinal pigment epithelial (RPE) cells express the sigma-2 receptor (S2R, TMEM97) Low-density lipoprotein (LDL) uptake assay in RPE cells serves as S2R functional assay S2R modulators, including zervimesine (CT1812), increase RPE cell LDL uptake S2R modulator effects are TMEM97- and LDLR- dependent

Part 1. The Lewis acid-promoted cyclization of a variety of 5-alkenyl acetals is reported. Oxocenes with $\\Delta\\sp4$-unsaturation (3,6,7,8-tetrahydro-2H-oxocins) can be accessed in this fashion with moderate efficiency and perfect regiochemical fidelity. Cyclizations of acetals derived from secondary alcohols proceed with excellent stereoselectivity to provide, in a single step, cis-2,8-disubstituted-$\\Delta\\sp4$-oxocenes. The competing pathway that is most significant in undermining the yield of $\\Delta\\sp4$-oxocene in the cyclization of the 5-hexenyl acetals is not bimolecular oligomerization reactions, but rather cyclization to form 2-oxocanyl cations. The importance of this pathway was established by the isolation of a variety of oxocanyl acetals, alkylated oxocanes, and 11-oxabicyclo (5.3.1) undecanes. Part 2. Both the intermolecular (kinetic) and intramolecular (product) hydrogen-deuterium isotope effects were determined to be 1.65 for the formation of 2-methyl-4-(trimethylsilyl)-$\\Delta\\sp4$-oxocene from the SnCl$\\sb4$-promoted cyclization of mono- and dideuterated 5-(trimethylsilyl)-5-hexenyl acetals. These results provide strong evidence that formation of 4-(trimethylsilyl)-$\\Delta\\sp4$-oxocenes from the SnCl$\\sb4$-promoted cyclization of 5-(trimethylsilyl)-5-hexenyl acetals takes place by a concerted intramolecular ene mechanism. Also reported are SnCl$\\sb4$-promoted exchange reactions of formaldehyde- and aldehyde-derived acetals. These reactions occur readily at -10 to 0$\\sp\\circ$C and -70$\\sp\\circ$C, respectively.

Intrastromal cell therapy utilizing quiescent corneal stromal keratocytes (qCSKs) from human donor corneas emerges as a promising treatment for corneal opacities, aiming to overcome limitations of traditional surgeries by reducing procedural complexity and donor dependency. This investigation demonstrates the therapeutic efficacy of qCSKs in a male rat model of corneal stromal opacity, underscoring the significance of cell-delivery quality and keratocyte differentiation in mediating corneal opacity resolution and visual function recovery. Quiescent CSKs-treated rats display improvements in escape latency and efficiency compared to wounded, non-treated rats in a Morris water maze, demonstrating improved visual acuity, while stromal fibroblasts-treated rats do not. Advanced imaging, including multiphoton microscopy, small-angle X-ray scattering, and transmission electron microscopy, revealed that qCSK therapy replicates the native cornea’s collagen fibril morphometry, matrix order, and ultrastructural architecture. These findings, supported by the expression of keratan sulfate proteoglycans, validate qCSKs as a potential therapeutic solution for corneal opacities. This study demonstrates the opacity resolution and visual function improvement following intrastromal injection of quiescent corneal stromal keratocytes but not stromal fibroblasts. The keratocyte therapy recapitulates native cornea’s collagen fibril organization and proteoglycans.

Neuroblastoma: a genetic link to ALK Neuroblastoma is the most common childhood cancer. There is a strong familial association and it was predicted over 30 years ago that there was a genetic element to the disease. Four groups now report the identification of mutations in the tyrosine kinase receptor ALK (anaplastic lymphoma kinase) in neuroblastoma patients. ALK acts as a neuroblastoma predisposition gene, and somatic point mutations occur in sporadic neuroblastoma cases. These mutations promote ALK's kinase activity and can transform cells and display tumorigenic activity in vivo . ALK inhibitors decrease neuroblastoma cell proliferation, so have potential as anticancer drugs. This is one of four papers in this issue that identifies mutations in the tyrosine kinase receptor ALK in neuroblastoma, the most frequent childhood cancer. ALK is found to be a neuroblastoma predisposition gene and somatic points mutations were found in sporadic cases of neuroblastoma. These mutations lead the ALK kinase activation and are able to transform cells and display tumourigenic activity in vivo . ALK inhibitors decrease neuroblastoma cell proliferating and are potential anti-cancer drugs for the treatment of neuroblastoma. Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer 1 . High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal 2 , 3 . Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK , of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4 ). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.

Active surveillance (AS) represents a fundamental shift in managing select cancer patients that initiates treatment only upon disease progression to avoid overtreatment. Given uncertain outcomes, patient engagement could support decision-making about AS. Little is known about how to optimize patient engagement for AS decision-making. This scoping review aimed to characterize research on patient and provider communication about AS, and associated determinants and outcomes. MEDLINE, EMBASE, CINAHL, and The Cochrane Library were searched from 2006 to October 2016. English language studies that evaluated cancer patient or provider AS views, experiences or behavioural interventions were eligible. Screening and data extraction were done in duplicate. Summary statistics were used to describe study characteristics and findings. A total of 2,078 studies were identified, 1,587 were unique, and 1,243 were excluded based on titles/abstracts. Among 344 full-text articles, 73 studies were eligible: 2 ductal carcinoma in situ (DCIS), 4 chronic lymphocytic leukemia (CLL), 6 renal cell carcinoma (RCC) and 61 prostate cancer. The most influential determinant of initiating AS was physician recommendation. Others included higher socioeconomic status, smaller tumor size, comorbid disease, older age, and preference to avoid adverse treatment effects. AS patients desired more information about AS and reassurance about future treatment options, involvement in decision-making and assessment of illness uncertainty and supportive care needs during follow-up. Only three studies of prostate cancer evaluated interventions to improve AS communication or experience. This study revealed a paucity of research on AS communication for DCIS, RCC and CLL, but generated insight on how to optimize AS discussions in the context of routine care or clinical trials from research on AS for prostate cancer. Further research is needed on AS for patients with DCIS, RCC and CLL, and to evaluate interventions aimed at patients and/or providers to improve AS communication, experience and associated outcomes.

Given the paucity of empirically based health promotion interventions designed by and for American Indian, Alaska Native, and Native Hawaiian (i.e., Native) communities, researchers and partnering communities have had to rely on the adaptation of evidence-based interventions (EBIs) designed for non-Native populations, a decidedly sub-optimal approach. Native communities have called for development of Indigenous health promotion programs in which their cultural worldviews and protocols are prioritized in the design, development, testing, and implementation. There is limited information regarding how Native communities and scholars have successfully collaborated to design and implement culturally based prevention efforts “from the ground up.” Drawing on five diverse community-based Native health intervention studies, we describe strategies for designing and implementing culturally grounded models of health promotion developed in partnership with Native communities. Additionally, we highlight indigenist worldviews and protocols that undergird Native health interventions with an emphasis on the incorporation of (1) original instructions, (2) relational restoration, (3) narrative-[em]bodied transformation, and (4) indigenist community-based participatory research (ICBPR) processes. Finally, we demonstrate how culturally grounded interventions can improve population health when they prioritize local Indigenous knowledge and health-positive messages for individual to multi-level community interventions.