Cognition Therapeutics (United States)

Abstract 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 ). Highlights 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

BackgroundsDigital, online assessments are efficient means to detect early cognitive decline, but few studies have investigated the relationship between remotely collected subjective cognitive change and cognitive decline. We hypothesized that the Everyday Cognition Scale (ECog), a subjective change measure, predicts longitudinal change in cognition in the Brain Health Registry (BHR), an online registry for neuroscience research.MethodsThis study included BHR participants aged 55 + who completed both the baseline ECog and repeated administrations of the CANTAB® Paired Associates Learning (PAL) visual learning and memory test. Both self-reported ECog (Self-ECog) and study partner-reported ECog (SP-ECog), and two PAL scores (first attempt memory score [FAMS] and total errors adjusted [TEA]) were assessed. We estimated associations between multiple ECog scoring outputs (ECog positive [same or above cut-off score], ECog consistent [report of consistent decline in any item], and total score) and longitudinal change in PAL. Additionally we assessed the ability of ECog to identify ‘decliners’, who exhibited the worst PAL progression slopes corresponding to the fifth percentile and below.ResultsParticipants (n = 16,683) had an average age of 69.07 ± 7.34, 72.04% were female, and had an average of 16.66 ± 2.26 years of education. They were followed for an average of 2.52 ± 1.63 visits over a period of 11.49 ± 11.53 months. Both Self-ECog positive (estimate = -0.01, p < 0.001, R²m = 0.56) and Self-ECog consistent (estimate=-0.01, p = 0.002, R²m = 0.56) were associated with longitudinal change in PAL FAMS after adjusting demographics and clinical confounders. Those who were Self-ECog total (Odds ratio [95% confidence interval] = 1.390 [1.121–1.708]) and SP-ECog consistent (2.417 [1.591–3.655]) had higher probability of being decliners based on PAL FAMS.ConclusionIn the BHR’s unsupervised online setting, baseline subjective change was feasible in predicting longitudinal decline in neuropsychological tests. Online, self-administered measures of subjective cognitive change might have a potential to predict objective subjective change and identify individuals with cognitive impairments.

INTRODUCTIONBrain steady‐state gamma oscillations evoked using a non‐invasive medical device (Spectris) have shown potential clinical benefits in patients with mild–moderate Alzheimer's disease (AD), including reduced functional and cognitive decline, reduced brain volume and myelin loss, and increased brain functional connectivity. We analyzed changes in cerebrospinal fluid (CSF) proteins after Spectris treatment in mild cognitive impairment (MCI) and their relationship to established biological pathways implicated in AD.METHODSUnbiased proteomic analysis of CSF samples from participants with amyloid‐positive MCI (n = 10) was conducted from the FLICKER (NCT03543878) clinical trial. Participants used the Cognito Therapeutics medical device (Spectris), confirmed to evoke steady‐state gamma oscillations. Participants were instructed to use the device daily for 1 hour each day during the trial. CSF was collected prior to the start of stimulation and after 4 and 8 weeks of treatment. The proteome was analyzed using tandem mass tag mass spectrometry.RESULTSDifferential expression analysis of proteins at baseline and after 8 weeks of treatment (N = 5) revealed that 110 out of 2951 proteins met the significance threshold (analysis of variance, P < 0.05, no false discovery rate). Sixty proteins were upregulated, and 50 proteins were downregulated after treatment. Changes in protein expression were mapped to the consensus human AD protein network, representing co‐expressed and functionally linked modules linked to cell type and biochemical pathways. Treatment altered CSF proteins linked to AD‐related brain proteome modules, including those involved in myelination (proteolipid protein 1, ecotropic viral integration site 2A), synaptic and neuroimmune functions, and regulation of cellular lipid transportation. Biological pathway analysis revealed that most impacted pathways were associated with lipoproteins, cholesterol, phospholipids processing, and phosphatidylcholine biosynthesis.DISCUSSIONThe CSF proteomic changes observed in this study suggest pleiotropic effects on multiple pathways involved in AD, including myelination, synaptic and neuroimmune function, and lipid transport. These findings are also consistent with observations of white matter and myelin preservation after Spectris treatment of AD.HighlightsWe analyzed changes in cerebrospinal fluid (CSF) proteins in response to sensory‐evoked gamma oscillations in individuals with mild cognitive impairment.Sensory evoked steady‐state gamma oscillations were evoked by Spectris medical device.Changes in CSF proteins were observed after 8 weeks of daily 1 hour treatment.Affected proteins were related to myelination, synaptic and neuroimmune functions, and regulation of cellular lipid transportation.Proteomic changes support clinical outcomes and myelin preservation of Spectris treatment.

Abstract BackgroundSynapse loss represents the closest correlate of cognitive decline in Alzheimer’s Disease (AD). Standard microscopy, due to increased diffraction of light with tissue depth, imposes a limit on axial resolution extending to ∼ 700nm. Array tomography (AT), developed by Micheva &amp; Smith (2007), extends this axial limit via physical sectioning of resin‐embedded tissue into ribbons of 70nm contiguous sections that are serially imaged and reconstructed into 3D volumes; thus, allowing for nanometric synaptic puncta to be resolved at the mesoscale. Our group has, for the past decade, adapted AT to investigate synapse loss in human post‐mortem brain tissue from people who died with Alzheimer’s disease; other neurodegenerative diseases, and control subjects. We have published recent developments to AT that further improve X‐Y resolution, permitting in‐depth investigation of synapse‐protein interactions. Highlighted here are Förster Resonance Energy Transfer (FRET), Reconstruction Microscopy (dsSTORM) and DNA‐PAINT to assess interactions between Aβ, tau and protein binding partners, at the synapse. This work was funded by Cognition Therapeutics, Medical Research Council (MRC), UK Dementia Research Institute (UKDRI) and Race Against Dementia.MethodFixation, embedding, sectioning and immunostaining are detailed in work published previously by Kay et al. (2013). Advances to AT presented here include FRET, dsSTORM, DNA‐PAINT, and investigation of synaptic composition in organotypic human brain slices from surgical resections challenged with disease‐relevant proteins. Further, we report advances in our image analysis pipeline with scripts available to use on https://github.com/Spires‐Jones‐Lab.ResultFRET‐AT has been used to profile over 1 million individual synaptic puncta in the temporal cortex and generates sufficient signal to indicate molecular interaction between Aβ and putative binding partners including TMEM97 in control (n = 9) and Alzheimer’s disease (n = 11) human brain tissue. FRET‐AT also suggests interaction between p‐tau Ser356 and synaptic terminals (n = 5/group). This, coupled with evidence of synaptic tau from dsSTORM/DNA‐PAINT, provides indirect evidence of disease progression via tau‐synapse interaction.ConclusionAT can be combined with other methodologies, allowing for in‐depth investigation of synapse‐protein interactions at a scale larger than afforded by electron microscopy (EM). This provides important insight into neurodegenerative disease and presents targets for potential therapeutics disrupting protein‐protein interactions.