bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age Differences in Heritability of a Latent Dementia Index Score in Men and Women
Authors: Luczak Susan E , Beam Christopher R. , Tureson Kayla , Reynolds Chandra A. , Panizzon Matthew S. , Lee Teresa , Sachdev Perminder S. , Gatz Margaret ,   IGEMS Consortium
Published: December 2022

AbstractBackgroundHeritability estimates of dementia are ∼50‐60% of the total variance across older adulthood. Earlier age of onset, however, might be associated with greater genetic influence whereas older age of onset might be associated with greater environmental influences. The categorical nature of dementia diagnosis outcomes has made testing the relative importance of genetic and environmental influences on dementia difficult due to low statistical power. To overcome this methodological limitation, we tested linear and quadratic effects of age on genetic and environmental variance underlying a continuous measure of dementia likelihood in men and women.MethodThe analytic sample was 5,670 (53% female) pairs of twins from 10 studies in the Interplay of Genes and Environment Across Multiple Studies (IGEMS) consortium. Dementia likelihood is quantified continuously using a latent dementia index measure that is estimated from twins’ available cognitive, memory‐specific, and functional ability measures. Linear and quadratic age differences in genetic and environmental influences on dementia likelihood were tested by modeling univariate correlation between twins’ dementia scores as a linear function of zygosity and age in Mplus. Separate models were estimated for male and female twin groups.ResultsAge moderated genetic and environmental influences on dementia likelihood scores. Both genetic and nonshared environmental variance increased as a function of age, whereas common environmental variance declined. Sex significantly moderated the effect of zygosity on the twin correlations (monozygotic male: .57, monozygotic female: .51, dizygotic male: .19, dizygotic female: .25). Notably, MZ twin correlations were consistent with previously reported heritability estimates for dementia. The pattern of age moderation was the same in men as women, although the linear effect of age on both genetic and common environmental influences was greater in men than women (see Figure 1).ConclusionAge linearly moderated genetic and environmental variance underlying dementia likelihood similarly for both men and women, despite quantitative genetic and environmental sex differences in dementia likelihood. Genetic variance accounted for similar proportions of total variance at younger ages, whereas genetic variance accounted for greater variance in men than in women at older ages.
Quantitative proteomic analysis reveals apoE4‐dependent phosphorylation of the actin regulating protein VASP
Authors: Cakir Zeynep , Polacco Benjamin , Krogan Nevan J , Mahley Robert W , Swaney Danielle L 
Published: December 2022

AbstractBackgroundApolipoprotein E4 (APOE4) is the major genetic risk factor for Alzheimer’s disease (AD). Current evidence suggests that neuronal expression of apoE4 is sufficient to promote neuropathology via a gain‐of‐function mechanism; however, the precise molecular mechanisms mediating this process are still unclear. To elucidate specific protein targets and cellular pathways dysregulated due to apoE4 expression, we performed global proteomic profiling of ubiquitylation and phosphorylation signaling in Neuro‐2a cells stably expressing either apoE3 or apoE4.MethodNeuro‐2a cells (apoE3 or apoE4) were lysed and proteins digested into peptides. Peptides were enriched for either phosphorylation or ubiquitylation post‐translational modifications, and the resulting peptides were detected and quantified using a label‐free quantitative proteomics workflow. Modification sites were detected by MaxQuant, and statistical analysis was performed using MSstats to identify significantly regulated modification sites (p<0.05) between apoE3 and apoE4‐expressing cells. Immunoblotting was performed to validate protein phosphorylation sites of interest.ResultThe expression of apoE3 versus apoE4 in Neuro‐2a cells results in the differential regulation of thousands of ubiquitylation and phosphorylation sites. Gene ontology and pathway analysis of these regulated sites reveal an enrichment for a variety of cellular processes, including proteasomal biology, redox homeostasis, spindle organization, as well as cytoskeletal regulation. Accordingly, among the most differentially regulated phosphorylation sites is the vasodilator‐stimulated phosphoprotein, VASP, in which there is a 14‐fold increase in phosphorylation at position S235 in Neuro2a‐apoE4‐expressing cells (p=5.5e‐10) as compared to Neuro2a‐apoE3. This phosphorylation was reduced upon siRNA knockdown of APOE4, as well as by pharmacological inhibition of PKA, indicating that VASP S235 is phosphorylated by PKA in an apoE4‐dependent manner. VASP S235 phosphorylation results in reduced filopodia and cytoskeletal filament formation. Thus, we hypothesize that phosphorylation of VASP at S235 represents a mechanism regulating the well‐established defects in neurite outgrowth and dendritic spine formation in apoE4‐expressing neurons.ConclusionOur data demonstrate that VASP S235 is highly phosphorylated by PKA in apoE4‐expressing neurons compared to apoE3. Future experiments will evaluate the effect of VASP S235 phosphorylation on actin cytoskeleton remodeling and neurite outgrowth and will be extended to the evaluation of PKA inhibitors as a therapeutic opportunity in apoE4‐associated AD.
Discovery of DA‐7503 as a Novel Tau‐targeted Therapeutic Candidate for the Treatment of Alzheimer’s Disease
Authors: Pae Ae Nim , Lim Sungsu , Lim Sang Min , Lee Hyangsoo , Lee Min Jung , Kim Yun Kyung 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a late‐onset, progressive, age‐dependent neurodegenerative disorder. The load of neurofibrillary tangles correlates strongly with clinical progression of the disease. Although tauopathy has been extensively studied as a key hypothesis in AD, there are currently no clinical tau‐targeted drugs that produce a noticeable improvement. Therefore, we studied and developed novel tau‐targeted therapeutic drug candidates for the treatment of AD; in particular, tau aggregation inhibitors.MethodWe performed high‐content screening based on a Tau‐BiFC cell‐based assay platform and identified novel tau aggregation inhibitors. Lead optimization was subsequently performed to improve potency and ADME/Tox properties, resulting in the production of DA‐7503. In vivo efficacy of the candidate was validated by demonstration of memory impairment restoration in two transgenic animal models of P301L Tau‐BiFC and rTg4510. The non‐clinical GLP‐Tox studies of DA‐7503 is ongoing in order to proceed to clinical studies.ResultDA‐7503 exhibited excellent tau aggregation inhibitory activities (cell‐based IC50, 0.02 mM, in vitro IC50, 0.96 mM) with good cell viability (MTS IC50, 77.8 mM). DA‐7503 reduced tau oligomerization and protected against neuronal cell death. It restored memory impairment in P301L Tau‐BiFC and rTg4510 Tg mouse models (NOR, Open Field, and Morris Water Maze test) with reduction of tau pathology. The mode of action of DA‐7503 was confirmed by MALDI‐TOF Mass Spectrometric Analysis, 2D HSQC NMR and TR‐2 competition study to show reversible covalent inhibition of disulfide‐dependent oligomer formation.Conclusion
DA‐7503, a highly potent inhibitor of tau aggregation, significantly improved memory impairment and reduced tau pathology in P301L Tau‐BiFC and rTg4510 Tg mouse models with good pharmacological properties. Currently, the GLP‐Tox safety profile of DA‐7503 as a non‐clinical candidate is being evaluated, and early results are promising enough to proceed to clinical studies.
A novel neurofilament light chain Simoa assay that can quantify age‐dependent changes in control plasma samples over small time periods
Authors: Das Shreyasee , Dewit Nele , Blennow Kaj , Zetterberg Henrik , Vanmechelen Eugeen 
Published: December 2022

AbstractBackgroundNeurofilament light chain (Nf‐L) is an established biomarker for axonal degeneration, and it is well documented that Nf‐L shows an age‐ dependent increase in plasma. Currently, all highly sensitive immunoassay formats to quantify Nf‐L in plasma are based on one antibody pair alone, i.e., the commercial UmanDiagnostics monoclonal antibodies.MethodsIn the novel Nf‐L Simoa, we have used Fab fragments of ADx206 as the capture antibody coupled to paramagnetic beads and biotinylated NfL23 as the detector antibody. Routine plasma and serum samples were collected according to established preclinical guidelines at baseline (BL) and after 7‐8 months of follow‐up (FU) for 23 individuals. The age range of these individuals was between 22 and 70 years.ResultsAll plasma and serum samples could be quantified and the lower limit of quantification (LLOQ) of the novel immunoassay was 2.2 pg/mL. The average coefficient of variation for plasma Nf‐L concentrations was 8% and that for serum was 13%. The plasma and serum concentrations correlated significantly with concentrations obtained using the commercial Quanterix Nf‐L Simoa kit (Plasma: Spearman’s rho= 0.93, p<0.0001; Serum: Spearman’s rho= 0.92, p<0.0001). However, in contrast to the Quanterix assay, Nf‐L concentrations detected in serum were lower than in plasma. Since the age range of the individuals were between 22 to 70 years, we were able to observe a significant age‐dependent increase of Nf‐L at BL in plasma as well as in serum. Furthermore, a positive 5% average annual rate of change in the Nf‐L plasma concentrations can be discriminated from BL to FU with the current assay format. Therefore, in this cohort, Nf‐L plasma concentrations increase from BL to FU, consistent with data reported from other cohorts.ConclusionThe novel Nf‐L Simoa is precise and can be used to quantify small scale changes in Nf‐L plasma concentrations. Our assay measured lower concentrations of Nf‐L in serum than in plasma, although quantification of serum samples using this assay format probably requires further optimization.
Ageing‐associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer’s disease
Authors: Depp Constanze Martha , Nave Klaus‐Armin , Lab Klaus‐Armin Nave 
Published: December 2022

AbstractBackgroundThe prevalence of Alzheimer’s disease (AD), the leading cause of dementia, shows a strict age‐dependency, but why ageing constitutes the main risk factor for this disease is still poorly understood. Brain ageing markedly affects oligodendrocytes and the structural integrity of myelin sheaths which is associated with secondary gliosis. Since oligodendrocytes support axonal and neuronal health, we hypothesised that ageing‐associated loss of myelin integrity could be an upstream risk factor for neuronal amyloid‐β (Aβ) deposition, the primary neuropathological hallmark of AD.MethodWe used AD mouse models and combined them with genetic myelin dysfunction models (CNP−/−, PLP−/y, Emx‐Cre MBPfl/fl forebrain shiverer) as well as mouse models of acute demyelination (Cuprizone, EAE) and investigated the effect of myelin defects on amyloid deposition using in toto quantitative light sheet microscopy. Bulk and single cell transcriptomics, immunohistochemistry and biochemical approaches were used to investigate the potential mechanism of action.ResultWe identified myelin defects as potent drivers of amyloid deposition in vivo. Conversely, the lack of myelin in the forebrain provides protection against plaque deposition. Mechanistically, we find that myelin dysfunction causes the accumulation of the Aβ producing machinery within axonal swellings and increases cortical amyloid precursor protein (APP) cleavage. Surprisingly, AD mice with dysfunctional myelin lack plaque‐corralling microglia but show a disease‐associated microglia (DAM)‐like signature. These activated microglia, however, are primarily engaged with myelin, preventing the protective reactions of microglia to Aβ plaques.ConclusionOur data suggest a working model, in which age‐dependent structural defects of myelin promote plaque formation, directly and indirectly, and are thus an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay AD.
White matter associated microglia in Alzheimer’s disease
Authors: Simons Mikael 
Published: December 2022

AbstractBackgroundWhite matter is composed of mostly myelinated axons that connect neurons from different brain regions into functional circuits. Aging results in both grey and white matter degeneration, but the specific microglial responses to the damage is unknown. Strikingly, in Alzheimer’s disease white matter alterations occur early in the disease course. Here, we analyzed microglia responses in the white matter in aging rodents and models of Alzheimer’s disease.MethodWe dissociated grey and white matter tracts and isolated microglia from young and aged mice and performed single cell RNA sequencing. To compare aging and neurodegeneration effects on microglia, we isolated microglia from a transgenic Alzheimer’s disease mouse model, and to study signaling pathways we included aged Trem2 and Apoe knockout mice into the analysis. Validation and characterization of the phenotypes occurred by in situ hybridization, immunohistochemistry, correlated light and electron microscopy.ResultsUsing single‐cell RNA sequencing from white and grey matter separately, we identified white matter associated microglia, which shared distinct parts of the disease‐associated microglia (DAM) gene signature. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin, depending on Trem2 signaling. In the aged brain, white matter associated microglia form independently of ApoE, which is in contrast to mouse models of Alzheimer’s disease, in which microglia with white matter associated microglia gene signature are generated prematurely and in an ApoE‐dependent pathway similar to DAM.ConclusionWe propose that white matter associated microglia represent a protective metabolic response, required to clear the increasing amounts of myelin debris that accumulate during aging and AD. We speculate that premature formation of white matter associated microglia in AD may contribute to the development of neurodegenerative disease, possibly by attrition of microglia function leading to accumulation of toxic protein or lipid species within the brain.
An Innovative Approach to Empowering Care Partners Living with A Loved One Diagnosed with Younger‐Onset Alzheimer’s
Authors: Cose Diana Shulla 
Published: December 2022

AbstractAn Innovative Approach to Empowering Care Partners Living with A Loved One Diagnosed with Younger‐Onset Alzheimer's Our innovative approach at Lorenzo's House, a nonprofit in Chicago, empowers care partners living with a loved one with younger‐onset Alzheimer's. Lorenzo's Angels is a proven model designed to create one‐on‐one mentor matches between care partners. This personalized match offers connection with someone who shares a similar profile and understands. Families living with a younger‐onset diagnosis are often underserved and under‐discussed in the Alzheimer's community. With this diagnosis comes a dramatic shift in a younger family's dynamic and they are often alienated from popular Alzheimers' resources geared towards people who are diagnosed later in life. These care partner spouses are in a uniquely important and difficult position as they are responsible for being the primary care partner to their spouse, breadwinner for the household, and for parenting independently ‐ all while navigating the complexities of the diagnosis.A family culture changes after a younger‐onset Alzheimer's diagnosis, and there is a need for innovative care and personal connection. We recognize that the best guidance and support for care partners often comes from people who have or are still walking the path. We empower families by cultivating a care partner‐to‐care partner mentor model, building an International network of care partners matches. Our framework emphasizes social emotional wellness, practical information and resourcefulness so that families turn isolation to connectedness and darkness to light, living this journey together ‐ never alone. By creating this framework through digital and in‐person platforms, we provide sustenance to care partners everywhere living with a loved one with younger‐onset Alzheimer's.
Biophysical Kv channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer’s
Authors: Rowan Matthew JM , Olah Viktor Janos , Goettemoeller Anne M 
Published: December 2022

AbstractBackgroundIn Alzheimer’s disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal factors responsible for initiating cognitive decline in AD remain controversial. Toxic plaques and tangles correlate with progressive neuropathology, yet disruptions in circuit activity emerge before their deposition in AD models and patients. Parvalbumin (PV) interneurons are potential candidates for dysregulating cortical excitability, as they display altered AP firing before neighboring excitatory neurons in prodromal AD.MethodWe used an interneuron‐enhancer AAV labeling technique to specifically target PV interneurons for whole‐cell and outside‐out patch clamp recordings in young 5xFAD mice. Our findings were complemented by PV dyanmic clamp recordings, PV‐specific qPCR, quantitative proteomics, and NEURON modeling.ResultWe report a novel mechanism responsible for cortical PV hypoexcitability in young adult familial AD mice. We found that biophysical modulation of K+ channels, but not changes in mRNA expression, are responsible for dampened excitability. These K+ conductances could efficiently regulate near‐threshold AP firing, resulting in gamma‐frequency specific network hyperexcitability.ConclusionOur findings suggest that posttranslational modulation of ion channels can reshape cortical network activity prior to changes in their gene expression in early AD.
Quantitative myelin imaging with MPnRAGE‐derived R1 mapping: Applications to Alzheimer’s disease
Authors: Kohli Akshay , Kecskemeti Steven R , Yang Kao Lee , III Doug C Dean , Asthana Sanjay , Johnson Sterling C. , Alexander Andrew L , Bendlin Barbara B. 
Published: December 2022

AbstractBackgroundPost‐mortem observations of Alzheimer’s disease (AD) brain suggest that developmental patterns of myelin and AD pathology are inversely related (Braak and Braak, 1996). Myelin injury and repair processes have also been implicated in the amyloid cascade hypothesis (Bartzokis, 2004; Depp et al., 2021). While diffusion‐weighted imaging has been widely applied to examine white matter abnormalities in AD, there remains a dearth of high resolution and high contrast imaging methods that allow for accurate and precise measurement of brain myelin in vivo. Here, we leveraged a novel imaging sequence—MPnRAGE (Kecskemeti et al., 2016; 2018)—to derive R1 maps, a myelin sensitive metric, and assessed the potential of R1 to identify myelin abnormalities in relation to cognitive impairment in AD.Method791 cognitively unimpaired older adults, 30 with dementia, and 43 with MCI enrolled in the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center clinical core study underwent T1‐weighted (T1w) MPnRAGE with motion‐correction. T1w images and R1 maps were reconstructed at 1mm isotropic resolution. Preprocessing steps are outlined in Figure 1. As the T1w image and R1 map are inherently coregistered, no additional preprocessing was applied to the R1 map.ResultA whole‐brain vertex‐wise cortical R1 map for a single participant and bilaterally averaged group mean parcellations for both cortical and WM R1 can be seen in Figure 2. Notably, densely‐myelinated regions are typically spared in AD, while thinly‐myelinated regions are vulnerable to AD pathology. In the cortex, sensory/motor regions exhibited the highest R1 (indicative of greater myelin content) and frontal/temporal regions had the lowest R1. In shallow WM, pericingulate WM exhibited the highest R1 and visual‐adjacent WM had the lowest R1. Participants with dementia and MCI had substantially reduced cortical adjacent WM R1 compared to unimpaired individuals (Figure 3).ConclusionThis is the largest study to date to examine R1 maps among older adults with and without AD. These R1 maps are expected to facilitate analyses between myelin content and regional AD pathology accumulation as indexed by tau and amyloid PET, as well as testing the role of longitudinal myelin injury and repair in disease progression.
Investigating P2×7R‐mediated inflammatory signalling in Alzheimer’s disease
Authors: Lobo Paula Beltran , Hughes Martina M , Kassiou Michael , Perez‐Nievas Beatriz G. , Noble Wendy 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is pathologically characterised by the presence of amyloid plaques and neurofibrillary tangles accompanied by a marked neuroinflammation which contributes to the onset and progression of AD. Astrocytes and microglia recognize danger‐associated molecular patterns (Aß, ATP) through a myriad of sensors including the purinergic receptor P2×7 (P2×7R). These interactions lead to the release of inflammatory mediators that could participate in damaging inter‐cellular cascades. Inhibition of P2×7R in AD models ameliorates cognitive deficits and supports a neuroprotective effect of P2×7R blockade in vivo. However, the cell type‐specific inflammatory signals downstream of P2×7R in AD are not fully understood.MethodWe used biochemical and histological methods, including in situ RNA detection (RNAscope), to examine P2×7R expression and localization relative to disease hallmarks and local inflammatory features in temporal and prefrontal cortex at different Braak stages. A series of P2×7R antagonists were used to study P2×7R‐mediated responses to inflammatory stimuli in primary glial cells and to assess the effects of P2×7R blockage on tau and synapse health in brain slice cultures.ResultWe found elevated levels of P2×7R in AD relative to control brain together with an increased amyloid burden, synapse mislocalization of tau and loss of synaptic markers. P2×7R was detected in human astrocytes as well as other neural cell types and its increased abundance was accompanied by an upregulation of inflammatory cytokines including CCL2 and IL‐1ß. In cultured astrocytes, P2×7R activation contributes to the production of the inflammatory cytokines CCL2, IL‐6 and the synaptotoxic molecule lipocalin‐2, whereas microglial P2×7R activation induces IL‐1ß secretion through the NLRP3 inflammasome pathway. Treatment of organotypic brain slice cultures with specific P2×7R antagonists suggests that P2×7R inhibition modulates glial function in response to neurodegenerative disease relevant stimulation.ConclusionThese data show that P2×7R expression is elevated in AD prior to marked synapse loss and point towards distinct P2×7R‐mediated responses in astrocytes and microglia. Ongoing work aims to determine if pharmacological blockade of P2×7R‐inflammatory signals has benefits for tau‐associated neurodegeneration in AD.