bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential drivers of age‐ and beta‐amyloid‐related neurodegeneration in early and late Alzheimer’s Disease regions in cognitively normal older adults
Authors: Wuestefeld Anika , Berron David , van Westen Danielle , Stomrud Erik , Mattsson‐Carlgren Niklas , Strandberg Olof , Smith Ruben , Palmqvist Sebastian , Glenn Trevor , Hansson Oskar , Wisse Laura
Published: December 2021

Background

Aging, cerebrovascular disease, β‐amyloid (Aβ), and tau pathology are hypothesized to play a role in neurodegeneration, but their interplay is unclear. We investigate associations of these predictors with neurodegeneration, and potential mediating effects on age‐ and Aβ‐related neurodegeneration, in an early Alzheimer’s disease (AD) region (medial temporal lobe (MTL)), and other earlier/later AD neocortical regions in cognitively normal older adults and a low‐Aβ subgroup.

Method

351 adults (41‐91 years) from the Swedish BioFINDER‐2 study were included (65.5±11.8 years; low‐Aβ: n=232, 63.1±11.9 years). Using the Automated Segmentation for Hippocampal Subfields package for T1‐ and T2‐weighted MRI, volumes (dentate gyrus, subiculum (SUB), cornu ammonis 1) and thickness (entorhinal cortex, Brodmann areas (BA) 35/36, and parahippocampal cortex (PHC)) were obtained. FreeSurfer parcellation was used to obtain thickness of neocortical regions involved earlier/later in AD. [18F]RO948‐ and [18F]flutemetamol‐PET standard uptake value ratios were calculated for local tau (partial‐volume corrected) and global Aβ. White matter lesion volumes (WML) were obtained to estimate cerebrovascular disease. Global Aβ‐PET and cerebrospinal fluid Aβ‐42/40 ratio determined Aβ status.

Results

In the whole group, negative (partial) correlations of age/local tau‐PET/WML with structure in most examined regions were observed (Table 1). In the MTL, these predictors were mostly associated with SUB/BA35/PHC. Global Aβ‐PET showed consistent negative associations with neocortical thickness. Low‐Aβ group associations were comparable. In the whole group, age‐structure associations were mediated serially via Aβ‐local tau and directly via tau‐PET in regions with early AD pathology (SUB/BA35, precuneus/posterior cingulate (PPC); Fig.1). In a later AD region (inferior parietal cortex (IP)), local tau‐PET mediated Aβ‐IP association. In low‐Aβ individuals, local tau‐PET mediated the age‐PPC association (Fig.2). Global WML mediated age‐structure associations in posterior MTL and parietal regions in the whole (Fig.1) and low‐Aβ group (Fig.2).

Conclusion

The role of both Aβ‐ and tau‐PET in mediating age‐structure associations in regions typically linked to either early Aβ or tau, could point to an earlier role of Aβ in the MTL and tau in PPC than expected. WML mediating age‐effects on neurodegeneration, in posterior MTL and parietal regions, indicates a potential vulnerability of the posterior‐medial network to cerebrovascular disease.
Testing the neuroinflammatory role of tau‐induced transposable elements in tauopathy
Authors: Thomas Elizabeth Ochoa , Ramirez Paulino , Hyman Bradley T , Ray William J , Frost Bess
Published: December 2021

Background

Novel mechanisms through which pathogenic tau leads to neuronal toxicity remain largely unexplored as therapeutic targets for tauopathies. Activation of retrotransposons has been identified as a mechanism by which pathogenic tau contributes to neurotoxicity (Guo et al., 2018; Sun et al., 2018). To mobilize, retrotransposons are transcribed into RNA, reverse transcribed into DNA, and reinserted into the genome in a new location. Control of retrotransposons occurs at two levels, 1) transcriptional control via the location of retrotransposons within highly condensed heterochromatin and 2) by post‐transcriptional silencing mechanisms. While activated retrotransposons can create novel mutations via the “copy‐and‐paste” mechanism, double stranded RNAs (dsRNAs) formed from transposable element transcripts trigger the innate immune response, further contributing to cell toxicity (Cuellar et al., 2017; Kassiotis & Stoye, 2016; Roulois et al., 2015). Elevation of dsRNAs is documented in models of AGS and TDP‐43 proteinopathy, where dsRNA derived from repetitive elements can stimulate an interferon response (Ahmad et al., 2018; LaRocca, et al., 2019; Rodriguez et al., 2021).We are currently testing the hypothesis that transposable element‐derived dsRNAs stimulate the immune response in tauopathy.

Method

Bioinformatic analysis of bidirectional transcription was completed on RNA‐sequencing data from control and tau transgenic Drosophila. dsRNAs were quantified by J2 anti‐dsRNA antibody via immunofluorescence and ELISA. Analysis of inflammatory markers in Drosophila was completed by RNA‐sequencing and with a custom NanoString Gene Expression codeset.

Result

We find that dsRNAs are elevated in the brains of tau transgenic Drosophila, in the cortex of a mouse model of tauopathy, and in post‐mortem brain tissue from human tauopathy. Based on bioinformatic analysis, we identified retrotransposons that are bidirectionally transcribed in tau transgenic Drosophila. RNA sequencing and NanoString analysis of tau transgenic flies reveals elevated levels of innate immune response gene transcripts. Loss of transposon transcriptional silencing results in similar dsRNA production and immune system activation found in tau transgenic Drosophila.

Conclusion

Our goal is to determine if RNA intermediates from tau‐induced transposable elements are a therapeutic target for tauopathies. Overall, our findings support a model where dsRNA production induced by loss of transcriptional transposon silencing contributes to inflammation in tauopathy
Identification of state‐specific proteomic characteristics of microglia‐derived exosomes
Authors: Santiago Juliet V , Rayaprolu Sruti , Xiao Hailian , Seyfried Nicholas T. , Rangaraju Srikant
Published: December 2021

Background

Alzheimer’s disease (AD) is the most common neurodegenerative disorder defined by progressive pathological protein aggregation (amyloid‐beta and tau) and deterioration of cognitive function. Microglia‐mediated neuroinflammation is a key pathological component of AD; however, there are critical gaps in our understanding of how microglia perpetuate AD pathology. One proposed mechanism of microglia‐mediated neuroinflammation and neurodegeneration is exosome release because of their critical role in the transport of macromolecules between cells to facilitate intercellular communication. Thus, it is possible that microglia‐derived exosomes transfer pathogenic cargo which could perpetuate AD pathology. The proteomic profiles and influence of different microglia‐derived exosomal populations on AD pathology remain unknown. We hypothesize that different microglia states determine the molecular composition of exosomes.

Method

We treated a murine microglia cell line, BV2 cells, with various cytokines to polarize them and collect their exosomes for downstream mass spectrometry (MS) analyses. Three groups of BV2 cells (n=4/group) were treated with either lipopolysaccharide (LPS) to polarize to a pro‐inflammatory state, interleukin 10 (IL‐10) to polarize to an anti‐inflammatory state, or transforming growth factor beta (TGF‐β) to polarize to a homeostatic state. Untreated BV2 cells served as a control group. Following 72 hours of treatment, BV2 cells were lysed and cell culture media was collected for exosome isolation.

Result

Transmission electron microscopy images and western blotting for exosomal marker, CD9, confirmed exosome purification by our isolation method. In MS studies, we identified 533 proteins in exosome fractions and 1,866 proteins in BV2 cell proteomes. We found that known exosome related proteins, Sdcbp and Igsf8, were significantly increased in the exosomal proteome compared to the whole cell proteome. We identified proteins that are differentially expressed across polarization with unique proteins increased in exosomes derived from LPS, IL‐10, and TGF‐β treated BV2 cells. Validation studies of these top hits are ongoing, and studies are underway to replicate these findings in primary microglia.

Conclusion

Our results indicate that exosomes derived from microglia adopt distinct state‐associated protein profiles which may have differential effects on other cell types. This work will guide future studies concerning the role of exosomal cargo in perpetuating AD pathology.
Evaluation of Metformin and Dehydrozingerone against fluorosis induced neurodevelopmental toxicity in preclinical models
Authors: Ahuja Tejas , Kumar Nitesh , Begum Farmiza , Shenoy Rekha R
Published: December 2021

Background

Inorganic fluoride is widely used in dental practices to treat problems like dental caries and also to prevent bone related issues. It has been reported that exposure to excess amounts of fluoride either through drinking water or other sources impairs vital functions of the body and can prove to be toxic specially for the central nervous system. Many studies have shown that sodium fluoride (NaF) crosses the blood brain barrier in early developmental stages and causes impairments related to learning and memory, anxiety, decreased locomotor ability and in some cases, depression like behaviour specially in children. This study aims at evaluating the neurotoxic effects of chronic exposure of NaF in developmental stages in albino Wistar rats using Pre‐Natal in‐vivo model.

Method

In this model, adult male & female Wistar rats were procured & mated. Once the pregnancy was established in female rats, NaF (100 ppm) was fed via drinking water to the groups. For treatment groups, Metformin (200 mg/kg) & Dehydrozingerone (DHZ) (200 mg/kg) were administered along with NaF. Dosing was continued throughout the gestation and lactation period to the newly born pups via mother. After 21 days, pups were separated from mothers & direct dosing of both NaF & test doses to the rat pups was initiated until the end of experiment. At the end of dosing period, animals were taken for behavioural tests, biochemical estimation & histopathological studies.

Result

NaF exposure significantly decreased learning, memory & locomotor ability was able to induce anxiety like behaviour. Levels of AchE & lipid peroxidation was found to be significantly elevated. GSH levels were significantly decreased in hippocampus & frontal cortex in disease group. Histopathology studies showed presence of degenerated neurons in hippocampus of disease group. It was also observed that treatment with Metformin & DHZ was able to ameliorate the cognitive impairment, improve condition of oxidative stress & decrease neuronal degeneration in rat pups (at p<0.05).

Conclusion

This study shows that chronic exposure to NaF led to cognitive impairment & results showed that Metformin & DHZ has neuroprotective ability with special emphasis on antioxidant properties.
Identification of Kv1.3 potassium channel interacting proteins in mammalian cells.
Authors: Bowen Christine A , Dowling Tia C , Lin Young , Bagchi Pritha , Nguyen Hai Minh , Wulff Heike , Seyfried Nicholas T. , Rangaraju Srikant
Published: December 2021

Background

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuronal loss, accumulation of amyloid‐beta(Aβ) plaques, and neuroinflammation. Microglia, the immune cell of the brain, transition to disease associated microglia (DAM) in AD. A subset of DAM, known as proinflammatory DAM, promote neuronal injury and release proinflammatory cytokines. Our lab established that proinflammatory DAM highly express Kv1.3 potassium channel, which consist of a homotetramer of Kv1.3 that interacts with a homotetramer of Kvβ2. Blockade of the Kv1.3 channel reduces microglial immune responses in mouse models. Both Kv1.3 and Kvβ2 contain motifs that interact with immune signaling proteins, however more evidence is needed to support this hypothesis. TurboID is a biotin ligase that biotinylates proteins within a 10nm radius. Split‐TurboID consists of two functionally inactive fragments of TurboID that within proximity of each other, fuse and actively biotinylate proteins within proximity. We will identify molecular interactors of Kv1.3 channels in mammalian cells using proximity labeling.

Method

We fused TurboID or Split‐TurboID to the N‐ or C‐terminal Kv1.3 and Kvβ2 using a 15 amino‐acid inert linker and transfected the constructs into Hek293 cells. TurboID not fused to Kv1.3 and sham transfection acted as controls. Flow cytometry and patch‐clamp electrophysiology confirmed the presence of functional Kv1.3 channels. Biotinylated proteins were streptavidin bead affinity‐enriched from cell lysates and confirmed using western blots.

Result

Label free quantitation mass spectrometry (LFQ‐MS) identified 2,195 biotinylated proteins of which very few were enriched in negative controls. There were 313 proteins as N‐term interactors, 385 as C‐term interactors, and 226 proteins common to both N and C term fusions, representing proteins indirectly associated with Kv1.3 channels. we identified 14 unique N‐term interactors (including metabolic proteins, eg. Naca, Txnl1, Stub1) and 38 unique C‐term interactors (including membrane trafficking proteins, eg. Ank3, Plekha7, Erlec1). Split‐TurboID interactions between Kv1.3 and Kvβ2 indicate that these interacting proteins are largely dependent on the fully functional Kv1.3 with the Kvβ2 subunit present. We packaged these plasmids into lentiviruses to transduce into mouse microglial cell lines.

Conclusion

Our findings indicate Kv1.3 channels interacting with Kvβ2 are a novel molecular mechanism of immune regulation in mammalian cells.
miR‐277 targets hid to ameliorate Aβ42‐mediated neurodegeneration in Drosophila eye model of Alzheimer’s Disease
Authors: Deshpande Prajakta , Chen Chao‐Yi , Yeates Catherine , Chen Chun‐Hong , Kango‐Singh Madhuri , Singh Amit
Published: December 2021

Background

Alzheimer’s disease (AD), an age‐related progressive neurodegenerative disorder, exhibits reduced cognitive functions with no cure to date. One of the reasons for AD is the extracellular accumulation of Amyloid‐beta 42 (Aβ42) plaques. Misexpression of human Aβ42 in the developing retina of Drosophila exhibits AD‐like neuropathology. Accumulation of Aβ42 plaque(s) triggers aberrant signaling resulting in neuronal cell death by unknown mechanism(s).

Method

: Alzheimer’s disease (AD), an age‐related progressive neurodegenerative disorder, exhibits reduced cognitive functions with no cure to date. One of the reasons for AD is the extracellular accumulation of Amyloid‐beta 42 (Aβ42) plaques. Misexpression of human Aβ42 in the developing retina of Drosophila exhibits AD‐like neuropathology. Accumulation of Aβ42 plaque(s) triggers aberrant signaling resulting in neuronal cell death by unknown mechanism(s).

Result

Gain‐of‐function of mir‐277 rescues Aβ42 mediated neurodegeneration whereas loss‐of‐function of mir‐277 enhances Aβ42 mediated neurodegeneration. Moreover, misexpression of higher levels of mir‐277 in the GMR>Aβ42 background restores the retinal axonal targeting indicating functional rescue. Furthermore, we have identified head involution defective (hid) as one of the targets of mir‐277. The hid transcript levels are decreased by one third when mir‐277 is misexpressed in the GMR>Aβ42 background in comparison to the GMR>Aβ42 fly model.

Conclusion

Hereby we provide a mechanism of how mir‐277 modulates Aβ42 mediated neurodegeneration by regulating hid transcript levels and demonstrate its neuroprotective role in Aβ42‐mediated neuropathology.
Effect of insulin resistance on the association between cardiorespiratory fitness and cognition in adults at risk for Alzheimer's disease
Authors: McIntyre Clayton Connor , Okonkwo Ozioma C. , Gaitán Julian M. , Bendlin Barbara B , Edmunds Kyle J
Published: December 2021

Background

Cardiorespiratory fitness (CRF) and cognition have been found to be correlated, though it is unclear what mechanisms are responsible for this correlation. CRF and cognition are also closely related to insulin resistance. We investigated whether insulin resistance explains the relationship between CRF and cognition.

Method

This study included 1157 participants, all cognitively unimpaired and without history of diabetes. CRF was estimated using a validated equation that takes age, sex, BMI, resting heart rate, and self‐reported physical activity habits as inputs. Insulin resistance was quantified by the Homeostatic Model Assessment for Insulin Resistance (HOMA‐IR). Composite scores for executive function, immediate learning, delayed recall, and the Preclinical Alzheimer’s Cognitive Composite (PACC3) were calculated from neuropsychological tests administered by trained technicians. For each cognitive score, linear regression models were utilized to test the influence of CRF on cognition. Mediation analyses were performed to determine whether HOMA‐IR contributed to significant associations between CRF and cognition. All analyses controlled for age, sex, years of education, familial history of Alzheimer’s disease, and Apolipoprotein E4 (APOE4) carriage. Bootstrapped confidence intervals were used to estimate the effect of HOMA‐IR on the CRF/cognition relationship.

Result

The sample was comprised of 69.8% females and 38.7% APOE4 carriers with a mean age of 64.5 ± 7.2 years and a mean 16.3 ± 2.8 years of education. CRF was positively associated with executive function (total effect: B=.015, SE=.005, p=.003), but was not associated with immediate learning (p=.920), delayed recall (p=.970), or PACC3 (p=.258). HOMA‐IR was further investigated as a mediator between CRF and executive function. CRF was negatively associated with HOMA‐IR (B=‐.241, SE=.013, p<.001) and HOMA‐IR had a non‐significant negative association with executive function (B=‐.013, SE=.012, p=.264). While adjusting for HOMA‐IR as a mediator, the association of CRF with executive function was positive and significant (direct effect: B=.012, SE=.006 p=.040). The bootstrapped estimate of the effect of HOMA‐IR on the CRF/executive function relationship was insignificant (B=.0031, CI = [‐.0020, .0087]).

Conclusion

HOMA‐IR did not significantly mediate the relationship between CRF and executive function among individuals at heightened risk for Alzheimer’s disease.
Colocalization of the β amyloid peptide with bacteria in postmortem brain tissue of patients with familial Alzheimer's disease
Authors: Gomez Johana , Villegas‐Lanau Carlos Andrés , Mesa Ana ,   Neuroscience research group
Published: December 2021

Background

β‐amyloid (βA) is a highly conserved peptide throughout the evolution of species that has been proposed as a participant in vital functions. This peptide has been related to the onset and progression of Alzheimer’s disease (AD). Additionally, recent scientific reports have demonstrated in vitro activity against bacteria, fungi and virus. The aim of this study is to describe the colocalization between βA and bacteria in postmortem brain tissue of patients with familial AD.

Method

Initially, we observed bacterial accumulations in brain tissue of two patients with familial Alzheimer's disease and in one case colocalization of βA with bacteria was observed. In order to confirm whether this finding was repeated, shortly after donation and before being fixed with formaldehyde, five cases fresh cerebral samples from five cases with early onset AD were immediately inoculated in vitro with Enterococcus faecalis and Lactobacillus rhamnosus. After different periods of time, both immunostaining for βA detection and Gram staining for bacteria observation were performed on each sample.

Result

Colocalization of βA and gram positive bacteria were observed in all cases. In those infected in vitro, the phenomenon was observed after a period of 24 h of incubation at 35 °C. In the cases fixed with formaldehyde to 10%, its observed multiples cavitations macroscopic in white substance throughout the brain

Conclusion

These results suggest that the βA agglutinates the bacteria, then it’s possible a relationship between βA and bacteria, possibly due to the antimicrobial activity that has been attributed to βA. However, it is necessary to carry out studies with a larger number of samples to confirm the phenomenon and to attempt to explicate it from the cellular and molecular points of view.
Fibroblast Growth Factor 21 and Autophagy Modulation Ameliorates Amyloid β‐Induced Alzheimer Disease Pathology in Rats
Authors: Taliyan Rajeev , Kakoty Violina , KC Sarathlal , Kumari Shobha
Published: December 2021

Background

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition and the most common cause of its initiation is accumulation of oligomeric amyloid beta1‐42 (Aβ1‐42). In recent past, several studies have shown autophagy deficits in AD may resulted accumulation of misfolded protein, Aβ1‐42 and phosphorylated tau (ptau). Fibroblast growth factor 21 (FGF21), a metabolic hormone, has shown strong neuroprotective efficacy via increasing autophagic flux in AD. Therefore, this study was designed to investigate the synergistic neuroprotective efficacy of lentiviral FGF21 gene (LV‐FGF21) delivery and rapamycin‐autophagy modulator in Aβ1‐42 induced AD in rats.

Method

LV‐FGF21 was administered 4weeks before inducing AD by oligomeric Aβ1‐42 into the lateral cerebral ventricles. Rats were divided into control, sham group administered with PBS intracerebroventricularly (ICV), ICV‐Aβ1‐42 group, ICV‐Aβ1‐42 group pre‐treated with LV‐FGF21, and pre‐treated LV‐FGF21 group combined with rapamycin. Morris water maze (MWM), ELISA assay for measuring protein levels of Aβ1‐42, ptau, soluble amyloid precursor protein (sAPP) and beta‐site APP cleaving enzyme 1 (BACE1), oxidative stress measurement, mRNA expression and immunofluorescence analysis were performed after treatment completion.

Result

Aβ1‐42 oligomer formation was confirmed by FESEM analysis. After 14 days, MWM analysis showed that the combination group considerably restored the cognitive ability while attenuated the level of Aβ1‐42, ptau, sAPP, and BACE1. Moreover, oxidative stress parameters considerably improved for the combined treated group as compared with ICV‐Aβ1‐42 group. Also, mRNA expression of main autophagy mediators (beclin‐1, LAMP‐2, LC3, ATF4, p62/SQSTM1) reflected positive outcome for the combination treatment group.

Conclusion

The findings of the present study confirmed the neuroprotective potential of FGF21 and rapamycin in debilitating AD pathology in rats.
Simultaneous RNA and protein profiling using a TurboID proximity‐labeling strategy
Authors: Ramelow Christina C , Sunna Sydney N , Rayaprolu Sruti , Sampson Maureen , Seyfried Nicholas T. , Sloan Steven , Rangaraju Srikant
Published: December 2021

Background

Biologically relevant insights into cellular disease mechanisms of neurons and glia can be obtained by complimentary molecular profiling of the transcriptome and proteome of these cells. While mutually exclusive pipelines are available, the information surveyed is often from different samples leading to poor correlation between the transcriptome and proteome. Our goal was to develop a method for concomitant cell type‐specific analyses of RNA and protein.

Method

We utilized a proximity‐labeling strategy that uses the biotin ligase, TurboID, to efficiently label the proteome, in a mouse microglial BV2 cell line. We created a stable BV2‐TurboID cell line that expresses TurboID fused to a nuclear export sequence. Biotin treatment of BV2‐TurboID cells resulted in robust biotinylation of the cellular proteome as confirmed by Western blot and by label‐free quantitation mass spectrometry (LFQ‐MS) of biotinylated proteins enriched with streptavidin beads. LFQ‐MS revealed that TurboID biotinylates several RNA‐binding proteins (RBPs) including ribosomal units, suggesting that transcripts associated with RBPs may also be pulled down simultaneously with proteins. To test this, we homogenized BV2‐Turbo and control BV2 cells, enriched biotinylated proteins with streptavidin beads while maintaining RNA‐protein interactions, and then eluted RNA.

Result

Quality control studies showed negligible mRNA from streptavidin pulldowns from control BV2 cells, while BV2‐TurboID pulldowns had larger mRNA yields with high quality. NanoString neuroinflammatory profiling (800 genes) of whole cell RNA from control BV2 and BV2‐TurboID cells and streptavidin pulldowns from both cell types were performed. We observed a 23‐fold higher mRNA yield in the BV2‐TurboID pulldowns compared to control BV2 cells for 550 genes included in the analyses. Transcript abundances from total RNA and BV2‐TurboID pulldowns were highly comparable (R2=0.97; no differentially expressed genes) with equivalent abundance of microglial genes (e.g., Spp1 and Apoe) suggesting a faithful transcriptome capture.

Conclusion

Our novel TurboID proximity labeling approach can simultaneously capture cell type‐specific transcriptomes and proteomes. We are now validating this method in other cell types using RNA‐sequencing and MS approaches. Once validated, this concurrent RNA and protein profiling approach can be applied to in vivo and ex vivo model systems to investigate the distinct roles brain cell types play in development, aging, and disease.
CHOP is not a main contributor to tau‐mediated toxicity
Authors: Criado‐Marrero Marangelie , Blair Laura J.
Published: December 2021

Background

In Alzheimer's disease (AD), the accumulation of the microtubule associated protein tau is linked with neuronal loss, but the major cell death pathway remains to be identified. Pathogenic tau promotes endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR) activation. However, the contribution of ER stress to tau‐mediated toxicity in neurons is unknown. A previous study demonstrated that mice lacking CHOP/Ddit3, an important regulator of ER stress‐induced cell death, were protected from ER stress induced neuronal loss. We hypothesized that silencing CHOP would prevent tau toxicity through the ER stress pathway and reveal the contribution of tau toxicity that is mediated through this pathway.

Method

To investigate this, we generated a mouse‐targeting CHOP/Ddit3 shRNA AAV9 that also expresses GFP by a separate promoter. We injected shCHOP AAV9 or a shScrambled control AAV9 in the brains of 8‐month‐old male and female rTg4510 tau transgenic mice and harvested them at 12‐months of age, when ER stress is activated, and neuronal loss is occurring in these mice. We performed behavioral studies using the Y‐Maze, Open field, and 2‐day Radial‐Arm water maze task with a reversal paradigm. Unbiased stereology was used to determine neuronal health and effect of CHOP shRNA on CHOP levels was evaluated by immunofluorescence.

Result

AAV9 CHOP shRNA did not alter spatial learning and memory in tau transgenic mice. Evaluation of the tissue revealed a modest, but non‐significant increase in neuronal loss from CHOP knock down, while the DG shows a non‐significant decrease in neuronal loss. Tissue volume was unchanged in both regions. Very surprising to us, and opposite of what was expected, we found that in these regions of interest the CHOP levels increased in the animal expressing the CHOP.

Conclusion

Overall, this suggests that shCHOP AAV9 does not alter tau‐modified behaviors such as learning and memory particularly at this timepoint. Our results also suggest that there may be a compensatory increase in CHOP signaling in neighboring cells, suggesting that the activation of the UPR in the brains of these mice may be a protective mechanism.
Genome‐wide meta‐analysis of age‐related cognitive decline in population‐based older individuals
Authors: Acharya Vibha , Fan Kang‐Hsien , Snitz Beth E , Ganguli Mary , DeKosky Steve , Lopez Oscar L. , Feingold Eleanor , Kamboh M. Ilyas
Published: December 2021

Background

Cognitive decline is a major characteristic of aging and neurogenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease and other dementias. With worldwide increases in life‐expectancy and elderly population, cognitive decline is a major public health concern. Understanding genetic contributors to age‐related decline in cognition may facilitate identification of the molecular mechanisms of cognitive decline.

Method

To discover genetic influences on cognitive decline, we conducted genome‐wide meta‐analyses on longitudinal performance of five cognitive domains (attention, language, executive function, visuospatial, memory) and the global domain, constructed from five domains, using 3068 individuals aged 65 and above across three longitudinal cohorts: the Gingko biloba Memory Evaluation Study (GEMS), Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) and Monongahela Valley Independent Elders Survey (MoVIES). A linear mixed effect model was used to find individual specific slopes by adjusting for baseline age, years of education and sex.

Results

APOE*4 (rs429358), a well‐known risk factor for AD, demonstrated a genome‐wide significant association with the memory (P= 1.37E‐09) and global (P= 9.26E‐10) domains. Previous studies have also reported APOE*4 ‘s association with memory decline. In addition to APOE*4, multiple suggestive associations of gene loci with cognition were also observed for each domain as follows: attention on chromosome 9 near RASEF/FRMD3 (P = 8.29E‐08), memory on chromosome 6 near ID4/MBOAT1(P = 1.27E‐07), visuospatial function on chromosome 11 near PAMR (P = 2.74E‐07), language on chromosome 9 near PSAT1 (P = 4.08E‐07), executive function on chromosome 4 near SNHG27 (P = 6.49E‐07), and global function on chromosome 4 near LINC00290 (P=8.80E‐07).

Conclusion

Our result suggests that in addition to APOE, multiple genetic loci affect cognitive decline in older individuals. These findings may offer new insights into understanding the genetic architecture of cognitive decline.
INPP5D regulates the amyloid pathology in Alzheimer’s disease.
Authors: Lin Peter Bor‐Chian , Tsai Andy Po‐Yi , Nho Kwangsik , Lamb Bruce T. , Oblak Adrian L
Published: December 2021

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome‐wide association studies highlighted a prominent role for microglia in late‐onset AD (LOAD). Specifically, inositol polyphosphate‐5‐phosphatase (INPP5D) is selectively expressed in brain microglia and one of its common intronic variants (rs35349669; OR=1.08, 95%CI=1.06‐1.11) has been reported to be associated with increased risk of LOAD. INPP5D is linked to the triggering receptor expressed on myeloid cells 2 (TREM2) signaling, but little is known about the function of INPP5D in microglia and how INPP5D regulates TREM2‐related AD pathogenesis. Therefore, we aim to understand the role of INPP5D in microglia and AD pathology.

Method

We performed differential gene expression analysis to investigate INPP5D expression in LOAD and its association with plaque density using transcriptomic (RNA‐Seq) data from the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP‐AD) cohort. We also performed quantitative real‐time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression and microglial markers in the 5xFAD amyloid mouse model with INPP5D deficiency. Using the INPP5D knockout animal crossed with the 5xFAD, we perform the behavioral assays and IHC staining to reveal how the INPP5D regulates the amyloid pathology.

Result

INPP5D gene expression was upregulated in LOAD and positively correlated with the amyloid plaque density. Inpp5d expression increased along with the disease progression in the 5xFAD mice, and is selectively expressed in plaque‐associated microglia. Also, Inpp5d inhibition mitigated the plaque burdens in the 5xFAD mice and further protected against behavioral deficits induced by amyloid pathology.

Conclusion

Our findings show that INPP5D expression increases throughout the AD progression and is predominantly in the plaque‐associated microglia. Importantly, inhibited INPP5D expression reduces amyloid pathology, highlighting INPP5D as a potential therapeutic target.
TasTest: Moving towards a digital screening test for pre‐clinical Alzheimer’s disease
Authors: Alty Jane , Bai Quan , George Rebecca J St , Bindoff Aiden , Li Renjie , Lawler Katherine , Hill Edward , Garg Saurabh , Bartlett Larissa , King Anna E , Vickers James C
Published: December 2021

Background

There is urgent need to develop population‐level digital biomarkers that can detect Alzheimer’s disease (AD) across the continuum, including the preclinical phase. This would allow risk stratification for specialist tests and early recruitment to clinical trials. Motor function declines in the preclinical phase but there has been little exploration of digital motor biomarkers. We have developed ‘TasTest’, an online test that assesses multiple cognitive domains, including movement. The aim of this study was to compare performance on TasTest with subtests of the Cambridge Neuropsychological Test Battery (CANTAB), a validated digital measure of cognitive decline, and determine how performance on the TasTest items varies with age in a large community sample of older adults.

Method

The TasTest items include measures of motor control (speed and coordination of keyboard tapping), processing speed (single and choice reaction time), attention and visual perception (identification of an animal in a distorted image), and visuospatial memory (identifying features from delayed recall of a complex figure). A total of 510 adults aged over 50 years (30% male; mean 65.5 years; SD 7.36), performed TasTest and CANTAB online assessments in their homes. We compared performance on TasTest items to performance on the Paired Associates Learning (PAL) task, which has been previously validated as predictive of accelerated cognitive decline (Barnett et al. 2015, Current Topics in Behavioral Neurosciences, vol 28, Springer, Cham).

Result

All TasTest items were significantly associated with PAL scores except the total number of correct responses on the reaction time tasks (Table 1). Several TasTest items had stronger correlations with age than the PAL, these included the keyboard tapping tasks, the number of correctly identified animals on the distorted image, and both simple and choice reaction times (Figure 1).

Conclusion

Older people were able to readily complete TasTest tasks remotely from their homes, and performance on most items was significantly associated with scores on a previously validated test of cognition, and correlated with age. TasTest shows potential as a non‐invasive, scalable dementia screening tool.
Electrophysiological Examination of Executive Functioning in Lean and Obese Younger Adults
Authors: Larsen Brittany A , Klinedinst Brandon S , Grundy John , Willette Auriel A
Published: December 2021

Background

Obesity rates of adults in the United States have increased from 30.5% in 1999‐2000 to 42.4% in 2017‐2018, with a further projected prevalence to nearly 50% by 2030. Greater adiposity has been consistently associated with exacerbated brain atrophy and central glucose hypometabolism in prefrontal cortices that govern executive functions, including inhibitory control, working memory, emotion regulation, and cognitive flexibility. However, there is a paucity of research elucidating how neural physiology that governs these executive functions is impacted by obesity. Thus, our primary aim of this study was to investigate whether such electrophysiological changes due to obesity could be detected in healthy young adults.

Method

In this cross‐sectional study, we recruited 60 participants (18‐40 years, 55% female) and examined real‐time neural electrophysiology using electroencephalography (EEG) on 34 lean participants (mean body mass index (BMI)=22.1±2) and 26 overweight/obese participants (mean BMI=34.9±6.1) while they completed four cognitive tasks which separately focused on inhibitory control, working memory, emotion regulation, and cognitive flexibility. Serum proteomics were collected, and glycemic control was quantified from glycated hemoglobin (HbA1c) serum measures. We directly assessed body composition via dual energy X‐ray absorptiometry (DXA). Structural equation modeling was utilized in to probe direct/indirect associations between body composition, cardiometabolic biomarkers, and EEG waveforms.

Result

After controlling for age, sex, HbA1c, and DXA android/gynoid ratio, we found that higher body fat percentage was associated with a significantly slower response in order to reach trough amplitudes on the FC1 electrode (196.3±134.4 milliseconds (ms) versus 204.4±311.1ms; β=0.94, p<0.001), as well as a significantly slower response in order to reach peak amplitudes on the FT7 electrode (215.9±129.9ms versus 334.1±327.2ms; β=‐0.537, p=0.019) during a Stroop task. Furthermore, we found that higher body fat associated with significantly slower responses in order to reach trough and peak amplitudes on the FT7 electrode (202.9±95.4ms versus 567.2±434.5ms, β=‐0.87, p=0.032; and 543.4±205.2ms versus 613±333.9ms, β=‐0.79, p=0.049, respectively) during an Operation Span task. No differences were observed between obese and lean subjects for emotion regulation or cognitive flexibility tasks.

Conclusion

Young adults with greater adiposity may have impaired cognitive inhibition and decreased working memory capacity compared to lean counterparts.
The Best Approximation of an Objective State With a Given Set of Quantum States
Authors: Zhang Li‐qiang , Zhou Nan‐nan , Yu Chang‐shui
Published: December 2021

Approximating a quantum state by the convex mixing of some given states has strong experimental significance and provides alternative understandings of quantum resource theory. It is essentially a complex optimal problem which, up to now, has only partially solved for qubit states. Here, the most general case is focused on that the approximation of a d‐dimensional objective quantum state by the given state set consisting of any number of (mixed‐) states. The problem is thoroughly solved with a closed solution of the minimal distance in the sense of l2 norm between the objective state and the set. In particular, the minimal number of states in the given set is presented to achieve the optimal distance. The validity of this closed solution is further verified numerically by several randomly generated quantum states.
Effect of drying method and wall material composition on the characteristics of camellia seed oil microcapsule powder
Authors: Song Fei , Li Yannan , Wang Bo , Shen Xiaojun , Wang Hui , Li Rui , Xia Qiuyu
Published: December 2021

Camellia seed oil (CSO) is one of the richest sources of oleic acid (75–80%) and it is considered to provide beneficial health effects to humans. However, its susceptibility to oxidative degradation prevents its widespread use in the food industry. This study was aimed to improve the stability of camellia seed oil by microencapsulation. CSO was microencapsulated using whey protein concentrate (WPC) and maltodextrin (MD) or starch sodium octenylsuccinate (SSOS) as wall materials. The produced oil‐in‐water emulsion was subsequently dehydrated to produce microcapsule powder using spray and freeze drying techniques, respectively. Various characteristics of oil‐in‐water emulsion and final microcapsule powder including particle size distribution, encapsulation efficiency, morphology, rheological properties of reconstituted emulsions, in vitro digestion behavior and oxidative stability were determined to investigate the effect of wall material composition and drying method on these microcapsule powder characteristics. The spray‐dried powder had significantly higher bulk density and smoother surface compared to freeze‐dried powder while the freeze‐dried CSO microcapsule powder with WPC/SSOS as wall material had the highest encapsulation efficiency and the lowest surface oil. The subsequent in vitro digestion test suggested the microencapsulated CSO could be successfully controlled‐released in the simulated gastric (10.28–13.03%) and the subsequent intestinal fluid (72.89–89.61%). Oxidative stability of camellia seed oil was significantly improved by microencapsulation. The freeze dried CSO microcapsule powder in WPC/SSOS wall material exhibited highest encapsulation efficiency (95.17%) and best oxidative stability (peroxide value and p‐anisidine values of 3.57 meq/kg oil and 3.01, respectively, during the 45 days storage at 25°C.
Isocyanate‐free synthesis of ureas and polyureas via ruthenium catalyzed dehydrogenation of amines and formamides
Authors: Langsted Christopher R. , Paulson Samuel W. , Bomann Blake H. , Suhail Shanzay , Aguirre John A. , Saumer Emily J. , Baclasky Amelia R. , Salmon Kyle H. , Law Ariah C. , Farmer Ryan J. , Furchtenicht Casey J. , Stankowski Dakota S. , Johnson Mary L. , Corcoran Louis G. , Dolan Connor C. , Carney Michael J. , Robertson Nicholas J.
Published: December 2021

Ethyl formate is very effective for the formylation of amines and diamines to yield formamides and diformamides, respectively. Subsequent dehydrogenation of 1:1 mixtures of formamides and amines or diformamides and diamines with ruthenium pincer catalysts furnishes ureas and polyureas, respectively. This approach provides access to a large structural variety of ureas and polyureas because a wide range of primary amines and diamines are readily converted to the corresponding ureas and polyureas. Small molecule ureas were isolated in yields of up to 95%, whereas polyureas were isolated in lower yields (up to 68%) due to strong adhesion to the reaction flask and poor solubility impeding product removal. Furthermore, the ease with which hydrogen can be removed from the reaction medium enables the synthesis of polyureas with molecular weights that are among the highest reported to date (Mn up to 31,100 g mol−1). Notably, this synthetic approach does not necessitate high pressure conditions, simplifying equipment needed for their preparation, and it avoids the use of isocyanates, which have significant health concerns.
Palladium Nanoparticles Supported on Cellulosic Paper as Multifunctional Catalyst for Coupling and Hydrogenation Reactions
Authors: Kalanthoden Abdul Nasar , Zahir Md. Hasan , Aziz Md. Abdul , Al‐Najar Basmah , Rani S. Kutti , Shaikh M. Nasiruzzaman
Published: December 2021

Hallmark of a successful catalyst is its high efficiency, economic aspects, operational simplicity, extensive reusability, higher environment friendliness, and potential use in multiple industrial applications. Herein, a facile protocol involving a catalyst with Pd nanoparticles supported on cellulose paper (also known as a “dip‐catalyst”) for the hydrogenation of a series of quinolines, nitroarene, and C−C bond formation reactions in most benign solvents such as water is described. The mere insertion/removal of the “dip‐catalyst” strip enables instantaneous start/stop of the reaction, which enhances its reusability and ease of separation of products. Cellulose paper (CP) strips decorated with Pd nanoparticles (Pd/CP) are prepared by the reduction of K2PdCl4 soaked strips using formic acid as reductant. The resulting spherical shaped Pd particles, confirmed by scanning electron microscopy, form stable catalysis centers on the support. XRD signature confirms the crystallinity of the Pd nanoparticles and the TEM images display 15–20 nm size particles uniformly decorating CP. X‐ray photoelectron spectroscopy indicates the formation of metallic Pd. The catalyst is tested for the C−C bond formation reactions. Pd/CP catalyzed Suzuki‐Miyaura coupling reaction demonstrate >99% conversion with optimum selectivity. On the other hand, Mizoroki‐Heck reaction produced 87% conversion with the reaction of 4‐methoxycarbonyl phenylboronic acid and iodobenzene in ethanol:water (1 : 1 v/v) using KOH as base. The developed Pd/CP construct produces >99% of the pyridine‐ring hydrogenated product on quinoline hydrogenation using tetrahydroxydiboron (THDB) as the hydrogen source. Diverse and highly reducible functional groups were also evaluated for transfer hydrogenation, which demonstrates a high efficiency in terms of both reactivity and selectivity. The used catalysts are recyclable for the multiple cycles.
Adaptive finite‐time cooperative platoon control of connected vehicles under actuator saturation
Authors: Gao Zhenyu , Zhang Yi , Liu Qingmeng
Published: December 2021

This paper investigates cooperative platoon control of connected vehicles subject to parameter uncertainties, external disturbances, and actuator saturation. Firstly, a approximation method based on radial basis function neural network (RBFNN) is employed to approximate the nonlinear vehicle dynamics and adaptive estimation laws are introduced to tackle the environment disturbances and the unknown upper bound of the actuator saturation, external disturbances and actuator saturation.Then, based on the backstepping technique, compensator‐based command filter and the finite time theory, a robust finite‐time cooperative controller is proposed, with which the tracking error will converge to a small region of origin within settling time. Namely, the given control method can guarantee all the signals in the control system to be finite‐time stabilized. Besides, the problem of “explosion of complexity” in backstepping control is solved by command filter technique. Finally, the correctness and effectiveness of the proposed control scheme is demonstrated by numerical simulations.
Assessment of liver stiffness measurement and ultrasound findings change during inotuzumab ozogamicin cycles for relapsed or refractory acute lymphoblastic leukemia
Authors: Ravaioli Federico , Marconi Giovanni , Martinelli Giovanni , Dajti Elton , Sartor Chiara , Abbenante Maria Chiara , Alemanni Luigina Vanessa , Nanni Jacopo , Rossini Benedetta , Parisi Sarah , Colecchia Luigi , Cristiano Gianluca , Marasco Giovanni , Vestito Amanda , Paolini Stefania , Bonifazi Francesca , Curti Antonio , Festi Davide , Cavo Michele , Colecchia Antonio , Papayannidis Cristina
Published: December 2021

In adult patients, acute lymphoblastic leukemia (ALL) is a rare hematological cancer with a cure rate below 50% and frequent relapses. With traditional therapies, patients with relapsed or refractory (R/R) ALL have a survival that may be measured in months; in these patients, inotuzumab ozogamicin (IO) is an effective therapy. IO was linked to increased risk of veno‐occlusive disease/sinusoid obstruction syndrome (VOD/SOS), liver injury, and various grade of liver‐related complications during clinical trials and real‐life settings; however, hepatologic monitoring protocol is not established in this population. In our institution, 21 patients who received IO (median of 6 doses of IO administered) for R/R ALL were prospectively followed for hepatologic surveillance, including clinical evaluation, ultrasonography, and liver stiffness measurement (LSM) biochemistry. After a median follow‐up of 17.2 months, two SOS events were reported (both after allogeneic transplant) as IO potentially related clinically relevant adverse event. Mild alterations were reported in almost the totality of patients and moderate‐severe liver biochemical alterations in a quarter of patients. Within biochemicals value, AST and ALP showed an augment related to IO administration. LSM linearly augmented for each IO course administered. Baseline LSM was related to liver‐related changes, especially with the severity of portal hypertension (PH)‐related complications. Pre‐transplant LSM was higher in patients receiving IO when compared with a control cohort. PH‐related complications were discovered in nearly 77% of patients, with clinically significant PH occurrence and development of ascites in 38% and 14%, respectively. This prospective experience constitutes the rationale to design a hepatologic monitoring program in patients receiving IO. LSM may be of pivotal importance in this program, constituting a rapid and effective screening that quantitatively correlates with liver alterations.