bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell type‐specific enhancer‐promoter connectivity maps in the human brain and associations with Alzheimer’s disease risk
Authors: Nott Alexi , Holtman Inge , Coufal Nicole , Schlachetzki Johannes CM , Yu Miao , Rissman Robert A , Brewer James B , Ren Bing , Gage Fred H , Glass Christopher K
Published: December 2020

Background

There is no clear genetic cause for most cases of late‐onset Alzheimer’s disease (AD), however, genome‐wide association studies have identified multiple genetic variants associated with increased risk of AD. These AD‐risk variants are often located in non‐coding DNA regulatory regions called enhancers, which upon transcription factor binding, modulate the expression of nearby genes. One of the major challenges facing the field of AD research is the assignment of cell‐type specificity and functionality to these genetic variants.

Method

Nuclei of microglia, neurons, astrocytes and oligodendrocytes were isolated from frozen human cortical tissue. Sorted nuclei were processed using chromatin immunoprecipitation and sequencing (ChIP‐seq) to define cell type promoter and enhancer regions. The assay for transposase accessible chromatin sequencing (ATAC‐seq) was used to define open chromatin regions, which indicates likely transcription factor binding sites. Proximity Ligation‐Assisted ChIP‐seq (PLAC‐seq) is a chromatin conformation assay that was used to link distal enhancers to target genes. Enhancers were validated by CRISPR‐mediated deletion of putative regions in induce‐pluripotent stem cells (iPSCs) that were derived into neurons, microglia and astrocytes followed by gene expression analysis.

Result

Genetic variants associated with increased risk of AD were largely confined to microglia enhancers, whereas genetic variants for psychiatric disorders such as autism and schizophrenia were enriched in neuronal enhancers. Enhancer‐promoter interactome maps connected disease‐risk variants located in enhancers to gene promoters. Integrative analysis of promoter‐enhancer interactome maps has not only revised and expanded the gene repertoire influenced by AD‐risk variants but has also revealed the probable cell types in which they function. Lastly, the BIN1 locus, the second highest putative AD‐risk gene after APOE, has a microglia‐specific enhancer that harbors AD‐risk variants. CRISPR‐deletion of the microglia BIN1 enhancer in iPSCs ablated BIN1 gene expression in iPSC‐derived microglia and not neurons or astrocytes.

Conclusion

There has been intense interest in elucidating mechanisms that link human non‐coding genetic variation to risk of neurodegenerative and psychiatric diseases. Towards this effort, enhancer‐promoter connectivity maps in the human brain has enabled an initial cell‐type‐specific interpretation of human genetic variation associated with disease risk for AD and other brain disorders.
Impact of familiar olfactory stimulation on self‐consciousness
Authors: Castro Arbeláez María Alejandra , Arrollo‐Anlló Eva María , Acosta Daysi
Published: December 2020

Background

Autobiographical memory facilitates the construction and meaning attributed to a lifetime story. The episodic autobiographical memory involves the personal experiences related to a place and a specific time, and the semantic autobiographical memory is associated to a general knowledge related to repetitive events and past experiences over a long period of time (Allen, Doyle, Commins & Roche, 2018). Autobiographical events trigger an autonomic consciousness in which it revives the past memories, while the autobiographical semantic knowledge involves a consciousness of past limited and noetic familiar sensation (Irish et al., 2018; El Haj, Nandrino & Kapogiannis, 2015; Rathbone, Ellis, Ahmed, Moulin, Ernst, & Butler, 2019). Decline of autobiographical episodic memory involves a progressive loss of self‐consciousness in Alzheimer’s disease (A.D). Some studies like Glachet, Gandolphe, Gallouj, Antonie, and El Haj (2018) demonstrate positive effects of olfactory stimulation on autobiographical memory. However, no research has evaluated the influence of familiar olfactory stimulation on A.D related to improve self‐consciousness in Dominican Republic. This study aims to evaluate the evoked autobiographical memories from familiar olfactory stimulation has an enforcement or facilitator effect on self‐consciousness.

Method

Fifty people with mild and moderate A.D will participate. The Control group, will have an olfactory stimulation without familiar smells and the experimental group, will have an olfactory stimulation with familiar smells. After intervention: Evaluation of autobiographical episodic memory (controlled process) and self‐consciousness. During Intervention: Olfactory familiar stimulation with experimental group and placebo olfactory stimulation with control group. Then there will be an evaluation of autobiographical episodic memory (automatic process). Before intervention: Post olfactory stimulation of self‐consciousness.

Results

We expect that the positive valiance of familiar olfactory intervention will be evoked more in the autobiographical episodic memories than the placebo stimulation olfactory in patients with A.D; and that autobiographical episodic automatic or involuntary memories evoked will be more elevated about subjective content that the voluntary or explicit ones. We also hope that the group of patients with familiar olfactory stimulation evoke autobiographical episodic memory and improve their level of self‐consciousness.

Conclusion

This study will be a framework for non‐pharmacologic interventions and future clinical trials with familiar olfactory intervention.
Hypoxia‐induced changes in microglia in the vhl‐/‐ zebrafish
Authors: Almasnouri Taghreed S , Hamilton Noémie , Heath Paul , van Eeden Van Eeden Freek , Simpson Julie E
Published: December 2020

Background

Age‐associated white matter lesions are associated with chronic cerebral hypoperfusion resulting in a hypoxic environment, and are characterised by high levels of microglia with an amoeboid phenotype. These observations suggest that sustained activation of the hypoxia‐inducible factor (HIF) signalling pathway modifies the microglial phenotype. This study aimed to perform a detailed characterisation of the microglial response associated with hypoxia by exploiting vhl‐/‐ zebrafish, a model which displays highly up‐regulated hypoxic signalling.

Method

In order to exploit the in vivo imaging capabilities of zebrafish and visualise microglia, a reporter for macrophage‐expressed gene‐1 (mpeg1) was crossed into the vhl‐/‐. The number and morphology of mpeg1::mCherry microglia were characterized by light‐sheet florescence microscopy for ten mutant vhl‐/‐ zebrafish and their wild‐type siblings, at a single time point between the ages 3.2 ‐ 3.6 dpf. Furthermore, time lapse video was employed to monitor the microglial response to hypoxia across 24 hours.

Result

At the single time‐point measurement, vhl‐/‐ zebrafish contained 59±0.1 microglia (14±1.3 with a resting morphology, 46±0.2 with an amoeboid morphology), while their wild‐type siblings contained 59±2 total microglia (12.5±1.5 resting morphology and 45±1.8 amoeboid morphology. There was no significant different in the total (p=0.69), resting (p=0.26) or amoeboid microglia (p=0.91). Time‐lapse recordings over 24 hours confirmed this result.

Conclusion

No significant differences in microglia numbers or morphology was detected at 3 dpf. At 5 dpf, microglia number increased and adopted a round, amoeboid morphology. This represent is similar to the microglia phenotype associated with age‐associated WML.
Mitochondrial pathway‐specific Alzheimer’s disease polygenic risk scores are associated with increased risk of Alzheimer’s disease
Authors: Paliwal Devashi , Andrews Shea J , Easteal Simon , McInerney Timothy
Published: December 2020

Background

Increasing evidence from genetic, biomolecular, cell biology, clinical endophenotypes, animal, and epidemiological studies suggest a potential role of mitochondria in Alzheimer’s disease (AD). Here we investigate the association of AD‐associated polygenic risk scores (PRS) composed of genetic variation within genes associated with known mitochondrial pathways (pathway‐PRS) with AD risk.

Method

Using data from the Alzheimer’s Disease Neuroimaging Initiative we constructed mitochondrial pathways‐specific AD PRS in 698 non‐Hispanic whites (AD = 463, Controls = 235) and investigated their association with AD. We constructed thirteen PRS in total – a whole genome PRS, a nuclear‐encoded mitochondrial genome (nMT‐DNA) geneset (comprising of all nMT‐genes) and eleven mitochondrial pathways based on genesets obtained from the Molecular signatures database (MsigDB). PRS were constructed using the ‘standard weighted allele’ method, with SNPs weighted by their effect size from a GWAS of clinical AD. P‐value thresholding (p ≤ 0.5) and LD clumping for the whole genome and set‐based LD clumping for pathway‐specific PRS (250 kb window, r2 < 0.1) was performed. A competitive empirical p‐value approach was applied as a correction for the multiple testing burden. Finally, logistic regression was used to assess the association of pathway‐PRS with AD, adjusting for age, sex, APOE, and ancestry.

Result

We found that nMT‐DNA PRS was significantly associated with AD risk (OR: 2.12 [95% Cl: 1.77, 2.57], p < 0.001). In pathway analyses, three biological pathways showed significant association with increased AD risk: (i) cellular response to oxidative stress (OR: 2.11 [95% Cl: 1.75, 2.56], p < 0.001); (ii) mitochondrial transport (OR: 1.89 [95% Cl: 1.58, 2.28], p < 0.001); and (iii) Hallmark oxidative phosphorylation and respiratory chain (OR: 1.27 [95% Cl: 1.08, 1.49], p < 0.05).

Conclusion

Our findings suggests that higher baseline genetic risk conferred by AD‐associated SNPs within genes involved in three pathways ‐ cellular response to oxidative stress, mitochondrial transport, and oxidative phosphorylation significantly contributes to higher AD risk. This is the first study to demonstrate these findings and suggests the therapeutic potential of targeting these pathways. Further investigations are required to validate and establish the causal role of these pathways in AD pathology.
Effect of combined WeChat video and comprehensive medical therapy on severe COVID‐19 with moderate Alzheimer's disease: A case report
Authors: Zhang Fengxia , Lu Yinshan , Hu Jun , Hu Mengting , Ma Siliang , Zhu Shanshan
Published: December 2020

Objective

We present a case report of recovery from severe COVID ‐ 19 (novel coronavirus 2019) in a patient with cognitive decline (84‐year old, female), behavioral and psychiatric symptoms, hip arthroplasty, sacroiliac decubital necrosis, cachexia, after comprehensive therapy.

Background

Because of cognitive and behavioral disorders, patients with Alzheimer’s disease have poor coordination of treatment especially in an unfamiliar environment. Communicating with close family members through WeChat video can relieve patients' anxiety and other mental symptoms, leading to better cooperating with drug treatment and nasal feeding diet.

Methods

Patient received 1 hour daily WeChat video communication with her son at isolation ward, including psychological comfort, care and positive words. The WeChat video communication were last for 4 weeks, during this time, the elderly patient was also treated with methylprednisolone (for 5 days), immunoglobulin (for 5 days), ulinastatin, thymus methoxide (for twice a week), acetylcysteine, antibiotics, low molecular weight heparin, probiotics, nutrition and other symptomatic support therapy.

Results

Before WeChat video communication about 4 weeks, the patient refused medical treatment, consisting of extraction of infusion set and removal of gastric tube, which greatly affects the treatment of drugs and the nutritional intake of patients; and the state of the patient’s condition became even worse. However, after 4 weeks WeChat video communication, the patient showed a significant improvement in the Mini‐mental state examination scores from 8 to 12 (Education: illiterate) and in the Neuropsychiatric questionnaire scores from 35 to 10. Besides, after 4 weeks WeChat video communication and comprehensive therapy, the patient’s pneumonia improved significantly and the nucleic acid test turned negative.

Conclusions

WeChat video communication may be a promising noninvasive approach for patients with Alzheimer’s Disease, which may help alleviate neuropsychiatric behavioral symptoms and can be more cooperative with medical workers.
Chimera traumatic brain injury induces tauopathy in the RTG4510 mice
Authors: Cheng Wai Hang , Wilkinson Anna , Cheung Honor , Barron Carlos J , Cripton Peter A , Wellington Cheryl L
Published: December 2020

Background

Traumatic brain injury (TBI) is a major cause of death and disabilities in developed countries. We have previously designed an animal TBI model called Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA). CHIMERA has the advantage of inducing precise non‐surgical head impacts without restricting head motion, thus inducing TBI relevant to a real‐world scenario. Using CHIMERA, we showed that repetitive mild TBI in a mouse model of amyloidosis led to neuropathological changes including neuroinflammation, fear memory deficits, and accumulation of soluble high molecular weight Aβ oligo/fibril. In the current study, we aim to study if CHIMERA TBI exacerbates tau pathologies, by inducing moderate/severe TBI (msTBI) to rTg4510 mice.

Method

4‐mo male rTg4510 mice were used for this study. For the test group, a single msTBI TBI was induced at 4.0 J impact energy, with CHIMERA interface. For sham group, the animals received only anesthesia but no impact. 8 out of 13 animals survived the moderate/severe TBI procedure (38% mortality). The surviving animals were kept for 2‐mo, and the brain tissues were harvested for analysis using immunohistochemistry and Western blotting for multiple tau epitopes, neuroinflammation, and axonal injury. Blood samples were collected biweekly for biomarker analysis.

Result

TBI animals showed a significant increase duration of loss of righting. Histological analyses indicated significant microgliosis (Iba1) and axonal injury (Neurosilver) at white matter (optic tract), but no significant change in neuronal number (NeuN), astrocytes (GFAP), endothelial cells (CD31), or blood brain barrier integrity (IgG). There was a significant increase of one p‐tau epitope (PHF1), but not others (CP13, AT8, MC1, RZ3, or DA9). TBI also reduced the level of an inactive form of GSK‐3b (p‐GSK‐3b at S9). Interestingly, TBI animals showed a significant increase of P62 signals particularly at hippocampus, suggesting impaired autophagy.

Conclusion

Our current findings suggest a single msTBI is sufficient to induce p‐tau in rTg4510 mice, possibly through a reduction of inactive GSK‐3b. In addition, increased P62 signals may indicate impaired autophagy, which may lead to increased accumulation of neurodegenerative proteins at a later stage. More work has to be done to confirm long‐term tau and autophagy changes after TBI.
The effects of increasing dementia knowledge on alleviating stigmatizing attitudes among elementary school students in Taiwan
Authors: Kuo Ching‐Yi
Published: December 2020

Objectives

Based on the published research that disseminating dementia knowledge reduced stigmatizing attitude toward persons with dementia, this project is going to carry out the research results into dementia care practice through disseminating dementia knowledge to school age children in Taiwan.

Background

Stigma attached to dementia is a common theme across cultures as reported in the literature. Despite retaining cultural adherence to filial piety, which includes respect for the aging, stigmatizing attitudes toward dementia remain a hindrance to timely diagnosis and services utilization in Asian communities (Chiu et al., 2014). Community education about dementia may be helpful to lower this barrier to early detection and intervention (Cheng et al., 2011; Devlin et al., 2007). Most studies focus on the impact of disseminating knowledge to adults. Little is known regarding its effects of increasing dementia knowledge in school age children on combating dementia stigma and mental health issues in aging populations in Asia.

Methods

A Quasi‐experimental design will be employed in this study. The third and fourth graders in selected elementary schools in southern Taiwan will be administered a questionnaire eliciting current understanding of dementia prior to a power point introducing dementia, and followed by the repetition of the questionnaire for a pre and post‐ test elicitation and identification of concepts grasped and concepts missed.

Results

This is an on‐going research project and the results are in process. Implications: Young children often help older family members care for older persons with dementia who are home‐bound; they may be more empathetic if they know more about the condition affecting their relative.
Self‐administered gerocognitive examination for the early detection of cognitive impairment at primary care provider visits
Authors: Scharre Douglas W. , Vrettos Nicole E , Nagaraja Haikady N
Published: December 2020

Background

Currently 50%‐75% of dementia cases are undiagnosed, untreated, and unmanaged. The average diagnosis time is 32 months after symptom onset. Primary Care Providers (PCP) are critical for case finding of cognitive impairment to provide management, referrals, and treatments. Cognitive assessments are time consuming and difficult to incorporate into time‐limited PCP visits. Self‐Administered Gerocognitive Examination (SAGE) is a reliable, valid, pen and paper, cognitive assessment that is easily incorporated into PCP visits without needing staff administrators. PCP visits with and without SAGE were compared to determine differences in diagnoses, treatment, and management of new cognitive disorders.

Method

Subjects without diagnosed cognitive disorders and with acceptable reading, vision and English language comprehension, aged 65‐89 who completed a non‐acute office visit were enrolled. Two physically separate PCP offices conducted their visits as they normally would for 100 consecutive subjects each. One office, in an additional 100 subjects, used SAGE and asked an informant, if available, to ascertain if the subject experienced significant cognitive change (based on PCP opinion) over the previous year. Chart reviews were conducted 60 days from the initial visit. One‐way analysis of variance and Fisher exact tests were used to compare the groups and outcomes.

Result

There were no differences in age, race, or gender between the intervention (n=100) and control (n=200) subgroups. When SAGE was utilized, the PCP documented detection of new cognitive conditions/concerns six times (9% versus 1.5%) as often (p=0.003). In the intervention group, detection rate was nearly 4‐fold higher when SAGE scores were in the cognitively impaired range (p=0.034). New cognitive conditions/concerns were recorded by the PCP in 31% of 16 cases where informants noticed cognitive changes and in none of 22 where informants noted no changes (p=0.009). Combining low SAGE scores and informant concerns, those with one of the factors were 15‐fold as likely to have new cognitive conditions/concerns documented (p=0.007).

Conclusion

SAGE was easily incorporated into PCP visits and resulted in significantly increased awareness of new cognitive conditions/concerns leading to new diagnoses, treatment, and management changes, which increased 4‐fold when combined with informant reports of significant cognitive declines over a year.
Emerge and Engage topline results: Phase 3 studies of aducanumab in early Alzheimer’s disease
Authors: Haeberlein Samantha Budd , von Hehn Christian , Tian Ying , Chalkias Spyros , Muralidharan Kumar Kandadi , Chen Tianle , Wu Shuang , Skordos LeAnne , Nisenbaum Laura , Rajagovindan Raj , Dent Gersham , Harrison Katie , Nestorov Ivan , Zhu Ying , Mallinckrodt Craig , Sandrock Alfred
Published: December 2020

Background

Aducanumab is a human monoclonal antibody that selectively targets aggregated forms of Aβ, including soluble oligomers and insoluble fibrils. EMERGE and ENGAGE are two 18‐month, randomized, double‐blind, placebo‐controlled, global Phase 3 studies with identical design that evaluated the efficacy and safety of aducanumab in patients aged 50–85 years with early Alzheimer’s disease (MCI due to AD or mild AD dementia).

Method

Key inclusion criteria included positive amyloid PET, MMSE score of 24–30, CDR Global score of 0.5, and an RBANS‐DMI score ≤85. During the 18‐month placebo‐controlled period, patients were randomized 1:1:1 to low‐dose aducanumab, high‐dose aducanumab, or placebo, administered via IV infusion every 4 weeks. The primary endpoint for EMERGE and ENGAGE was change from baseline at Week 78 on the CDR‐SB. Secondary endpoints included change from baseline on MMSE, ADAS‐Cog13, and ADCS‐ADL‐MCI.

Result

Following pre‐planned futility analysis, analysis of the data from the final database lock showed that EMERGE met its primary endpoint, based on the pre‐specified statistical analysis plan. Patients treated with high dose aducanumab showed a significant reduction of clinical decline from baseline in CDR‐SB scores at 78 weeks (22% versus placebo, P = 0.01). ENGAGE did not meet its primary endpoint. However, data from patients in ENGAGE who achieved sufficient exposure to high dose aducanumab supported the findings of EMERGE.

Conclusion

EMERGE met its primary endpoint, based on the pre‐specified statistical analysis plan. Data from a subset of patients in ENGAGE support the results of EMERGE. The safety and tolerability profile of aducanumab in EMERGE and ENGAGE was consistent with previous studies of aducanumab.
ATP as a catalyst for amyloid fibrillation of tau protein
Authors: Heo Chae Eun , Kim Hugh Inkon
Published: December 2020

Background

Intracellular tau protein tangle is a hallmark of various neurodegenerative diseases, which include Alzheimer’s disease (AD). For this reason, characterizing the physiological factors associated with tau aggregation and the aggregation mechanism has been considered crucial for understanding tau pathology. Recent evidence implies that (i) intracellular ATP level may be dysregulated and (ii) the increased ATP level may have an influence on the tau aggregation. However, the effects of ATP on tau fibrillation and its mechanistic details are not fully elucidated.

Methods

For characterizing K18 fibrillation mechanism catalysed by ATP, we performed multiple biophysical experiments such as thioflavin assays, circular dichroism, small‐angle X‐ray scattering, and native mass spectrometry. We further measured cellular ATP amount in presence of TNFα, and intracellular tau aggregation was examined by bimolecular fluorescence complementation experiments.

Results

Herein, we report the catalytic role of ATP and its mechanistic details in tau aggregation at a molecular level for the first time. Using multiple approaches including solution small angle X‐ray scattering (SAXS), native mass spectrometry (MS) and molecular dynamics (MD) simulations, we observed that nonspecific electrostatic interactions between negatively charged triphosphate moiety in ATP and basic residues in tau K18 (i.e. four‐repeat domain of tau) direct the dimerization of K18 by charge neutralization of the protein in the early stage of the aggregation. We observed that ATP was excluded in the late stage of fibrillation and acted to accelerate K18 fibrillation even at lower stoichiometric ratios for the charge neutralization, indicating that ATP acted as a catalyst for K18 fibrillation. Moreover, our bimolecular fluorescence complementation (BiFC) and immunoblotting (IB) experiments suggested a correlation between ATP dyshomeostasis and tau aggregation in cellular environment.

Conclusion

We believe that our observations would provide valuable insights into the mechanism of tau aggregation and the importance of ATP in tauopathies.
Psychotherapeutic interventions in individuals at risk for Alzheimer’s dementia: A systematic review
Authors: Rostamzadeh Ayda , Kahlert Anna , Kalthegener Franziska , Jessen Frank
Published: December 2020

Background

Expanding technologies of early detection of Alzheimer’s disease (AD) allow to identify individuals at‐risk in very early and asymptomatic disease stages. Neuropsychiatric symptoms, such as anxiety and depression, are common in in the course of AD and may be clinically observed many years before the onset of significant cognitive symptoms. To date, therapeutic interventions for AD focus on pharmacological and non‐pharmacological strategies. However, despite good evidence for psychotherapy in late‐life depression, evidence for such therapeutic options in the course of cognitive decline related to AD is sparse.

Method

A systematic review was conducted in PUBMED, PsycINFO and Web of Science to summarize the state of evidence on psychotherapeutic‐psychoeducational interventions for individuals at‐risk for Alzheimer’s dementia. Eligible articles needed to apply a manualized and standardized psychotherapeutic or psychotherapeutic‐psychoeducational intervention administered by trained professionals for individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI).

Result

The literature search yielded 35 studies that were included in this narrative summery. The data illustrates heterogeneous therapeutic approaches with mostly small sample sizes of study participants and short follow‐up monitoring. There is evidence that interventions have an antidepressive effect and a positive impact on disease acceptance, including positive effects on life quality. However, specific therapeutic determinants of efficacy have not been identified to date.

Conclusion

This review underlines the need of specific psychotherapeutic‐psychoeducational therapeutic approaches for individuals at‐risk of Alzheimer’s dementia, particularly in terms of early interventions aiming at improving well‐being, mental health and quality of life in the course of the neurodegenerative disease. One paramount challenge is the modification of psychotherapeutic techniques according to the different stages of cognitive decline in the course of AD, which is needed to be sensitive to the individual needs and preferences.
Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in Alzheimer's disease patients
Authors: Llorens‐Martin María
Published: December 2020

Background

Memory impairment in Alzheimer’s Disease (AD) can be attributed to a significant decline in the functioning of the hippocampal formation, a brain region crucial for learning and memory. Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely the addition of new neurons throughout lifetime. While synapse loss and consequent death of mature neurons may be responsible for much of the hippocampal malfunctioning in AD, studies in mice suggest that the disease could also target the generation of new neurons – or adult hippocampal neurogenesis (AHN). Nonetheless, direct evidence of AHN in humans has remained elusive.

Method

We have developed a novel reliable method to study AHN in post‐mortem human brain samples. We revisited the occurrence of continued neurogenesis in the human hippocampus of aged healthy subjects and AD patients, using brain material obtained under tightly controlled conditions and applying state‐of‐the‐art tissue processing methods.

Result

We observe a dynamic population of immature neurons in the human dentate gyrus at least until the tenth decade of life. Slight variations in histological and tissue processing methodologies have a great impact on the study of AHN in the human DG. AHN is dramatically impaired in AD patients.

Conclusion

Our data evidence that AHN is a robust phenomenon in the human brain, and points to impaired neurogenesis as a potentially relevant mechanism underlying AD that may be amenable to novel therapeutic strategies.
Oligomeric amyloid‐beta 1–42 inhibits antigen presentation
Authors: Gericke Christoph , Mallone Anna , Engelhardt Britta , Nitsch Roger M , Ferretti Maria Teresa
Published: December 2020

Background

Beyond microglia, the involvement of other immune cell types and immune functions in Alzheimer’s disease (AD) is not well understood. Here, we investigated the potential immunomodulatory properties in vivo and in vitro of oligomeric species of beta‐amyloid‐peptide (Aβ) on microglia and other putative antigen presenting cells (APCs).

Methods

We used multicolour flow‐cytometry, confocal microscopy and MSD biochemical analysis to characterise amyloid deposition and brain immunephenotype of APP‐PS1‐dE9 mice of 3, 6, 12 and 20 months of age. Next, we applied a customised in vitro systems (using OT‐II ovalbumin‐specific transgenic CD4+ T cells and ovalbumin as antigen) to study the effect of recombinant, oligomeric preparations of human Aβ1‐42 on antigen presentation by primary dendritic cells. Finally, via RNAseq, we investigated the effect of oligomeric Aβ 1‐42 on the transcriptome of primary dendritic cells.

Results

We show that, in the APP‐PS1‐dE9 mouse model, the deposition of the first beta‐amyloid plaques at 6 months of age is accompanied by a significant reduction in MHC class II surface levels on brain APCs, suggesting impaired antigen presentation capability induced by beta‐amyloid. This hypothesis was confirmed by our in vitro experiments, using the prototypical antigen presenting cells, primary bone‐marrow derived dendritic cells. Incubation with a preparation containing various forms of oligomeric Aβ1‐42 (but not of scrambled peptide) inhibited antigen presentation by primary dendritic cells, in a dose‐dependent manner. Finally, we found that human oligomeric Aβ 1‐42 alters the transcription of key immune mediators in dendritic cells, including cytokines, chemokines and adhesion molecules.

Conclusions

Our results suggest that, beyond their well‐characterised neurotoxic effects, oligomeric forms of Aβ 1‐42 exert hitherto unknown immunomodulatory properties. By inhibiting antigen presentation by cerebral APCs, Aβ 1‐42 might interfere with physiological brain immune surveillance, thus facilitating Aβ 1‐42 and tau spreading in AD.
Motor dysfunction as a marker for mild cognitive impairment and Alzheimer’s disease
Authors: Koppelmans Vincent , Weisenbach Sara , Duff Kevin M , Ruitenberg Marit FL
Published: December 2020

Background

Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD) are associated with motor impairments that can precede cognitive symptoms by several years. While prior studies suggest that such motor impairments may be an early disease marker and predict AD progression, most only included a single motor measure. Here, we tested the hypothesis that a broad motor assessment can distinguish MCI and AD from healthy controls (HC).

Method

To identify which measures jointly have the strongest predictive power we developed a comprehensive test battery assessing hand grip force, finger tapping speed (single and dual synchronized/alternating), Archimedes spiral and Trail Making Test drawing, and motor sequence learning. HC and MCI individuals additionally completed a 6‐meter walking test, timed up‐and‐go test, and Romberg balance test.

Result

So far 10 patients with amnestic MCI (70±5y; 5 males), 10 patients with AD (75±6y; 4 males), and 13 HC (69±6y; 5 males) completed the battery. We observed a pattern of mild to moderate motor deficits across motor domains in MCI patients compared to HC, including grip force, finger tapping and walking speed (medium‐to‐large effect sizes; eta2=0.08‐0.16). AD patients showed deficits in simple reaction time and drawing speed (large effect sizes; eta2=0.18‐0.2) compared to HC.

Conclusion

Our findings suggest that specific motor measures could be used as novel, inexpensive, non‐invasive biomarkers for dementia. If these cross‐sectional motor differences persist with larger samples, then it will be important to examine them longitudinally.
Social network structure and dementing processes
Authors: Zhang Yun , Natale Ginny , Clouston Sean
Published: December 2020

Background

How are components of individual social relationships associated with the dementing process? We examined associations between social network structure on incidence of mild cognitive impairment (MCI) and conversion to probable dementia, and on mortality rate.

Method

We utilized six waves of a nationally representative cohort of residents aged over 65 years and older in the United States (2011‐2016; National Health and Aging Trends Study; NHATS). Respondents were categorized into normal cognition, MCI, or probable dementia. Four‐status multi‐state survival models (MSMs) were used to provide multivariable‐adjusted measures, fit with a misclassification matrix, assessed effects of social network structure on the dementing process.

Result

Eligible NHATS participants (N=6,078) were mostly female (58.42%), and the majority were Non‐Hispanic white (68.99%). At baseline, the average age was 77.49±7.79 years and respondents reported an average number of 1.93 ±1.31 members of their social networks. In multivariable‐adjusted MSMs accounting for age, sex, education and race/ethnicity, having larger social networks was associated with lower hazards of conversion from MCI to probable dementia (adjusted Hazard Ratio (aHR): 0.82; 95%C.I.=[0.67‐0.99]). Having at least one friend within social network was associated with lower hazards of conversion from MCI to dementia (aHR=0.48 [0.33‐0.71]) but was associated with higher risk of mortality in the MCI group (aHR=2.58 [1.47‐4.51]). Finally, participants with at least one college graduate in their social network reported lower incidence of dementia (aHR=0.37 [0.26‐0.51]).

Conclusion

Our study is one of the first studies exploring effects of social network structure on the dementing process in a nationally representative prospective cohort of older adults. We found that having at least one friend, a larger social network, or having a college graduate within social network was associated with lower risk of MCI or conversion to dementia. We also reveal substantial disparities in cognitive dementing by education and race/ethnicity as well as clustering risks for low‐educated families.
Reading of the speedometer value in elderly drivers with cognitive impairments: A comparison of analog and digital speedometer
Authors: Peng Zhouyuan , Kinoshita Ayae , Shimosaka Momoyo , Miyamoto Masakazu , Kuzuya Akira
Published: December 2020

Background

With cognitive functions deteriorated, the capability to get the information of speed, one of the essential element needed to perform safe driving1, may be influenced. We aim to investigate the reading of the speedometer (SM) values in elderly driver with cognitive impairments by comparing the recognition of analog and digital SM values, and examine its correlation with cognitive functions.

Methods

Elderly subjects with driving experience who visited the outpatient neurology clinic in the Kyoto university hospital for cognitive complaints from July 2018 to December 2019 were investigated. Cognitive tests were carried out, as well as a test asking participants to read the speed values of analog SM and digital SM presented on the iPad within the time limit.

Results

Among 48 participants slightly more than half of them returned their driving licenses (retired drivers) whereas 22 still hold a valid driving license (current drivers). Based on the result of Wilcoxon test, among all participants the result of reading test of digital SM had significant higher scores than analog SM (Z=‐3.996, p<0.0001). According to the Mann‐Whitney U test, there was no significantly different about their reading ability of both analog and digital SM values between current drivers and retired drivers. Additionally, the reading ability of digital SM was significantly correlated with the score of Mini‐mental state examination, block design test and clock drawing test.

Conclusions

Among elderly drivers with cognitive impairments, it was shown that digital SM was easier to read than analog SM. This newly gained information provides an innovative insight to the design of SM. Reference: Francois M, Osiurak F, Fort A, Crave P, Navarro J. Analogue versus digital speedometer: effects on distraction and usability for truck driving. European Conference on Human Centred Design for Intelligent Transport Systems; 2016‐06‐30, 2016; Loughborough, France.
Selective impairment of molecular interaction between ADP and ATP synthase by anesthetics
Authors: Liang Feng , Xie Zhongcong
Published: December 2020

Background

Isoflurane, sevoflurane, and desflurane have been shown to have different neurotoxic effects. However, the underlying mechanism at the single molecular level remains unknown. Isoflurane, sevoflurane, and desflurane can differently induce mitochondrial dysfunction and ATP synthase is the critical component of mitochondrial function. We, therefore, set out to assess whether different anesthetics can selectively impair the interaction of ADP and ATP synthase at a single molecular level.

Method

The human H4‐APP cells were treated with 2% isoflurane, 4% sevoflurane, or 12% desflurane for 6 hours. The mitochondrial function was measured by using a Seahorse XFp Extracellular Flux Analyzer. Next, we employed a nanobeam technology‐based single molecular dynamic interaction detection method to determine the interaction of ADP and ATP synthase following the administration of isoflurane, sevoflurane, and desflurane. Each of resonance shifts, detected by a nanosensor, corresponded to single molecular interaction of ADP and ATP synthase. Finally, the single molecular dynamics computer simulation was used to identify the binding sites between ATP synthase and each of the anesthetics.

Result

The Seahorse XFp Extracellular Flux Analyzer demonstrated that isoflurane, but not sevoflurane or desflurane, induced mitochondrial dysfunction in the H4‐APP cells. The nanobeam technology‐based single molecular dynamic interaction detection method demonstrated that isoflurane significantly impaired the interaction of ADP and ATP synthase as evidenced by the decreased numbers of resonance shift, longer duration between the resonance shifts and decreased disassociation constant. Neither sevoflurane nor desfluraneimpaired such interaction. Mechanistically, the single molecular dynamics computer simulation study, assessing the various energy binding ability and different binding dynamic activity, demonstrated that there were 7, 1 and 2 binding sites in ATP synthase by isoflurane, sevoflurane and desflurane, respectively. Note that all of the identified 7 binding sites in ATP synthase by isoflurane are dominated binding position of amino acid related to the generation of ATP.

Conclusion

These findings suggest that isoflurane has more binding sites with ATP synthase than sevoflurane or desflurane, which impairs the molecular interaction of ADP and ATP synthase, leading to the selective mitochondrial dysfunction and neurotoxicity observed following the administration of isoflurane but not sevoflurane or desflurane.
Hierarchical involvement of molecular players in human neocortex in the course of preclinical and symptomatic Alzheimer’s disease
Authors: Li Xiaohang , Tsolis Konstantinos C , Koper Marta J , Ronisz Alicja , Ospitalieri Simona , von Arnim Christine , Otto Markus , Vandenberghe Rik , Tousseyn Thomas , Scheuerle Angelika , Economou Tassos , Carpentier Sebastien , Thal Dietmar Rudolf
Published: December 2020

Background

Proteomic profile changes have been reported in the brains from individuals having Alzheimer’s disease. However, it is not yet clear whether they represent a continuous process from mild to severe changes, or whether the proteins become involved step‐by‐step in a hierarchal manner. Additionally, in previous studies, cases with initial Aβ plaque and NFT pathology were considered as controls, and brain homogenates were not separated into distinct fractions. Therefore, there is a gap of knowledge regarding the initial steps of AD pathogenesis and the spatial resolution of the respective protein changes in terms of subcellular distribution.

Method

We analyzed soluble, dispersible (insoluble proteins and vesicles in mixtures with the intra‐/extracellular fluid), membrane‐associated (SDS‐soluble), and plaque‐associated (formic‐acid‐soluble) fractions of brain homogenates from 19 control cases without AD pathology, 17 pathologically preclinical AD (p‐preAD), and 17 symptomatic AD (symAD) cases by label‐free liquid chromatography coupled to tandem mass spectrometry. Proteomic changes and related pathways involved in p‐preAD and symAD were determined by integrated analyses combining quantitative proteomics, neuropathological measurements, regression analysis, and gene ontology overrepresentation tests.

Result

Three hierarchical classes of proteins, namely early‐ and late‐responding proteins and gradually changing proteins were identified across control, p‐preAD and symAD samples. Additionally, five proteins exhibited reduced abundance in the soluble fraction accompanied by increase in the membrane‐associated fraction between symAD and the group of p‐preAD + control cases, suggesting pathological alterations in their functions. Gene ontology analysis showed that the synaptic vesicle cycle and other endocytosis‐related pathways were overrepresented by early‐responding and gradually changing proteins, whereas caspase‐mediated cleavage of cytoskeletal proteins were enriched in the late‐responding protein class.

Conclusion

We identified an apparent hierarchy of key proteins in the human brain during AD pathogenesis, from which the early responding proteins point to pathways that are not yet a main focus in AD research. This hierarchy of proteome change in the neocortex clearly distinguished the preclinical phase from the symptomatic phase and identified the synaptic vesicle cycle as a likely primary affected function in AD initiation. Our results may open new roads for therapies by intervening on those key proteins and their respective pathways.
Gender dimorphism in serotonin dopamine and norepinephrine neurons of isodendritc core in postmortem human and nonhuman primate control subjects
Authors: Reddy Arubala P , Sawant Neha , Bunquin Lloyd S , Reddy Hemachandra
Published: December 2020

Background

Comorbidity of depression in bMets, NPSs and NDDs is resource demanding clinical area considering treatment challenges and patient care. NPSs represent prodromal symptoms of dementia results of neurobiological changes in specific subcortical region. Dynamic cascade of Aβ shifts from nonamyloidogenic is implicated in early cognitive impairment and depressive symptoms. Serotonergic system is implicated in Aβ pathology and NE is important to compensatory in Aβ degradation. Although the role of DA is not investigated in AD pathology. Overall neuromodulation in IDC of midbrain is imperative and intriguing aspect of monoaminergic association in AD and other NDDs pathology.Here we present genetic dimorphism of key area of the brain (5HT: dorsal raphe, DA:substantia nigra, Noradrenaline: locus ceruleous).

Method

4males and 4 females midbrain of control subject were collected from Neurobiobank (NIH) and ONPRC. Brain sections were collected 20‐micron sections on cover glass plain slides. 4mm tissue punches were used to collect RNA from tissues. Enough tissues used to generate 10ug‐20 ug average quality RNA. 4ug RNA from Raphe, substantia nigra and locus ceruleous was isolated using trizol isolation and sent to UTSW microarray core. The RNA was hybridized to Clariom D Human chip and CEL chip data obtained from UTSW core. CEL files were uploaded in Transcriptome Analysis Console (TAC4.0). Statistically significant data in Excel file is uploaded in Ingenuity Pathway analysis software to find biological pathways dominate female and male brains. Microarray analysis of adult serotonin neurons in human and NHP dorsal raphe, Substantia nigra and Locus ceruleous (DR/SN/LC) Chip has expression of 500.000 known and unknown RNA species transcript encoding 135,000 RNA

Result

Human DR/SNC/LC have 6643/13475/9194 number of probe set and 850/896//501 pathways, and Rhesus DR/SNC/LC have 7261/2157/1938 probe sets and 872/218/198 pathways altered respectively with one or more genes. Major dominated pathways: electron transport chain. Oxidative phosphorylation, miRNA, mitochondria dysfunction, apoptosis signaling, will be presented in the poster

Conclusion

Major energy metabolism pathway dominates in all three area in male DR/SN/LC area clearly state female brain having lower energy metabolism may results in reduce homeostasis in Isodendritc core midbrain area. Although compensatory mechanism may still yet investigate.
Tau acetylation at K280 is critical for propagation and an antibody targeting it prevents in vivo tau propagation
Authors: Yoon Seung‐Yong , Song Halim , Kim Na‐Young , Kim Dong‐Hou
Published: December 2020

Background

The spread of tau pathology from the transentorhinal cortex to the hippocampus and neocortex in Alzheimer’s disease (AD) is explained by the prion‐like cell‐to‐cell seeding and propagation of misfolded tau aggregates. Hence, it is important to define the seeding‐ and propagation‐competent tau species and to develop targeted therapeutic antibodies.

Method

Various methods like thioflavin‐T, FRET, FACS, and in vivo stereotaxic injection of AD‐derived tau aggregate fractions were used to evaluate tau aggregation, propagation, and the efficacy of an antibody to inhibit these processes.

Result

Acetylation of tau at K280 is critical for the successive tau propagation processes, including secretion, aggregation, and seeding. An antibody targeting acetylated tau at K280 effectively prevented AD‐derived insoluble tau aggregates‐induced proteopathic seeding and propagation in in vitro assays and in vivo mouse brains.

Conclusion

Acetylated tau at K280 is a core species of seeding and propagation, which could be a therapeutic target for AD and other tauopathies.