bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise‐induced metabolic changes in astrocytes in the 5xFAD mouse model of Alzheimer’s Disease
Authors: Rosolen Sarah Alyssa
Published: December 2021

Background

Alzheimer’s Disease (AD), a progressive neurodegenerative disease and the second most common cause of death in Australia (ABS 2019), is an increasingly prominent societal issue, exacerbated by an ageing population and the absence of effective disease modifying treatments. Focus has shifted to targeting modifiable risk factors to slow or prevent AD onset and progression, such as exercise, diet and other lifestyle factors. Adiponectin, an anti‐inflammatory adipokine, regulates energy metabolism and is associated with metabolic pathways potentiated following exercise. Animal and human studies involving both healthy individuals and those with metabolic dysfunction, have consistently demonstrated increased serum adiponectin levels following various exercise regimes. The ability of adiponectin to cross the blood brain barrier and thus mediate neuronal metabolism is contentious. However, the expression of adiponectin receptors within neuronal cells implies adiponectin holds an important function within the brain.

Methods

We investigated the cortical expression of adiponectin receptors, AdipoR1 and AdipoR2, in the aged 5XFAD mouse model of AD following an exercise intervention. Immunohistochemical techniques were applied to double stain brain tissue for adiponectin receptor and astrocyte expression.

Results

We observed neuronal AdipoR1 and AdipoR2 expression throughout the cortex of both exercised and sedentary control mice, as well as extensive expression of activated astrocytes.

Conclusions

Colocalisation analysis suggests astrocytes may utilise adiponectin receptors to fuel their metabolic activity in degrading toxic amyloid plaques within the AD brain.
Increased Plasma brain‐derived neurotrophic factor (BDNF) as a Biomarker for Differentiating Mild Cognitive Impairment from Cognitive Healthy: A case‐control study
Authors: Ng Ted Kheng Siang , Coughlan Christina M , Heyn Patricia C , Tagawa Alex , Carollo James , Kua Ee‐Heok , Mahendran Rathi
Published: December 2021

Background

Across the spectrum of Alzheimer’s disease (AD), we previously conducted a meta‐analysis and concluded significantly decreased brain‐derived neurotrophic factor (BDNF) in AD. However, there are inconsistent findings on peripheral BDNF levels in mild cognitive impairment (MCI), even across different meta‐analyses, which have been attributed to the high heterogeneity caused by multiple clinical and laboratory factors. Thus, BDNF’s discriminative accuracy for identifying all‐cause MCI and its subtypes remains unknown.

Methods

This study, while accounting for heterogeneity, compared a healthy control cohort (n=56, 45 female) and an MCI cohort (n=40, 28 female) to determine whether plasma BDNF (pBDNF), hs‐CRP, and DHEA‐S can differentiate between healthy and MCI individuals, including the two MCI subtypes (amnestic [aMCI] and non‐amnestic [non‐aMCI]). Furthermore, the associations between the biomarkers and detailed neurocognitive tests were examined. Adults with cerebral palsy were included as sensitivity analyses.

Result

Compared to healthy controls, only pBDNF was significantly increased in all‐cause MCI, aMCI, and non‐aMCI. Furthermore, pBDNF had good (AUC=0.84, 95% CI=0.74 to 0.95, p<0.001) and excellent discriminative accuracy (AUC=0.92, 95% CI=0.84 to 1.00, p<0.001) for all‐cause MCI and non‐amnestic MCI, respectively. pBDNF was also significantly and positively associated with plasma hs‐CRP (β=0.26, 95% CI=0.02 to 0.50, p=0.038), despite attenuated association upon controlling for BMI (β=0.15, 95% CI=‐0.08 to 0.38, p=0.186). Multiple associations with detailed neurocognitive tests were observed.

Conclusion

These findings support increased pBDNF as a compensatory mechanism in preclinical dementia, and the neurotrophic and inflammatory hypotheses of cognitive impairment.
Astrocytic GLUT1 ablation improves systemic glucose metabolism and promotes cognition
Authors: Ardanaz Carlos G , Gil María Javier Ramírez , Smerdou Cristian , Solas Maite
Published: December 2021

Background

Glucose supply from the blood to the brain is controlled by the glucose transporter GLUT1, highly expressed in astrocytes, which coordinate brain glucose supply, metabolization and storage. Ablating GLUT1 at the blood‐brain barrier (BBB) endothelial cells leads to BBB breakdown, brain glucose hypometabolism and impaired cognition, but this approach cannot discriminate between insufficient glucose supply and BBB breakdown‐derived effects. Such question is the focus of the present work, which aims to elucidate the relevance of astrocytic GLUT1 to cellular, brain and systemic glucose metabolism, and to cognition.

Methods

To address these questions, GLUT1 was ablated from primary astrocytes. Cellular metabolism was examined using an extracellular flux analyzer (Seahorse). In vivo, astrocytic GLUT1 was ablated using a tamoxifen‐inducible Cre/LoxP approach (GLUT1ΔGFAP mice). 18F‐FDG PET, glucose and insulin tolerance and insulin secretion and fasting‐induced hyperphagia were characterized. BBB integrity was examined by vessel immunostaining and capillary‐depleted brain analysis. Recognition and spatial memory were assessed using Novel Object Recognition and Morris Water Maze tasks. To address the implication of purinergic signaling in those effects, a purinergic receptor antagonist (PPADS) was intracerebroventricularly administered before each behavioral test.

Results

GLUT1‐ablated astrocytes showed reduced glucose uptake and glycolysis, although preserving total ATP production. Unexpectedly, postnatal astrocytic GLUT1 deletion increased CNS glucose utilization. GLUT1ΔGFAP mice showed an improved metabolic status from which obese animals especially benefited. Specifically, GLUT1ΔGFAP mice were more efficient at suppressing hyperphagia and readjusting systemic glucose levels after hyperglycemia, exhibiting marked increase in insulin secretion. These effects were coupled with enhanced BAT activity, and reduced BAT adiposity. In parallel with this improved systemic homeostasis, GLUT1ΔGFAP mice performed both recognition and spatial memory tasks properly, even outperforming control mice. Noteworthy, those effects could be due to higher astrocytic ATP release. Indeed, central administration of PPADS could reverse improvements in metabolic and cognitive behaviors in mice with astrocyte GLUT1 knockout.

Conclusion

Overall, this study demonstrates that astrocytic GLUT1 ablation impairs astrocytic glucose availability but enhances brain glucose utilization, reprograms systemic glucose metabolism towards a more efficient glucose‐handling phenotype and promotes cognitive abilities, which could be a key factor in neurodegenerative diseases such as Alzheimer’s disease.
English Lessons with the Use of Songs for People with Mild Cognitive Impairment
Authors: Makri Marina , CHRISTAKIDOU ALEXANDRA , Tsolaki Magda
Published: December 2021

Background

People suffering from Mild Cognitive Impairment (MCI) need to improve their cognitive abilities in order to avoid the deterioration of their condition. Learning a foreign language is a good way for cognitive enhancement. However, since these people have memory deficits and lack of attention abilities, conventional teaching methods cannot be used. The use of songs in foreign language lessons is proved to be a very good technique for more effective acquisition of the language while also improving well‐being and relaxation.

Method

The Erasmus+ funded “E.L.So.M.C.I” program is a 2 year pan‐European initiative that aims to develop an educational program on teaching English to people with MCI and using English songs as a main tool for the teaching process. The methodology of this educational program is based on innovative teaching approaches such as “Communicative Language Teaching” and “Natural Approach and the method of “Neuro‐linguistic Programming (NLP)”. These methods place great emphasis on verbal communication, creation of a positive environment in class, reduction of stress and encouragement of learners to learn step by step in a natural and pleasant way.

Result

In this moment, the project has entered its first operational phase, that has the objective of producing:

‐ A Workshops’ Methodological Guide which is a document provides trainers with guidelines for teaching languages that focuses on communication in English (for the learners) and preparation of the lesson plan for each lesson. The Methodological Guide includes two kinds of materials, one for the participants‐students and one for the professionals (trainers).

‐ Several Workshops for English learning, addressed to people with MCI (MMSE between 28 and 24).

‐ Co‐Created Methodological Guide and Training for trainers via MOOC.

Conclusion

This project and methodology can improve cognitive functions, prevent from Alzheimer’s disease, support the teaching process through the use of songs, reduce stress and increase positive emotions, improve participants’ socialization, as well as, develop the sense of belonging to a group.
Latin American Older people and neuropsychiatric symptoms: a mini‐systematic review of effects of COVID‐19 Pandemic
Authors: URAZAN JUAN CAMILO , Padilla Nubia Esperanza , Borda Miguel German , Pinilla Jonnathan , Fernandez Marcelo Abraham Gaete , Fan Marcela Veliz
Published: December 2021

Background

Ending December 2019, the world had to face to COVID‐19. Latin America and the Caribbean suffered the effects where the contiguous and the number of deaths has been significant. Studies indicate that older adults with some degree of cognitive impairment are at greater risk of worsening their cognitive status and mental health, for this reason it’s exposed that social isolation and loneliness has harmful effects on the health of this population. This mini‐review inquires on the effects of COVID‐19 due to social isolation on neuropsychiatric symptoms (NPS) in Latin American older adults with and without dementia.

Method

A search was carried out in PubMed, SCOPUS, and ScienceDirect identifying all articles published up to July 31, 2021 using the keywords “social isolation”, “lockdown”, “quarantine”, “COVID‐19”,, “neuropsychiatric symptoms ”, “neurobehavioral”, “dementia”,“ mild cognitive impairment ”,“ Older People ”, “aging”, “elderly”. Two independent reviewers screened and selected appropriate articles and a third researcher helped resolve disagreements. The selected articles met the following criteria: written in English, Spanish or Portuguese, original article; focused on elderly subjects, articles that provided information on the NPS effects in Latin American populations during the COVID‐19 pandemic. The review was based on the PRISMA Statement and used the SIGN criteria.

Result

From 61 articles recovered from electronic databases (PubMed, Science Direct and Scopus) 10 of them were chosen for this review. The majority of the articles reported in a general way a negative impact on the mental health of the population in Latin America. They referred to a significant increase in the anxiety and depression symptoms. The majority of the articles were studies developed in Brazil, Argentina and Chile.

Conclusion

The COVID‐19 has shown a negative impact on the mental health of older adults. Latin America is a region with important socio‐sanitary problems which increase the impact of the pandemic in SNP, especially in older adults. It's necessary to increase the studies in Latin America that glimpse the real situation in the region.
Senescence biomarkers in adults and elderly with Down syndrome
Authors: Cordeiro Augusto Magno Tranquezi , Bram Jessyka Maria de França , Talib Leda Leme , Forlenza Orestes Vicente
Published: December 2021

Background

The Down syndrome (DS) is a genetic disturb caused for the trisomy of chromosome 21. It is the most common cause of intellectual disability, in addition DS accelerates aging and others development and health problems. Some pathological aspects, common to DS with dementia and Alzheimer disease (AD) suggest common pathogenic aspects. This study aims to investigate biomarkers related to cellular aging and their interrelationship with pathological markers of AD in adults and elderly individuals with DS by determining the expression of apoptotic pathway proteins: β‐catenin plays a role int the cell adhesion, cell survival and cell proliferation, in addition it is a key factor in the Wnt pathway. The activation of Wnt/β‐catenin pathway can protect against neurotoxic effects caused by accumulation of β‐amyloid peptide and the phosphorylation of Tau protein, two neuropathological hallmarks in the AD. The Bcl‐2 protein prevents cell death a promoting the cell survival. The tumoral protein P53 functions in the conservation and stability of DNA. It is normally activated in response of cellular stress, acting in the cell cycle, apoptosis, DNA repairing and the cell metabolism.

Method

Proteins expressions were measured in platelets from non‐medicated older adults with DS (n=37), and healthy adults and older adults (n=28) by western blotting. The samples were analyzed in duplicate and normalization was done using β‐actin as control.

Result

β‐catenin and P53 expressions were higher in DS samples (p=0.001 and p=0.04 respectively). We found a higher expression of Bcl‐2 in healthy control samples (p=0.05).

Conclusion

We concluded that the increased expression of β‐catenin and P53, in addition with the decrease levels of Bcl‐2 might indicate a deregulation in the mechanisms responsible for the cell survival process. It is possible to speculate that these changes are related to the increase in cellular stress related to DS.
High‐content screening of Alzheimer's disease genetic risk factors based on synaptic density analysis
Authors: Coulon Audrey , Mendes Tiago , Kilinc Devrim , Dumont Julie , Chapuis Julien , Lambert Jean‐Charles
Published: December 2021

Background

Synaptic loss is one of the earliest pathological hallmarks and the strongest marker of cognitive decline in Alzheimer’s disease (AD). A strong genetic predisposition is linked to AD, and genome‐wide association studies have pointed out hundreds of genes associated with the risk of developing the disease. With this background, our objective is to develop a cell‐based screen to assess the impact of each genetic risk factor on synaptic density.

Method

We screened a lentiviral shRNA library targeting 200 AD genetic risk factors using primary rat hippocampal neurons in 384‐wells plates. Immunofluorescence was performed to reveal pre‐ and post‐synaptic compartments and the neuronal network. Synaptic connectivity was then assessed through high content analysis by assigning each post‐synaptic structure to the nearest pre‐synaptic structure using Columbus and Matlab software.

Result

We identified several AD risk genes which positively or negatively impacted synaptic density in our model.

Conclusion

We have developed a high‐content screening approach which allows us to define the genetic risk factors that are involved in the pathophysiological synaptic dysregulation observed in the early stages of AD.
Resting‐state EEG gamma power and coherence might be an indicator of hyperexitability in patients with early‐onset Alzheimer’s disease
Authors: Fide Ezgi , Yerlikaya Deniz , Yener Gorsev
Published: December 2021

Background

Early‐onset Alzheimer’s disease (EOAD) is characterized by disease onset age (<65 years) and non‐amnestic symptoms at the initial stage. Disease course is different from the late‐onset AD (LOAD) in terms of pathology, neuropsychological manifestations and topography of electrophysiological changes. Present study aims to investigate resting state gamma power and connectivity changes in patients with EOAD compared to healthy controls.

Method

The study included 24 individuals with CSF‐proven EOAD (who met the NIA‐AA diagnostic criteria, McKhann et al., 2011) and demographically matched 24 healthy controls. Four minutes of eyes closed resting state EEG was recorded. Artifact‐free six‐second epochs were obtained. Power and coherency were measured for the total gamma (30–48Hz), gamma‐1 (30‐35Hz), gamma‐2 (36‐40Hz), and gamma‐3 (41‐48Hz). Imaginary part of coherency (ICoh) and maximum absolute values were calculated for intra‐hemispheric, inter‐hemispheric and midline electrode pairs.

Result

FFT analysis showed higher gamma‐2 [F(1,46)=4,732,p=0.032], and gamma‐3 [F(1,46)=4,158,p=0.047] power in the EOAD group compared to controls. In the coherence analysis, the EOAD group had higher gamma‐2 inter‐hemispheric ICoh values than controls [F(1,46)=5.473;p=0.024]. The total intra‐hemispheric gamma values of the EOAD group were higher in the F8‐TP8 pair, but lower in the P8‐O2 and F4‐C4 pairs compared to controls [F(11,506)=1.901;p=0.037]. Intra‐hemispheric gamma‐2 values of the EOAD group were higher in the F8‐TP8 pair, but lower in the C3‐O1 pair [F(11,506)=2.207;p=0.031]. Midline gamma‐1 ICoh values were lower in the EOAD group than controls [F(1.46)=8.352;p=0.006].

Conclusion

To our knowledge this is the first study to examine resting state gamma changes in individuals with CSF proven EOAD. Increased gamma power and connectivity in patients with LOAD (Başar et al., 2016,2017; van Deursen et al., 2008,2011) and Parkinson’s disease dementia (Pal et al., 2020) were reported. Increased power and connectivity were thought to reflect shared tau pathology between brain regions (Franzmeier et al., 2019). Literature provides evidence for hyperexcitability due to increased glutamate in AMPA and NMDA receptors in patients with AD (Um et al., 2012). Our results from CSF‐proven EOAD patients suggest that gamma power and connectivity might be good indicators of hyperexcitability in AD.
Development and Validation of PEG‐PCL Based Nanoformulation of Rosiglitazone and Evaluation of its Brain Selectivity in Mice Model of Alzheimer’s disease
Authors: K C Sarathlal , Kakoty Violina K , Taliyan Rajeev
Published: December 2021

Background

Type‐2 Diabetes Mellitus and insulin resistance increases the risk of Alzheimer’s disease (AD). Recent studies highlighted the role of peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) in modulation of AD. This study was designed to investigate the effect of rosiglitazone alone or in its nanoformulated form for an effective drug delivery in mice model of AD.

Method

AD mice model was developed by intracerebroventricular (ICV) administration of streptozotocin (STZ). PEG‐PCL polymer was synthesized using ring opening polymerization of caprolactone with methoxy‐PEG as a macroinitiator and stannousoctoate as catalyst. Nanoformulation of rosiglitazone was developed using emulsion‐diffusion‐solvent evaporation method. Nanoformulation was evaluated by Scanning electron microscopy, particle size analyzer and HPLC method. Cognitive functions were evaluated by passive avoidance task, object recognition task and Morris water maze test. Amyloid beta (Aβ) and phosphorylated tau (p‐tau) level were assessed by ELISA, level of oxidative stress and pro‐inflammatory cytokines like tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) were measured in hippocampus homogenates and the expression level of CREB, BDNF, GDNF, NGF were assessed by RT‐PCR method.

Result

The rosiglitazone nanoformulation was observed within a range of 70±10 nm in size and the entrapment efficiency of rosiglitazone was 70±5%. The ICV‐STZ mice showed significant features of cognitive abnormalities. The mice treated with rosiglitazone and its formulation improved cognition, attenuated the elevated level of Aβ and p‐tau along with pro‐inflammatory cytokines‐TNF‐α and IL‐6 and oxidative stress was altered when compared with disease control animals. Moreover, these changes occurred concurrently with an increased expression level of BDNF, GDNF and NGF.

Conclusion

Nanoformulation of rosiglitazone imparted significant neuroprotective efficacy with greater amounts being observed in the brain at a lower dose compared to its free form.
Human Herpesvirus detection and identification in postmortem brain tissue of patients with Alzheimer's disease
Authors: Gomez Johana , Villegas‐Lanau Carlos Andrés , Mesa Ana
Published: December 2021

Background

The etiology of Alzheimer’s disease (AD) is not clear yet. One of the hypotheses in this regard is the participation of infectious agents in the origin of this neurodegenerative disease. Different viruses, mainly those that cause latent infections such as some of the Herpesviridae family, have been the most involved. The aim of this study was to detect and identify herpesviruses in postmortem brain tissue of patients with AD.

Method

frozen brain tissues from patients diagnosed with AD (n=22) and from healthy individuals (n=10), as a control group, were included. The search and identification of Human Herpesvirus in the tissues was carried out using microarray technology (Axiom™ Microbiome Array, Thermo scientific, USA) and real‐time multiplex PCR.

Result

no viruses were detected using the microarray technology; howeverer, using real‐time multiplex PCR, human herpesviruses VHH‐1, VHH‐2 or VHH4 were identified in two samples of patients with AD and one case in the control group.

Conclusion

Based on the results obtained in this study, it was not possible to establish an association between AD and the presence of viruses. Yet, it is possible that the viruses play a role in the pathogenesis of AD, perhaps in the early stages of this dementia.
Insertion of the Icelandic mutation (A673T) in the APP gene using the CRISPR/Cas9 base editing and Prime editing technologies, a preventive treatment for Alzheimer?
Authors: Tremblay Jacques P. , Tremblay Guillaume , Guyon Antoine , Joël Rousseau , Happi‐Mbakam Cedric
Published: December 2021

Background

There is currently no treatment for Alzheimer disease (AD). However, the Icelandic mutation in the APP gene (A673T) has been shown to confer a protection against the onset and development of AD (Jonsson et al. Nature 2012). This single nucleotide mutation in APP exon 16 reduces the cleavage of the APP protein by the beta‐secretase by 40% thus preventing the development of AD even in persons more than 95 years old.

Method

Our research group has initially shown that the presence of the A673T mutation in an APP gene reduced the secretion of beta‐amyloid peptides even if there is also a FAD mutation in the gene. This is the case for 14 different FAD mutations.We have also used the CRISPR/Cas9 base editing technology to insert the A673T mutation in the APP gene. We have compared several different cytidine base editor complexes to achieve the most effective and accurate genome modification possible in HEK293T cells and in SH‐SY5Y neuroblastomas. The insertion of the A673T mutation in cells containing the London mutation reduced the secretion of beta‐amyloid peptides.

Result

We have more recently used the Prime editing technology to insert only the A673T mutation without inducing the mutation of other nearby nucleotides. Repeated Prime editing treatment permitted to insert this mutation in up to 64% of the APP gene in HEK293T cells.

Conclusion

The insertion of the protective Icelandic mutation in the APP gene using these editing technologies opens a new potential preventive treatment for not only for Familial Alzheimer’s diseases but also for sporadic Alzheimer’s disease.
Functional characterization of hiPSCs‐derived glial cells and neurons from patients harboring a TREM2 loss of function mutation
Authors: Filipello Fabia , You Shih‐Feng , Martinez Rita , Korvatska Olena , Raskind Wendy H , Mahali Sidhartha , Ghezzi Laura , Wandy Beatty , Cella Marina , Piccio Laura , Karch Celeste M.
Published: December 2021

Background

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia in the adult brain. Homozygous loss of function TREM2 variants cause a rare leukodystrophy characterized by bone cysts and early‐onset dementia, Nasu‐Hakola disease (NHD). However, despite intense investigation, the role of TREM2 in NHD pathogenesis remains poorly understood.

Method

Here, we investigated the mechanisms by which a homozygous stop‐gain TREM2 variant (Q33X), which leads to a truncated TREM2 transcript, contributes to disease pathology in NHD. Human induced pluripotent stem cells (hiPSCs)‐derived microglia (iMGLs), neurons and astrocytes were obtained from two siblings homozygous for the TREM2 Q33X mutation and one non‐carrier sibling.

Result

Transcriptomic analysis and biochemical assays revealed that iMGLs from NHD patients display decreased activation, reduced lipid droplet content and defects in lysosomal function compared to related and unrelated controls. These in vitro findings were validated in brain tissues from NHD patients carrying loss of function TREM2 mutations. Strikingly, we observed defects beyond iMGLs. iPSCs‐derived neurons and astrocytes from NHD siblings displayed downregulation of pathways involved in synaptic activation, neuronal development and interferon response compared to the unaffected sibling. These pathways were also observed to be similarly altered in NHD brains. This could be due to the presence of low levels of mutant TREM2 transcripts in iPSC and neural progenitor cells, which may initiate a cascade of events that drives cellular dysfunction beyond microglia.

Conclusion

These finding open a new scenario on TREM2 function and reveal that NHD is a complex pathology affecting glial cells and neurons at multiple levels.
Pattern of proteolytic processing of Amyloid Precursor Protein in Down syndrome
Authors: Bram Jessyka Maria de França , Cordeiro Augusto Magno Tranquezi , Talib Leda Leme , Carvalho Claudia Lopes , Gattaz Wagner Farid , Forlenza Orestes Vicente
Published: December 2021

Background

Currently, it is estimated that 1 in 800 live births worldwide has Down syndrome (DS). In addition to the relationship with intellectual disability, DS is directly associated with a group of clinical manifestations resulting from premature aging, and may present patterns of comorbidities similar to those found in the elderly. Therefore, together with the greater number of years lived, there is an increased risk of developing Alzheimer's disease (AD) in DS, especially with regard to the interaction between pathogenic mechanisms related to cerebral amyloidogenesis and factors inherent to premature aging. Thus, this study aimed to investigate biological markers of AD in peripheral blood samples from adults and elderly individuals with DS and to compare them with individuals with normal karyotype, stratifying the groups according to the presence or absence of cognitive impairment.

Method

A total sample of 123 individuals was recruited. The experimental group consisted of 31 adults and elderly individuals with DS. Two comparative groups were categorized according to euploid individuals (EU), being 23 elderly with AD (EUAD) and 69 adults with normal cognition (EUNC). The DS group was subclassified according to the occurrence of cognitive decline, DS without evidence of cognitive decline (DSNC) and DS with cognitive decline (DSAD). AD biomarkers were determined in platelets, including the Amyloid Precursor Protein ratio (APPr), established by the ratio between the 130‐ and 110kDA secreted peptides (sAPP), as well as the protein expression of APP‐secretases α (ADAM‐10), β (BACE‐1) and γ (PSEN1).

Result

The comparison between DSNC vs. EUNC, showed lower protein expression of APP secretases among individuals with DS. When observed groups with cognitive decline (i.e., DSAD vs. EUAD), the DSAD group showed lower expression of APP130 and 110kDa and BACE1 fragments, as well as increased levels of APPr compared to EUAD. It was also observed a 2.5‐fold decrease expression of APP130 in SDAD, compared to SDNC.

Conclusion

These results demonstrate that people with DS may show different expression patterns of proteins involved in the amyloid cascade, detectable even in the absence of cognitive decline. However, more analysis is needed for these data to be confirmed.
Systems genetic dissection of Alzheimer’s disease brain gene expression networks
Authors: Zhao Pinghan , Mangleburg Carl Grant , El Fadel Omar , Lee Anh , Amoh Bismark , Sai Marella Aditi , Al‐Ramahi Ismael , Botas Juan , Shulman Joshua M.
Published: December 2021

Background

Alzheimer’s disease (AD) is the most prevalent cause of dementia. Large RNA‐Sequencing data sets have provided detailed molecular profiles of AD, but they cannot differentiate causal vs. non‐causal gene expression changes.

Method

We combined bioinformatic prioritization of human data with genetic screens in Drosophila melanogaster to identify human brain transcriptional changes that exacerbate or ameliorate neurodegeneration induced by Tau or amyloid‐β (Aβ), the proteins which form the hallmark pathologic aggregates that define AD. First, we used large, AD‐associated coexpression networks derived from Accelerating Medicines Partnership (AMP)‐AD human brain RNA‐Seq data to nominate candidate AD drivers based on multiple bioinformatic criteria. We then tested nominated drivers for modification of Tau‐ or Aβ‐induced neurodegeneration in vivo using a locomotor assay in Drosophila. For one module of our interest, PHGbrown, we analyzed its overlap with published differentially expressed gene (DEG) sets from mouse models to explore its potential functional roles in AD. Finally, we used the L1000 Connectivity Map database of perturbation‐associated gene expression changes to select small molecules which either reverse or promote the implicated AD‐associated gene expression signatures that are causally linked with disease progression.

Result

Through our screen, we identified a module, PHGbrown, with 14 of its 27 prioritized genes (51.9%) significantly modifying Tau/Aβ neurotoxicity in our screen. We integrated our screen data with PHGbrown’s module structure to identify a subnetwork containing genes involved in synaptic function including GRIN2A, GRIN2B, KCNJ6, GABRB2, and GABRB3. This synaptic subnetwork is downregulated in human AD and contains multiple loss‐of‐function suppressors of Tau/Aβ neurotoxicity. Interestingly, PHGbrown shows overlap and concordant down‐regulation with published mouse models of excitotoxicity. Our results suggest that PHGbrown down‐regulation may compensate for excitotoxic injury in AD. Based on in silico analysis of L1000 Connectivity Map data, the protein kinase C inhibitor, Chelerythrine, was identified as a promising “network therapy” capable of promoting PHGbrown down‐regulation and resilience to AD pathophysiology.

Conclusion

By integrating human coexpression networks and Drosophila genetic screen data, our results establish a causal chain connecting Tau/Aβ with neurodegeneration through network‐level gene expression changes. We additionally identify candidate drugs targeting causal subnetworks for development of network modulating therapies.
Dementia detection from brain activity during sleep
Authors: Ye Elissa M , Sun Haoqi , Krishnamurthy Parimala V , Lam Alice D , Westover M Brandon
Published: December 2021

Background

Dementia is a growing cause of disability and loss of independence in the elderly, yet remains largely under‐diagnosed. Early detection and classification of dementia may help close this diagnostic gap and improve management of disease progression. EEG sleep patterns have been identified as a potential biomarker to detect Alzheimer’s disease and other neurodegenerative diseases.

Method

From a dataset of 9834 polysomnograms, sleep architecture and microstructure features such as frequency band powers, EEG coherence, and spindle density were extracted. Patients were labeled as belonging to dementia, mild cognitive impairment (MCI), or cognitively normal (CN) groups based on clinical diagnosis, Montreal Cognitive Assessment (MoCA), Mini‐Mental State Exam (MMSE) scores, Clinical Dementia Rating (CDR) and medications. We trained logistic regression, random forest, and XGBoost models to classify patients into Dementia, MCI, and CN groups.

Result

Nested cross validation results show an AUC of 0.81 (F1 = 0.76) for binary classification of dementia vs CN groups and a mean AUC of 0.75 (F1 =0.57) for multiclass classification of dementia vs. MCI vs CN groups. REM latency, spindle activity, duration, frequency, slow wave oscillation, delta/alpha band power in wake, N1 theta/alpha band power in N1 were among the top weighted features.

Conclusion

Our dementia classification algorithms show promise for incorporating dementia screening techniques into routine sleep EEG and providing diagnostic, monitoring, and prognostication capabilities.
Defective proteostasis in patient‐derived iPSC‐astrocytes and neurons carrying a MAPT IVS10+16 mutation
Authors: Mahali Sidhartha , Karch Celeste
Published: December 2021

Background

Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the toxic protein accumulation. In a subset of frontotemporal dementia (FTD) cases, mutations in the microtubule‐associated protein tau (MAPT) that alter the relative levels of specific tau isoforms are sufficient to cause tau inclusions in neurons and astroglia and neurodegeneration without the presence of mutated protein (e.g. MAPTIVS10+16). However, the pathogenic events triggered by the expression of the alternatively spliced tau remain poorly understood.

Method

To determine whether altered tau splicing induced from MAPT IVS10+16 mutations is sufficient to alter proteostasis in neurons and glia, we used human induced pluripotent stem cell (iPSC)‐derived neurons and astrocytes from patients carrying the MAPT IVS10+16 mutation and CRISPR/Cas9, isogenic corrected controls.

Result

We found that neurons from MAPT IVS10+16 carriers exhibited significantly higher levels of 4 repeat tau, deficits in lysosomal trafficking, and reduced lysosomal acidity relative to isogenic‐control neurons. Additionally, MAPTIVS10+16 was sufficient to reduce genes associated with lysosomal biogenesis (regulated by TFEB). Interestingly, mutant astrocytes also produce elevated 4 repeat tau levels and exhibit several key hallmarks of cellular aging. Mutant astrocytes were larger in size with enlarged nuclei compared to isogenic controls. In addition to this hypertrophy phenotype, mutant astrocytes exhibited significantly elevated levels of senescence genes. Furthermore, markers of proteostasis were altered in mutant astrocytes: MAPT IVS10+16 carriers exhibited an increase in acidic lysosomes compared to isogenic‐control astrocytes, and TFEB‐regulated genes were upregulated MAPT IVS10+16 astrocytes.

Conclusion

Our findings suggest that altered tau splicing induced by the MAPT IVS10+16 mutation is sufficient to cause aging signatures, including hypertrophy, senescence, and altered proteostasis in a cell‐type specific manner.
Exercise‐Induced Alterations in TrkB expression in the 5XFAD Mouse Model of Alzheimer’s Disease
Authors: Moylan Christopher , Cao Thanh Vinh , Huynh Quy‐Susan , Pratap Anishchal , Holsinger R. M. Damian
Published: December 2021

Background

Alzheimer’s Disease (AD) is a slow progressing neurodegenerative disease with various environmental and endogenous factors implicated in its development. Two such factors include downregulation of tropomyosin receptor kinase B (TrkB) and its ligand, brain derived neurotrophic factor (BDNF), which normally facilitate the function and survival of neurons. While the exact causes of AD are still unknown, studies have shown that interventions such as aerobic exercise may reduce the risk of its progression. Interestingly, BDNF and TrkB each have unique expression patterns in the presence Aβ plaques and tau tangles, the main pathologies of AD; these patterns further fluctuate across different exercise types, intensities, and durations.

Method

In the current study, we used the 5XFAD mouse model of AD (36 weeks of age) to investigate the nature of exercise‐induced neurotrophin alterations. We compared transgenic mice (Tg) and their wild‐type (WT) littermates following an exercise regimen consisting of a 60‐minute/day steady‐state treadmill exercise protocol for 3 weeks. We used immunofluorescent staining to examine the cortical expression of BDNF and TrkB across these groups.

Result

We found similar levels of TrkB expression in both exercised groups (WT and Tg) but significantly lower TrkB expression in the exercised 5XFAD Tg mice compared to their sedentary littermates. We failed to observe changes in BDNF expression across any of the groups.

Conclusion

The ability of exercise to restore TrkB protein levels in 5XFAD Tg mice to those of exercised wildtype littermates, suggests that TrkB may be considered a potential target for therapeutic intervention. We further postulate that exercise may have a restorative function on cognition and thus may be a prospective therapeutic avenue of treatment for AD and associated cognitive disorders.
Global C3 lowering alleviates hippocampal dysfunction and cognitive impairment in aged mice
Authors: Batista Andre Felipe , Schroeder Maren K , Khan Khyrul , Li Shaomin A , Presumey Jessy , Yalcin Esra , Carroll Michael , Lemere Cynthia A
Published: December 2021

Background

Complement component C3, an innate immune molecule, is important for removing pathogens and eliminating synapses during brain development, aging, and Alzheimer’s disease (AD). Previously, our group demonstrated that C3 deficiency protected against synapse loss during normal aging in wild‐type and APPswe/PS1dE9 mice. Induction of C3 deficiency after normal brain development will help inform whether its inhibition in aging or early stages of AD may serve as a future therapeutic strategy.

Method

We crossed C3fl/fl mice with an inducible, global Cre line (Rosa26‐Cre‐ERT2+/‐) for 2 generations to generate novel inducible C3 conditional knockout C3fl/fl; Rosa26‐Cre‐ERT2+/‐ mice (C3iKO). In one cohort, four‐to‐five‐month‐old mice were injected with tamoxifen (TAM) or corn oil (CO) daily for 5 days. Behavioral tasks were performed when these mice reached 16‐17 months of age. In another study, three‐to‐four‐month‐old female mice were injected with either CO/TAM and electrophysiological recording of long‐term potentiation (LTP) was conducted in hippocampal slices of TAM‐treated and CO‐treated mice at 7‐8 months of age following incubation of the slices with neurotoxic Aβ S26 dimers.

Result

C3iKO mice had a significant 85‐95% reduction in serum C3 levels compared to controls, which was consistent at all timepoints analyzed (from Day 7 to Day 365). In this cohort, behavioral testing for hippocampal‐dependent spatial memory, object memory, and object location was performed when TAM‐treated and CO‐treated mice reached 16‐17 months of age. C3iKO+TAM mice performed significantly better than C3iKO+CO‐treated mice in these behavioral tasks, indicating that C3 lowering after brain development protected mice from age‐related cognitive decline. In the second study, we found that C3 lowering in adult mice protected hippocampal synapses from Aβ S26 dimer‐mediated LTP impairment.

Conclusion

Global C3 depletion in C3iKO young adult mice protected against hippocampal dysfunction as they aged, suggesting that C3 lowering may be an effective therapeutic strategy for aging and possibly, AD. Future studies are underway to investigate the C3‐mediated mechanisms of synaptic dysfunction in the hippocampus.
Impact of PLCG2 expression on Microglial Biology and Disease Pathogenesis in Alzheimer’s Disease
Authors: Tsai Andy Po‐Yi , Lin Peter Bor‐Chian , Dong Chuanpeng , Moutinho Miguel , Liu Yunlong , Bissel Stephanie J , Oblak Adrian L , Nho Kwangsik , Lamb Bruce T. , Landreth Gary E
Published: December 2021

Background

Alzheimer’s disease (AD) and other neurodegenerative diseases are typified by a robust microglial‐mediated immune response. Genetic studies have demonstrated that variants in microglial genes are linked to risk for AD. Phospholipase C gamma 2 (PLCG2), whose variants confer altered risk for AD, is a critical signaling element for various immune receptors and is a key regulatory hub gene for immune signaling. To date, it is known that PLCG2 might be important in AD due to the pervious findings that a hypermorphic variant in PLCG2, rs72824905, is protective against AD risk. However, the role of PLCG2 has not yet been comprehensively explored. We believe that genetic mouse models are needed to further clarify the role of PLCG2 in plaque‐associated microglia and to determine whether decreased PLCG2 expression in plaque‐associated microglia favors disease exacerbation or attenuation.

Method

To investigate the impact of reduced PLCG2 gene expression on microglia biology and disease pathology, we have generated PLCG2 inactivation mice, all crossed onto the 5XFAD amyloidogenic murine model of AD.

Result

We provide data demonstrating that in individuals with AD, there is increased expression of PLCG2 in the brain, a finding that is recapitulated in 5XFAD mice. We show that reduced PLCG2 gene expression program microglial phenotypes in 5XFAD mice, affect plaque pathology, and drive distinct transcriptional phenotypes of microglia in the presence of amyloid pathology. Analysis of plaque pathology revealed that 5XFAD PLCG2 inactivation mice have elevated plaque burden. Compared to 5XFAD mice, behavioral analysis of 5XFAD with PLCG2 inactivation mice demonstrated an impaired performance in the Y maze assay, reflecting impaired cognitive decline. Our data suggest that the inactivation of PLCG2 had accelerated and exacerbated disease‐related pathology.

Conclusion

Together, our findings provide evidence that PLCG2 plays an important role in AD pathophysiology, indicating PLCG2 as a potential new therapeutic target for AD.
AI‐based selection of superior proteomic biomarkers for classifying Alzheimer’s disease
Authors: Tandon Raghav , Seyfried Nicholas T. , Mitchell Cassie S
Published: December 2021

Background

Proteomic changes are a hallmark of Alzheimer’s Disease (AD) and related disorders. Thousands of different proteins can be measured in clinical patients. A succinct, universally available clinical AD protein diagnostic panel is needed. The objective of the present study was to utilize artificial intelligence (AI) to determine a subset of proteins best for differentiating healthy controls, asymptomatic AD (ASymAD) cases, and AD cases.

Method

An AI‐based protein selection approach is constructed using published clinical proteomic datasets, which had over 3300+ measured proteins from brain tissues in the dorsolateral prefrontal cortex. Four published data sets (n = 419 patients) were used to construct and train the model while two published data sets (n = 201 patients) were used to independently validate the model results. Machine learning classification with support vector machine and logistical regression was combined with recursive feature elimination to identify the most discriminative proteins, which distinguish between AD, Control, and AsymAD cases. The final protein subset was a small fraction of all the proteins measured in the data.

Result

The algorithm identified a primary subset of 29 important proteins out of the 3300+, which can differentiate AD cases from control cases with high accuracy (AUC = 0.93). However, 88 proteins of 3300+ are necessary to differentiate AD from asymptomatic AD with high accuracy (AUC = 0.96 for AD; AUC = 0.89 for Control; AUC = 0.85 for ASymAD). Selected proteins were significantly enriched for metabolic function, namely glucose metabolism. Notably, amyloid precursor protein (APP), VGF, and RABEP1 are strong differentiators of AD compared to Control or ASymAD. However, to differentiate ASymAD and AD, examples of superior predictive proteins include ALDH1A1, BDH2, C4A, FABP7, GABBR2, GNAI3, PBXIP1, and PRKAR1B.

Conclusion

Clinical cases can be successfully differentiated based on their measured biomarker levels. AI platforms can be leveraged to identify a subset of the most discriminative proteins useful for future AD clinical diagnostics and disease staging.
In silico identification of phytocompounds as potential inhibitors of Glycogen synthase kinase 3 beta (GSK‐3β)
Authors: Chowdhury Suman
Published: December 2021

Background

Alzheimer’s disease (AD) pathogenesis involves multiple pathological pathways, among different drug targets of AD,Glycogen synthase kinase 3 beta (GSK‐3β) is a well‐known therapeutic drug target. Identification of GSK‐3β inhibitors will also help in the treatment of other neurological disorders such as Parkinson’s disease, bipolar disorders, and traumatic brain injury. The therapeutic activity of phytocompounds in neurological disorders is already established, in this study phytocompounds from well‐known spices were screened for molecular interaction GSK‐3β enzyme.

Method

Selected phytocompounds such as cuminaldehyde, alpha terpinyl acetate, eugenol, piperine, and cinnamaldehyde mainly found in spices such as Cuminum cyminum L, Elettaria cardamomum L, Eugenia caryophyllus Thumb, Piper nigrum L and Cinnamomum zeylanicum Blume, respectively, were analyzed for interaction with GSK‐3β enzyme. In silicomolecular docking was performed using Schrodinger software, where the X‐ray crystallographic structure of GSK‐3β (PDB ID‐1Q3D) from Protein Data Bank server and 3D structure of phytocompounds from PubChem, were prepared using protein preparation wizard (PPW) and ligprep module. Extra precision (XP) docking was performed using a glide module. Phytocompounds poses were ranked based on docking scores and glide energy.

Result

The phytocompounds showed docking score and glide energy within the range of ‐6.3 to ‐4.6, and ‐22.6 to ‐19.5 kcal/mol, respectively. Among the five selected phytocompounds, cuminaldehyde showed the highest docking score of ‐6.3 and binding affinity of ‐22.6 kcal/mol, whereas the lowest docking score was observed for cinnamaldehyde of ‐4.6. Cuminaldehyde also showed hydrogen bonding with important amino acid residue Val135 of the binding pocket, contact with this is key to enhance affinity.

Conclusion

GSK‐3β is an important drug target due to its role in AD, among other disorders. Though many inhibitors have been reported, the challenge is discovering an inhibitor that can translate potent inhibition into cellular settings with low toxicity, here, phytocompounds play an important role due to low toxicity. Cuminaldehyde showed strong affinity towards GSK‐3β enzyme, which could be potential inhibitor and provides a lead towards finding anti‐AD drug.
Free Space Realization of the Symmetrical Tunable Auto‐Focusing Lommel Gaussian Vortex Beam
Authors: Tu Jialong , Wang Xinyue , Yu Xing , Wang Haonan , Deng Dongmei
Published: December 2021

An auto‐focusing beam with adjustable symmetry is proposed numerically and experimentally. The initial field of the auto‐focusing Lommel Gaussian vortex beam (ALoGVB) consists of the Lommel function and the Gaussian term. When the asymmetry factor ε of the beam approaches zero, the ALoGVB will degenerate into a circular Bessel Gaussian vortex beam (CBGVB). Compared with the CBGVB, the ALoGVB is more diverse. The shape, symmetry, normalized focusing intensity, and focus distance of the ALoGVB can be controlled by flexibly adjusting the asymmetry factor ε and the topological charge n. In addition, the effect of off‐axis vortices on the propagating characteristics of the beam is also discussed. The experiment is in good agreement with the numerical simulation. The results could be beneficial for potential applications in optical trapping or micromachining.