bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial phenotypes in iPSC AD models
Authors: Flannagan Kaitlin , Stopperan Julia A. , Troutwine Benjamin M , Lysaker Colton R , Strope Taylor , Draper Julia , Shaddy‐Gouvion Cynthia , Vivian Jay , Haeri Mohammad , Wilkins Heather M
Published: December 2021

Background

Mitochondrial dysfunction is observed in Alzheimer’s disease (AD). Altered mitochondrial respiration, cytochrome oxidase (COX) Vmax, and mitophagy are observed in human subjects and animal models of AD. Models derived from induced pluripotent stem cells (iPSCs) may not recapitulate these phenotypes after reprogramming from differentiated adult cells. We examined mitochondrial function across iPSC derived models including cerebral organoids, forebrain neurons, and astrocytes. Postmortem brain tissue was used as a comparison.

Method

iPSCs were reprogrammed from fibroblasts either from the University of Kansas Alzheimer’s Disease Research Center (KU ADRC) cohort or purchased from WiCell. Postmortem brain samples were from the KU ADRC cohort when available. A total of four non‐demented and four sporadic AD iPSC lines were examined. Postmortem brain tissue was derived from 9 ND and 12 AD subjects. iPSCs were differentiated into neurons, astrocytes, or cerebral organoids using StemCell Technologies protocols and reagents. iPSC derived models and postmortem brain tissue were subjected to mitochondrial respiration analysis using Seahorse XF technology and spectrophotometric COX Vmax assays. iPSC derived neurons and astrocytes underwent fluorescent assays to determine mitochondrial mass, mitochondrial membrane potential, and mitophagy levels.

Result

iPSC derived neurons and cerebral organoids showed reduced COX Vmax in AD subjects. These results were not observed in astrocytes. Postmortem human brain samples showed reduced COX Vmax in AD subjects. iPSC derived neurons had reduced mitochondrial respiration parameters, mitochondrial mass, mitophagy, mitochondrial membrane potential, and mitochondrial superoxide production. iPSC derived astrocytes had reduced mitochondrial respiration parameters but increased mitochondrial membrane potential and no change in mitochondrial superoxide production.

Conclusion

iPSC derived models from AD subjects show mitochondrial dysfunction phenotypes like what is observed in postmortem brain. As iPSCs do not maintain their epigenetic signatures after reprogramming the observed phenotypes are likely due to other somatic factors.
Praxis deficits in patients with Parkinson’s disease
Authors: Rounis Elisabeth
Published: December 2021

Background

Limb apraxia has been described in several neurological disorders including Parkinson’s disease (Leiguarda and Marsden, 2000) and may predict progression to Alzheimer’s dementia in patients with mild cognitive impairment. Our aim was to study presence of apraxia and subtypes of deficits in patients with idiopathic Parkinson’s Disease.

Method

20 patients with idiopathic Parkinson’s disease, recruited from the Oxford Parkinson’s Disease Centre, were tested for presence of limb apraxia, measured on a battery of tasks, comparing their performance to deficits measured using the UPDRS, and independent measures of cognition (MOCA), and dexterity. Results were analysed using Pearson’s correlations, with correction for multiple comparisons

Result

Detailed neuropsychological testing revealed significant deficits in praxis with 9 out of 20 patients displaying significant ideomotor deficits on finger and hand imitation, 2 patients showing ideational deficits on pantomime of tool use. Most patients made errors in the praxis tasks even though they did not qualify as apraxic per se, with only one patient performing faultlessly at all the screening tasks.

Both ideational and ideomotor deficits correlated with Part 3 of the UPDRS score. Similarly, Part 3 of the UPDRS correlated with cognitive performance on the MOCA. Ideomotor deficits also correlated with deficits in dexterity and response inhibition. Whereas deficits in dexterity correlated with PD severity; praxis and cognitive deficits did not.

Conclusion

The study shows different deficits in limb praxis assessed using batteries of tasks in patients with Parkinson’s disease. We identified relationships between praxis deficits and cognitive as well as motor performance in PD patients. Testing for apraxia in PD patients might provide a useful way for stratifying patients’ impairments, progression to PD dementia and response to treatment.
Investigating auditory electrophysiological measures of participants with mild cognitive impairment and Alzheimer’s disease: A systematic review and meta‐analysis of event‐related potential studies
Authors: Tarawneh Hadeel Y. , Mulders Wilhelmina H.A.M , Sohrabi Hamid R , Martins Ralph N , Jayakody Dona M P
Published: December 2021

Background

Objectively measuring auditory functions has been proposed as an avenue in differentiating normal age‐related cognitive dysfunction from Alzheimer’s disease (AD) and its prodromal states. Previous research has suggested auditory event‐related potentials (AERPs) to be non‐invasive, cost‐ effective and efficient biomarkers for the diagnosis of AD. The objective of this paper is to review the published literature on AERPs measures in older adults diagnosed with AD and those at higher risk of developing AD, i.e., mild cognitive impairment (MCI) and subjective cognitive decline (SCD).

Method

The search was performed on six major electronic databases (Ovid MEDLINE, OVID EMBASE, PsycINFO, PubMed, Scopus and CINAHL Plus). Articles identified prior to 7th May 2019 were considered for this review. A random effects meta‐analysis and analysis of between study heterogeneity was conducted using the Comprehensive Meta‐Analysis software.

Result

The search identified 1076 articles; 74 articles met the full inclusion criteria and were included in the systematic review, and 47 articles were included into the analyses. Pooled analysis suggests that AD participants can be differentiated from controls due to significant delays in ABR, N100, P200, N200 and P300 latencies. P300 amplitude was significantly smaller in AD participants compared to controls. P300 latencies differed significantly between MCI participants and controls based on the pooled analysis.

Conclusion

The findings of this review indicate that some AERPs may be valuable biomarkers of AD. In conjunction with currently available clinical and neuropsychological assessments, AERPs can aid in screening and diagnosis of prodromal AD.
Drug repurposing strategy for treating Alzheimer’s disease
Authors: Das Anik Kumar Kumar , Sharma Divya , Sharma Lalit
Published: December 2021

Background

Alzheimer’s disease with a long preclinical period of ∼20 years is a chronic, insidious, and progressive neurodegenerative disease of old age. Neuropathologically AD is characterized by the presence of accumulated Amyloid‐beta in plaques (in extracellular spaces, and walls of blood vessels) and aggregated tau protein in neurofibrillary tangles. Drug repurposing is the search for new indications or molecular targets distinct from a drug’s acknowledged activity, pharmacological effect or binding specificities. With the ever‐increasing rates of termination of drugs in clinical trials, drug repositioning has risen as one of the effective solutions against the risk of drug failures.

Method

A comprehensive literature search was performed in the Pub Med/Science direct/Google scholar/Plos one databases and connected papers to review relevant articles in English, using keywords ‘‘Drug repurposing and neurological disorder, drug repurposing and dementia, drug repurposing and Alzheimer 'disease. The research papers were scrutinized and studied thoroughly.

Result

According to literature it has been found that some repurposed drugs i.e, Allopurinol, Bromocriptine, Bupropion, Raloxifene, Thalidomide, Zidovudine may have a potential to treat Alzheimer’s disease.

Conclusion

The repurposing drug approach may be used to treat Alzheimer’s and these drugs are needed to studied further.
Exploring NSAIDs as anti‐amyloidal agents: A drug repurposing approach to treat Alzheimer’s disease
Authors: Sharma Palvi , Sharma Divya , Sharma Lalit
Published: December 2021

Background

Alzheimer is a severe, stealthy and progressive neurodegenerative disease. Maximum number of cases are arises after the age of 65 ie. called Late Onset of Alzheimer Disease. AD is characterised by the neuronal cell dysfunctioning / death, shrinkage of brain tissue and progressive cognitive, motor, behavioural impairment. Literature suggest that NSAIDs are able to alter the conformation of Aβ peptides exerting anti‐aggregation activity and induce the expression of amyloid‐binding proteins, e.g., transthyretin, that play an important role in sequestering Aβ peptides and preventing their aggregation.

Method

In‐silico studies are totally based on the computational work, leads to counting receptor and ligand preparation, docking simulations, grid formation and its analysis followed with in‐vitro investigation via Thioflavin T‐amyloid binding assay and protease (Trypsin) digestion assay.

Result

The computational approach provided us naproxen with higher estimated free energy of binding. The drug has the property to traverse the blood brain barrier and hence, it might have the possibility of curing or treating the Alzheimer’s through altering the conformation of Aβ peptides and exerting anti‐aggregation activity.

Conclusion

NASAIDs may alter the conformation of amyloid beta and exerts anti‐aggregation activity by inducing the expression of amyloid binding proteins.
7T imaging in progressive supranuclear palsy and behavioural variant frontotemporal dementia
Authors: Naessens Michelle , Cope Thomas E , Murley Alexander G , Malpetti Maura , Rua Catarina , Hughes Laura E , Perry Alistair , Ye Rong , Rodgers Chris T , Jones P Simon , Rowe James B
Published: December 2021

Background

Progressive supranuclear palsy (PSP) and behavioural variant frontotemporal dementia (bvFTD) are clinical syndromes associated with frontotemporal lobar degeneration (FTLD). Although distinct diseases, they have in common cognitive and behavioural changes, including personality, motivation and executive function. This phenotypic overlap between bvFTD and PSP is reflected in the MDS‐2017 criteria for the PSP‐F subtype (Höglinger et al., 2017), and frequent parkinsonism seen in bvFTD (Rowe, 2019). This study uses ultra‐high field MRI to identify the atrophy patterns in bvFTD and PSP, complementing neurochemical insights from spectroscopy (Murley, 2020).

Method

23 Healthy controls, 23 people with probable PSP, and 16 people with bvFTD underwent structural imaging with MP2RAGE sequence (0.7mm isotropic resolution) at ultra‐high field (7T) on a MAGNETOM Siemens TERRA scanner. Clinical and cognitive assessment was undertaken contemporary with imaging. Grey and white matter volumes were compared between groups using independent two‐sample t‐tests, including age and total intracranial volume as covariates of no interest. Significant effects were identified using cluster‐level statistics (p<0.05, family‐wise error corrected for multiple comparisons) above a height threshold of p<0.001 (uncorrected).

Result

Compared to controls, both patients with PSP and bvFTD show significant atrophy of the cingulate gyrus, frontal gyri, and the supplementary motor cortex with the parietal and especially occipital lobe being spared (p <0.05, FWE). Patients with PSP show additional white matter atrophy of the brainstem and basal ganglia (p <0.05, FWE). Compared to PSP, patients with bvFTD show more grey matter atrophy in the inferior frontal gyrus, inferior temporal gyrus, temporal pole, as well as the right insula. Patients with PSP show more white matter atrophy of the basal ganglia, brain stem, and superior cerebellum compared to those with bvFTD (p<0.001, uncorrected).

Conclusion

This is the first voxel‐based morphometry study comparing bvFTD and PSP at ultra‐high field, with higher resolution imaging than previous studies at 1.5T or 3.T. Although both classified as syndromes associated with FTLD, patients with bvFTD and PSP show both specific and complementary patterns of atrophy compared to those of healthy controls and each other.
Memory impairments and synaptic deficits in Tg19959 and APP/PS1 AD model mice are alleviated by eEF2K inhibitor A‐484954
Authors: Kasica Nicole P , Zhou Xueyan , Yang Wenzhong , Ma Tao
Published: December 2021

Background

Mounting evidence indicates synaptic failure as an early and key event in Alzheimer’s Disease (AD) pathophysiology. Maintenance of long‐term memory and synaptic plasticity requires de novo protein synthesis. Phosphorylation of mRNA translation factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis. Previous studies have shown elevated levels of eEF2 phosphorylation in post mortem AD human brain tissue and in AD mouse models. Here, we investigated whether suppression of eEF2 phosphorylation via eEF2K inhibitor A‐484954 can alleviate AD‐associated synaptic failure and memory impairments.

Method

Aged Tg19959 mice (6‐9 months), APP/PS1 (12‐16 months) and age‐matched controls were treated with a subcutaneous pellet containing A‐484954 or vehicle. The pellet continuously releases treatment over 30 days. Starting two weeks after pellet placement, the mice underwent cognitive assessment via the Novel Object Recognition (NOR) and Morris Water Maze (MWM) tasks. Golgi‐Cox Stain, Amyloid Beta immunohistochemistry, Western blots, SUnSET Assays, mass spectrometry (MS) proteomic analysis, and transmission electron microscopy (TEM) were also performed.

Result

We found that cognitive impairments displayed in aged Tg19959 and APP/PS1 mice were alleviated with treatment of A‐484954. Brain tissue from these mice also underwent high performance liquid chromatography (HPLC) to assess drug concentration in the brain. In addition, Golgi‐Cox stain was done to assess dendritic spine density and morphology. Spine analysis indicates a rescue in levels of mature spines in the CA1 region of the hippocampus in APP/PS1 mice treated with A‐484954. TEM analysis indicated a rescue in dendritic polyribosome assembly, post‐synaptic density (PSD) formation, and PSD length. Additionally, SUnSET assays revealed a rescue in translational capacity in the hippocampi of AD mice treated with A‐484954.

Conclusion

Taken together, our results suggest that treatment with a eEF2K inhibitor, A‐484954, alleviates cognitive impairments, restores synaptic morphology, and rescues translational capacity in mouse models of AD.
Alzheimer’s disease: A potential diabetes type 3
Authors: González Andrea , Camila Calfio , Maccioni Ricardo Benjamin
Published: December 2021

Background

Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism dysregulation has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes.

Methods

Within this revised topic, we provide an analysis regarding the influence of glucose metabolism in AD from three different perspectives: i) As a regulator of the energy source, ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence the activation of the immune system (e.g., insulin resistance, diabetes, etc.) and iii) as modulators of various key post‐translational modifications for protein aggregation.

Results

During our research, it was demonstrated the relationship between glucose metabolism dysregulation and the onset and Alzheimer’s disease: The latter is mediated by several metabolic alterations. Among those, included in our research, are metabolic dysregulation events (e.g insulin resistance), which in turn alters the proper ATP generation, and finally, post‐translational modifications, e.g., glycosylation and phosphorylation that mediates protein aggregation (i.e tau hyperphosphorylation that leads to misfolding and pathological self‐assembly).

Conclusions

Alzheimer’s disease onset and development is related to a glucose metabolism impairment that affects energy source (ATP) regulation, several metabolic alterations such as insulin resistance, and mediator of post‐translational modifications in key proteins (i.e tau) that promotes its self‐assembly and aggregation. Thus, considering all the above mentioned, is it seems plausible to consider Alzheimer as the diabetes type 3.
Characterization of novel neuropeptide proteolytic processing involved in dementia pathophysiology
Authors: Ethier Elizabeth C. , Quinn James P. , Kandigian Savannah E. , Trombetta Bianca A. , Arnold Steven E. , Carlyle Becky C.
Published: December 2021

Background

Neuropeptides are neurotransmitter‐like molecules with multiple roles in neuronal activity that are processed into functional peptides (aka proteoforms) by prohormone convertases and other currently unidentified proteases. Both neuropeptides and their proteoforms are implicated in the pathogenesis of different forms of dementia. The neuropeptide VGF is decreased in the cerebrospinal fluid (CSF) and brain of patients with Alzheimer’s disease (AD) and other forms of dementia. VGF356‐375 and VGF1‐40 decrease in the CSF of patients with AD and frontotemporal dementia (FTD), respectively, compared to healthy age‐matched controls. Although many such neuropeptide proteoforms are thought to be involved in dementia, current research has focused on the neuropeptides themselves, leaving the proteoforms and their physiological processing pathways understudied and their contribution to dementia pathogenesis unclear.

Method

Using recombinant proteolysis assays, we aimed to investigate the proteolytic processing of several neuropeptides involved in dementia. Neuropeptides of interest were identified by mass spectrometry analysis of pooled CSF samples obtained from five AD patients and five healthy controls. Proteasix, the MEROPS, and the human protein atlas databases were used to identify novel neuronally‐expressed proteases that may cleave these identified neuropeptides; proteases of interest were selected based on the predicted probability of cleavage. Recombinant protein assays and immunoblots with neuropeptide‐specific antibodies were used to investigate the ability of these proteases to cleave the neuropeptides, and banding patterns were confirmed in triplicate.

Result

Twenty‐two neuronally expressed proteases previously linked to dementia were identified that may cleave the neuropeptides chromogranin A (CHGA), secretogranin‐1 (SCG1), secretogranin‐2 (SCG2), secretogranin‐3 (SCG3), and VGF. The proteases a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), calpain‐1 (CAPN1), cathepsin S (CTSS), granzyme A (GZMA), and matrix metalloprotease‐3 (MMP‐3) displayed high probability for neuropeptide proteolysis. These proteases cleaved the neuropeptides into N‐terminal, mid‐region, or C‐terminal neuropeptide proteoforms, and all neuropeptide‐protease combinations except the SCG3‐CAPN1 pair demonstrated cleavage.

Conclusion

Overall, this work provides mechanistic insight into neuropeptide processing and expands our understanding of neuropeptide proteoform involvement in dementia. Future projects aim to confirm and expand upon these results using mass‐spectrometry, cell culture systems, and CSF and brain protein analysis.
Hypothiocyanous acid oxidizes collapsin response mediator protein 2 in brain pericytes
Authors: van Leeuwen Eveline
Published: December 2021

Background

Pericytes cover brain endothelium to enable maintenance of the blood‐brain barrier (BBB). Decreasing pericyte numbers are reported in Alzheimer’s disease and could lead to BBB dysfunction, triggering vascular inflammation and the recruitment of immune cells. Neutrophils contain high contents of myeloperoxidase, a heme enzyme that produces several oxidising species, including hypothiocyanous acid (HOSCN). HOSCN specifically targets cysteine residues in proteins and low molecular weight thiols, and is more stable than other oxidants in biological systems. A microtubule stabilising protein, collapsin response mediator protein 2 (CRMP2), is oxidised by hydrogen peroxide (H2O2) in some cell types, purportedly through a peroxiredoxin (Prx) relay mechanism. Here, we have tested whether HOSCN can oxidise CRMP2 and lead to disruption of microtubules (MT) in pericytes.

Method

Murine pericytes were harvested and cultured, then treated with sub‐lethal concentrations of HOSCN and H2O2. Western blotting was used to observe CRMP2 and Prx oxidation, along with CRMP2 phosphorylation at sites important for MT binding. Fluorescent staining, live‐cell imaging and in vitro scratch assays were used to view cytoskeleton alterations and pericyte migration. Immunoprecipitation and proximity ligation assays were used to investigate physical associations between CRMP2 and Prxs.

Result

Treatment of pericytes with HOSCN led to maximal CRMP2 oxidation after 60 min, whereas H2O2 reaches this in 5 min. Oxidation was closely associated with pericyte shrinkage, less growing microtubules and lower pericyte cell migration. CRMP2 oxidation occurred at the same time as Prx2 oxidation, and there was a physical association between these proteins, but it is not possible to conclude a redox relay occurs.

Conclusion

We hypothesized that the longer‐lived oxidant HOSCN could oxidize CRMP2 and impair pericyte function at sub‐lethal doses. Indeed, HOSCN led to less dynamic MTs and subsequent lower migration of pericytes, likely lowering their ability to cover empty area on the inflamed vasculature to protect endothelial function. This effect is reversible upon HOSCN removal, nevertheless HOSCN could be a cause of BBB disruption during neuroinflammation. The mechanisms of CRMP2 oxidation are currently being investigated. Strategies that protect this MT regulatory protein from oxidation could have therapeutic benefit in neurological disease.
Alterations in dendritic GABAB receptor expression in an Alzheimer’s disease mouse model
Authors: McArdle Colin J , Niere Farr , Uneri Ayse , Raab‐Graham Kimberly F
Published: December 2021

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory deficits and cognitive decline. Major hallmarks that occur during early stages of disease progression include amyloid beta plaque, neurofibrillary tangles, and synaptic loss. The mechanisms that particularly govern synaptic loss, however, remain under investigation. Local, dendritic mRNA translation is critical in maintaining proper synaptic architecture as well as engagement with presynaptic terminals. A master regulator of this process is controlled by mammalian target of rapamycin complex 1 (mTORC1), whose activity has shown to be significantly increased in AD patients as well as respective animal models. Increases in mTORC1 activity have consequently shown to upregulate the translation of various downstream synaptic proteins, one of those being GABAB receptors (Niere, 2016). Metabotropic, GABAB receptors are critical in maintaining slow, sustained inhibition throughout the central nervous system. However, their significance towards synaptic function is understudied in the context of AD.

Methods

Our study utilized immunocytochemistry and microscopy to determine changes in GABAB1 receptor subunit expression in hippocampal dissociated neurons. Additionally, APP/PS1 transgenic mice were used as our model for AD.

Results

Immunocytochemical results indicate approximately a 22% increase in dendritic GABAB1 subunit expression in AD mice as compared to wildtypes (p<0.01).

Conclusions

The data indicates increases in GABAB1 receptor subunits in AD while highlighting a potential avenue in which transsynaptic signaling is disrupted in early stages of AD.
Dementia‐linked TDP‐43 dysregulation in astrocytes impairs memory, antiviral signaling, and chemokine‐mediated astrocytic‐neuronal interactions
Authors: Murava Avital Licht , Meadows Samantha , Palaguachi Fernando , Song Soomin C. , Bram Yaron , Zhou Constance , Schwartz Robert E. , Froemke Robert C. , Orr Adam L. , Orr Anna G.
Published: December 2021

Background

TDP‐43 pathology is linked to cognitive deficits in diverse neurodegenerative disorders, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). The effects of TDP‐43 pathology in different cell types, including astrocytes, are not clear.

Method

In this study, we used postmortem human brain samples, extensive behavioral testing in numerous cohorts of doubly transgenic mice, gene profiling in different isolated brain regions and cells, glial‐neuronal co‐culture assays and physiology, and biochemical assays to identify specific signaling cascades linked to TDP‐43.

Result

Our results show that astrocytic TDP‐43 is mislocalized in postmortem human hippocampal tissue from AD cases. To assess the effects of widespread or hippocampus specific dysregulation of astrocytic TDP‐43 in complementary systems, we generated three novel astrocyte specific mouse models of TDP‐43 dysfunction. Consistently, these mouse models indicated that astrocytic TDP‐43 dysfunction causes progressive hippocampus‐dependent memory loss, but not motor deficits. Manipulation of astrocytic TDP‐43 also increased hippocampal levels of interferon ‐inducible chemokines CXCL9 and CXCL10, and altered cell‐autonomous antiviral signaling and defense against viral pathogens. Moreover, expression of CXCR3, the shared receptor for CXCL9 and CXCL10, was increased selectively in hippocampal presynaptic terminals. Acute or chronic stimulation of presynaptic CXCR3 modulated neuronal activities and presynaptic vesicles.

Conclusion

Overall, our findings shed new light on TDP‐43 dysregulation in astrocytes and its potential contributions to disease‐related impairments in cognitive and immune‐related functions. We report a novel chemokine‐mediated astrocytic‐neuronal pathway that is likely downstream of aberrant antiviral immune signaling in astrocytes that affects presynaptic release and neuronal activities. Together, these results implicate astrocytic TDP‐43 dysregulation in the pathogenesis of dementia and point to chemokine signaling and CXCR3 as potential therapeutic targets for alleviating cognitive decline.
The Drosophila K+‐dependent Na+/Ca2+ exchanger Nckx30C is implicated in temperature sensitive paralysis and age‐dependent neurodegeneration
Authors: Majlish Al Nahian Khan , Lye Shu Hui , Cytron Emilia , Bolus Harris , Marotto Kathleen , Chtarbanova Stanislava
Published: December 2021

Background

Increasing evidence links epileptic seizures to neurodegenerative disorders such as Alzheimer’s disease (AD) although the mechanisms underlying this relationship are not fully understood. Ion channels are crucial to the maintenance of intracellular calcium (Ca2+) signaling in the nervous system, and a perturbation in their structure and function could result in both neuropathology and seizures. Moreover, perturbed cellular Ca2+ homeostasis is known to be implicated in AD pathogenesis. Previous studies in the model organism Drosophila have established a connection between mutations linked to temperature‐sensitive (TS) paralysis, which is reminiscent of vertebrate epileptiform behavior, and neurodegeneration. Thus, Drosophila could serve as an excellent model to investigate the molecular mechanisms relating these two conditions.

Method

We performed an unbiased genetic screen to identify mutants that exhibit paralytic behavior at 38°C. We used gene mapping, and DNA sequencing to locate the mutation in the Nckx30C gene. We carried out TS paralysis assays, lifespan analysis, climbing assay and brain histology to look for neurodegeneration, as well as immunohistochemistry to examine synaptic morphology at the larval neuromuscular junction (NMJ). Knockdown using RNAi established the cell‐type specific basis of the TS‐paralytic and neurodegenerative phenotypes.

Result

Mutant line 426 exhibited TS paralysis and progressive neurodegeneration in comparison to controls. We mapped the mutation to the Nckx30C locus, in the region encoding the predicted ion‐binding domain. In comparison to wild type, 426 flies showed reduced lifespan, impaired climbing and changes in NMJ morphology, indicative of synaptic dysfunction. We found lifespan reduction and early‐onset neurodegeneration in flies carrying two other Nckx30C alleles. Neuron‐ but not glia‐specific knockdown of Nckx30C recapitulates the TS‐paralytic phenotype of 426 flies. Knockdown of Nckx30C in glia and neurons led to early onset climbing defects.

Conclusion

The Drosophila Nckx30C gene encodes for a K+‐dependent Na+/Ca2+ exchanger with enriched expression in brain tissue. Nckx30C is homologous to mammalian Solute Carrier Family 24 (SLC24) proteins of which pathophysiological involvement and function in the brain is poorly understood. Our studies of Nckx30C in flies could help to decipher the function of SLC24 proteins in both seizures and neurodegenerative conditions such as AD.
Regenerating spiral ganglion neurons employing the cochlear implant
Authors: Huynh Quy‐Susan , Holsinger R. M. Damian
Published: December 2021

Background

Sensorineural hearing loss is treated using cochlear implants. The electrodes in the implants directly stimulate spiral ganglion neurons (SGNs). However, SGNs continually degenerate and are difficult to access behind the bony modiolar wall of the cochlea. The electrode‐tissue interface needs to be improved to enhance hearing for users.

Implanting the electrode closer to the SGNs, requires a greater insertion depth and increases the amount of scar tissue that forms around the electrode. The introduction of neurotrophic factors has the potential to improve neural regeneration. However, currently there are a lack of methods to deliver neurotrophic factors locally and sustainably into the cochlea.

We propose a neural electrode system utilising electrical stimulation (ES) to increase the expression of brain‐derived neurotrophic factor (BDNF) and guide SGNs and their neurites towards the electrode. Additionally, the electrode system would utilise an electrospun nanofiber scaffold surrounding the electrode to act as a mechanical support to the cells and their projections.

Method

Nanofiber scaffolds were electrospun onto wires and glass coverslips and cultured with human SH‐SY5Y neuroblastoma and rat Schwann cells. Immunohistochemistry and scanning electron microscopy were used to characterise the scaffolds and biocompatibility.

Platinum electrodes were used to stimulate both rat Schwann cells and SH‐SY5Y cells for 3 hours using a 100mV/mm DC electric field. Following 20 hours of incubation, the cells were immunostained to measure changes in BDNF expression.

Result

We discovered that not only were the scaffolds biocompatible, but the cells aligned along the nanofibers, forming networks on the scaffolds. We observed statistically significant increases in BDNF expression in Schwann cells, as well as a limited BDNF increase in SH‐SY5Y cells that may be a result of the incubation period used in our experiment and is currently under investigation.

Conclusion

These results suggest the feasibility of the system and have the potential to improve cochlear implants.
Alzheimer’s disease associated AKAP9 I2558M mutation alters posttranslational modification and interactome of tau and cellular functions in CRISPR‐edited human neuronal cells
Authors: Hersh Samuel Walter , You Yang , Aslebagh Roshanak , Shaffer Scott A , Ikezu Seiko , Mez Jesse , Lunetta Kathryn L , Logue Mark W. , Farrer Lindsay A. , Ikezu Tsuneya
Published: December 2021

Background

Alzheimer’s disease (AD) is a pervasive neurodegeneration disease with high heritability. Whole exome sequencing study identified two rare African American (AA)‐specific variants in AKAP9, a kinase anchor protein 9, (rs144662445 and rs149979685), that increased the odds of AD more than 2.75‐fold. However, the functional impact of the AKAP9 rs144662445 (I2558M) mutation in the central nervous system and the underlying mechanism in AD remain unclear.

Method

AKAP9 I2558M mutation was introduced by CRISPR‐mediated knock‐in and validated by Sanger sequence in SH‐SY5Y cells stably expressing P301L Tau (SH‐SY5Y P301L cells), which was further differentiated into neuronal cells. Tau phosphorylated level between AKAP9 WT and I2558M cells was evaluated by immunocytochemistry and ELISA assay. Moreover, we analyzed the tau interactome in AKAP9 I2558M cells by affinity purification‐mass spectrometry. In silico analysis was performed to compare the differences between AKAP9 WT and mutation in tau‐interacting proteins. The protein synthesis and oxidative activity in SH‐SY5Y P301L neurons with and without I2558M were measured by using the Click‐iT protein synthesis kit and CellRox dye, respectively.

Result

No difference in the neuronal cell morphology was observed between differentiated WT and mutant SH‐SY5Y P301L cells. The AD‐associated AKAP9 I2558M mutation resulted in a significant increase in phosphorylated tau protein at residues S396 and S404 site in a differentiated SH‐SY5Y P301L cell line. The presence of this mutation altered the composition of tau‐interacting proteins, by increasing interaction of proteins associated with translation, RNA localization and oxidative activity. Importantly, functional studies showed a significant reduction in protein synthesis activity and excessive oxidative stress in AKAP9 mutant compared to wild type cells.

Conclusion

Our results demonstrated specific effects of rs14462445 on mis‐processing of tau and suggest a potential role of AKAP9 in AD pathogenesis.
p‐Coumaric acid protects against D‐galactose induced neurotoxicity by attenuating neuroinflammation and apoptosis in mice brain
Authors: Daroi Pratibha Atul
Published: December 2021

Background

D‐galactose (D‐gal) induced senescence in rodents is a widely used Alzheimer’s model. Chronic administration of D‐gal causes neuroinflammation leading to cognitive deficit and memory impairment.

Method

Present study investigated the neuroprotective effects of the natural phenol, p‐Coumaric acid (PCA) and its underlying mechanism against the chronic D‐gal induced senescence in Swiss albino mice. D‐gal (150 mg/kg) was administration s.c.ly to mice for 42 consecutive days.

Result

D‐gal produced cognitive impairment as observed in Morris water maize (MWM) and Y maze test, which was ameliorated by concurrent treatment with PCA (80 mg/kg, and 100 mg/kg, p.o.). Importantly, PCA treatment attenuated the D‐gal induced oxidative stress and significantly inhibited acetylcholinesterase (AChE) activity in mice brain. Furthermore, PCA treatment significantly lowered levels of inflammatory marker nuclear factor kappa B (NFκB) and reduced levels of proapoptotic enzyme caspase 3. We also observed that PCA treatment exhibited β‐secretase enzyme (BACE1) inhibitory effect. However, PCA treatment failed to decrease the level of advanced glycation end products (AGE) both in vitro and in vivo.

Conclusion

Current study demonstrated the significant neuroprotective effect of PCA against D‐galactose induced neuroinflammation, cognitive impairment and apoptosis.
Circulating klotho is elevated in cerebrospinal fluid, but not serum, among KLOTHO KL‐VS allele carriers at risk for Alzheimer’s disease
Authors: Gaitán Julian M. , Dubal Dena B. , Okonkwo Ozioma C.
Published: December 2021

Background

The klotho protein supports brain health and is encoded by the KLOTHO gene. The KL‐VS allele modulates klotho protein secretion and function, but it is unknown how KL‐VS genotype affects circulating klotho levels in blood and cerebrospinal fluid (CSF) among people at risk for AD.

Methods

1112 cognitively intact participants from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center underwent genotyping for KLOTHO KL‐VS (non‐carrier: KL‐VSNC; heterozygote: KL‐VSHET; homozygote: KL‐VSHOM) and APOE4 alleles. 1098 participants underwent venipuncture and 183 underwent lumbar puncture. Circulating klotho was measured by ELISA in serum and/or CSF. Linear regression adjusted for age and sex tested the effect of KL‐VS genotype on klotho in serum or CSF. In a subset of 169 participants with both serum and CSF data, linear regression adjusted for time between specimen collections tested the effect of specimen source on klotho level.

Results

Visual inspection for outliers excluded four high serum klotho values (range 2461.5–4171.3 pg/mL; two KL‐VSNC, one KL‐VSHET, one KL‐VSHOM); no CSF values were excluded. The mean participant age was 62.4 ± 6.6 and education was 15.8 ± 2.7 years. The majority were female (69.4%), White (92.6%), and had family history of dementia (72.6%), and 38.1% were APOE4 carriers. KL‐VS genotype distribution was 73.1% KL‐VSNC, 25.2% KL‐VSHET, and 1.7% KL‐VSHOM. Mean serum klotho in KL‐VSNC was 800.8 ± 252.8 pg/mL and was not different in KL‐VSHET (b=17.7, SE=17.5, p=.31) or KL‐VSHOM (b=84.0, SE=58.1, p=.15). Mean CSF klotho in KL‐VSNC was 932.2 ± 153.2 pg/mL and was significantly higher in KL‐VSHET (b = 225.8, SE = 25.1, p< .001) and KL‐VSHOM (b=327.8, SE=75.5, p< .001). Mean CSF klotho was significantly higher than serum klotho in the entire subset (b=162.8, SE=25.9), p< .001) and within each KL‐VS genotype (p’s< .05).

Conclusions

In adults at risk for AD, CSF klotho is elevated in heterozygotic and homozygotic carriers of the KLOTHO KL‐VS allele. Serum levels are lower than CSF and did not differ by genotype. Klotho specimen source should be considered in analyses of circulating klotho on brain health.
Home monitoring of daily living activities and prediction of agitation risk in a cohort of people living with dementia
Authors: Fletcher‐Lloyd Nan , Soreq Eyal , Wilson Danielle , Nilforooshan Ramin , Sharp David J , Barnaghi Payam
Published: December 2021

Background

People living with dementia (PLWD) have an increased susceptibility to developing adverse physical and psychological events. Internet of Things (IoT) technologies provides new ways to remotely monitor patients within the comfort of their homes, particularly important for the timely delivery of appropriate healthcare. Presented here is data collated as part of the on‐going UK Dementia Research Institute’s Care Research and Technology Centre cohort and Technology Integrated Health Management (TIHM) study. There are two main aims to this work: first, to investigate the effect of the COVID‐19 quarantine on the performance of daily living activities of PLWD, on which there is currently little research; and second, to create a simple classification model capable of effectively predicting agitation risk in PLWD, allowing for the generation of alerts with actionable information by which to prevent such outcomes.

Method

A within‐subject, date‐matched study was conducted on daily living activity data using the first COVID‐19 quarantine as a natural experiment. Supervised machine learning approaches were then applied to combined physiological and environmental data to create two simple classification models: a single marker model trained using ambient temperature as a feature, and a multi‐marker model using ambient temperature, body temperature, movement, and entropy as features.

Result

There are 102 PLWD total included in the dataset, with all patients having an established diagnosis of dementia, but with ranging types and severity. The COVID‐19 study was carried out on a sub‐group of 21 patient households. In 2020, PLWD had a significant increase in daily household activity (p = 1.40e‐08), one‐way repeated measures ANOVA). Moreover, there was a significant interaction between the pandemic quarantine and patient gender on night‐time bed‐occupancy duration (p = 3.00e‐02, two‐way mixed‐effect ANOVA). On evaluating the models using 10‐fold cross validation, both the single and multi‐marker model were shown to balance precision and recall well, having F1‐scores of 0.80 and 0.66, respectively.

Conclusion

Remote monitoring technologies provide a continuous and reliable way of monitoring patient day‐to‐day wellbeing. The application of statistical analyses and machine learning algorithms to combined physiological and environmental data has huge potential to positively impact the delivery of healthcare for PLWD.
Decreased O‐GlcNAcylation and mitochondrial dysfunction are involving in low glucose induced Alzheimer’s disease‐like phenotype in induced pluripotent stem cell‐derived neurons
Authors: Huang Chia‐Wei , Hart Gerald W.
Published: December 2021

Background

Evidence supporting that glucose metabolic abnormalities occur prior to Alzheimer’s disease (AD) symptoms. Reduced O‐GlcNAc (OGN) levels likely arise from impaired glucose metabolism or availability and correlates with AD pathogenesis. So far, the mechanism of sAD and the role of OGN in AD pathology remained largely unknown due to a lack of human sAD model.

Method

We generated human cortical neurons from human‐induced pluripotent stem cells and treated neurons with glucose reduction media. FluoroJADE staining and cell viability assays were used to study the effects of low glucose on the degenerative status and cell viability of neurons. Abnormal protein production, phosphorylation, and accumulation were detected by western blotting and immunofluorescence staining using antibody against p‐tau and beta‐amyloid. Neurite and synaptic structure were observed by immunofluorescence staining, while neuronal network activity was detected by multi‐electrode array electrophysiological analyses. Mitochondrial abnormalities, including increased oxidative stress, reduced membrane potential, and mitochondrial dysfunction, were evaluated using CM‐H2DCFDA, JC‐1 and Seahorse, respectively.

Result

We show that lowering glucose level to 2mM leads to dramatic increases of neuron degeneration on day 3 and 5 of treatment and decreased cell viability on day 7. Interestingly, long‐term low glucose treatment induces AD features in neurons, including abnormal hyperphosphorylated tau accumulation and increasing beta‐amyloid production. Besides, glucose deficiency also causes decreased neurite coverage, synapse density, and neuron network activity. Furthermore, we find that O‐GlcNAc levels are significantly reduced soon after low glucose treatment and remain low until the end of experiment. Raising O‐GlcNAc levels by thiamet‐G, inhibitor of O‐GlcNAcase, even in low glucose treated neurons, rescues low glucose‐induced AD phenotypes. Moreover, our data shows that O‐GlcNAc dysregulation causes mitochondrial abnormalities, which occur before any other degenerative phenotype appeared, and may be one of the underlying mechanisms of sAD onset and pathogenesis.

Conclusion

We established a human neuron model in which the pathological features are reproduced by glucose deficiency. This platform can serve as a tool for better understanding molecular processes involved in neurodegeneration in sAD. Our results also suggest that dysregulated O‐GlcNAc levels and mitochondrial dysfunction by glucose deficiency are involved in the onset and progression of sAD.
CGG Repeats in the FMR1 Gene as Predictor of Visuospatial Working Memory
Authors: Hickey Alexandra C , Friedman Laura , Klusek Jessica
Published: December 2021

Background

The FMR1 premutation, defined by an expansion of 55–200 CGG repeats on the FMR1 gene, occurs in 1 in 150 women in the US. The premutation is related to complications, including risk for neurodegenerative disease (Fragile X‐associated tremor/ataxia syndrome; FXTAS) and broader neurocognitive features occurring outside of the context of FXTAS. Understanding the premutation’s effect on cognition, such as visuospatial working memory (VWM), will provide a more comprehensive understanding of cognitive symptoms associated with the FMR1 premutation genotype. Previous findings demonstrated that premutation males with high CGG repeats perform worse on VWM tasks (Hocking et al., 2012). Few studies examined VWM in female carriers, who typically show milder symptoms. This study examined VWM in female carriers and its relationship with CGG repeat length.

Methods

Participants were 33 premutation carrier women and 22 neurotypical controls aged 27‐59 (M=45) years. Groups did not significantly differ in age (p=.132), education (p=.682), or race (p=.661). Participants completed Spatial Addition test of the WMS‐IV (Weschler, 2009). DNA from buccal swabs was analyzed for CGG repeat length using the Asuragen AmplideX kit.

Results

Given the incomplete penetrance the FMR1 premutation phenotype, where only a subgroup of women experience symptoms, analyses focused on identifying those who obtained low/at‐risk standard scores (1+SD below the mean), as opposed comparing mean performance across groups. Chi‐squared analyses indicated that premutation carrier women were more likely score 1+ SD below the mean on the Spatial Addition test (30% vs 0% of controls), X
2=8.14, p=.004. Logistic regression indicated that CGG repeat length was a significant predictor of scoring 1+SD below the mean, after controlling for education level, (χ2=‐7.50, p=.032). For every unit increase in CGG repeat length, the odds of scoring 1+SD below the mean increased by a factor of 1.07 (95% CI: 1.00, 1.12).

Conclusions

Female premutation carriers were more likely to show VWM difficulties, which were associated with genetic liability (i.e., CGG repeat length). Future research may explore VWM deficits in relation to FXTAS risk.