bluuebunny/crossref_metadata_2025_split huggingface dataset:
DRhQ: a novel therapeutic that improves cognition and mitochondrial function and reduces neuroinflammation in beta‐amyloid overexpressing Mice
Authors: Gray Nora E , Lockwood Denesa R , Hack Wyatt E , Brandes Mikah S , Meza‐Romero Robert E , Neff Cody E , Gladen‐Kolarsky Noah E , Quinn Joseph F , Vandenbark Arthur A 
Published: December 2023

AbstractBackgroundNeuroinflammation and mitochondrial dysfunction are central to the progression of Alzheimer’s disease (AD), provoking neuronal loss and cognitive decline. Identifying strategies for mitigating these responses could therefore be of significant therapeutic relevance. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factory (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders like AD. Our group has developed DRhQ, a novel CD74 binding construct that competitively inhibits MIF binding, blocks T‐cell and macrophage activation and migration into the CNS, enhances anti‐inflammatory microglia cell numbers and reduces pro‐inflammatory gene expression. DRhQ treatment resulted in reduced neuroinflammation and disease severity in a mouse model of multiple sclerosis. Because neuroinflammation is a prominent in the AD brain as well we hypothesized that DRhQ could be a similarly effective neuroprotective agent in the context of AD. We evaluated this hypothesis using the 5xFAD mouse model of β‐amyloid (Aβ) accumulation.MethodSix month old male and female 5xFAD mice and their wild‐type littermates will be treated with 0 or 100 ug of DRhQ subcutaneously for five days followed by a 3 day booster series weekly for the next 3 weeks. During the 4th week of treatment mice were evaluated cognitively using the novel object recognition test and brain tissue was harvested to evaluate mitochondrial function, Aβ pathology as well as markers of microglial activation and neuroinflammation.ResultDRhQ improved cognition and reduced neuroinflammatory markers in both male and female 5xFAD mice. DRhQ also significantly attenuated deficits in cortical mitochondrial function in female 5xFAD mice and elicited a similar, though non‐significant, effect in male 5xFAD mice. Aβ plaque burden was likewise reduced in the hippocampus and cortex of female 5xFAD mice but not significantly reduced in male 5xFAD animals.ConclusionThese results suggest that DRhQ attenuates Aβ pathology, mitochondrial dysfunction and neuroinflammation and improves cognitive function in 5xFAD mice. Future experiments will explore dose response effects and investigate the apparent sex differences in the magnitude of effect of DRhQ on specific endpoints in these mice as well as evaluate the effects of DRhQ in models of tauopathy.
circRNAs mediate the effect of chronic lysosomal dysfunction on Alzheimer’s disease pathology
Authors: Romero Skarleth Cardenas , Eteleeb Abdallah M , Nykanen Niko‐Petteri , O’Dell Kevin , Nunez Marie , Harari Oscar , Cirrito John R , Sands Mark , Benitez Bruno A. 
Published: December 2023

AbstractBackgroundCircular RNAs (circRNAs) and microRNAs (miRNAs) are non‐coding RNAs. CircRNAs modulate miRNA levels by sequestration. MiRNAs regulate amyloidogenic pathways, disrupting transcripts including APP, BACE1, and ADAM10. CircRNAs regulate key endolysosomal transcripts. Chronic lysosomal dysfunction (CLD) is linked to Alzheimer’s Disease (AD). However, the role circRNAs downstream of CLD and AD is unclear. Here, we tested whether CLD affects the amyloidogenic pathway in 5xFAD mice through circRNAs.MethodCortical circRNA expression was obtained of 5xFAD, PPT1+/−, 5xFAD: PPT1+/− (P5X), Naglu+/−, 5xFAD: Naglu+/− (N5X) mice. TruSeq Stranded total RNA was extracted with Ribo‐Zero to deplete rRNA and generate stranded‐RNA‐seq. Libraries were sequenced on a NextSeq 500 platform of Illumina and analysis was done with the DESeq2 package with an FRD <0.05. In silico microRNA binging was done using circAtlas 2.0 browser. The insoluble Aβ‐40 and Aβ‐42 were quantified by ELISA in the hippocampal fraction. The Aβ plaque load was quantified in coronal brain sections using immunohistochemistry.ResultThe P5X and N5X mice exhibit increased amyloid plaque load, hippocampal Aβ‐40, and Aβ‐42 levels, and reduced lifespan compared to 5xFAD mice. We detected 1286 cicRNAs in all the groups. 38 from P5X and N5X groups, 37 from PPT1+/−, and 29 from Naglu+/− passed FRD correction compared with 5xFAD mice. Both linear and circRNAs of 4933406I18Rik, Zfp609, Zfp532, and Nnt changed between PPT1+/− and P5X compared to 5xFAD. The levels of circAdam10, circPan3, circMbtd1, circ4930402H24Rik, circSt6gal2, and circCdc14b were reduced, while circZranb1 and circMyo9a were increased in P5X and N5X compared with 5xFAD. CircNlgn1 levels changed only downstream of PPT1+/−. In silico analyses show amyloidogenic‐related microRNAs exhibit circRNAs binding sites. MiR‐361‐3p has binding sites for circZranb1 and circADAM10, as well as miR‐298‐3p, can bind circNlgn1. Both miR‐361‐3p and miR‐298‐3p trap and inhibit BACE1 function and Aβ production, interfering in the amyloidogenic pathway. CircPan3 regulates the autophagy‐related miR‐421. Experimental evidence shows that overexpression of circPan3 suppresses autophagy through a miR‐421/Pink1 pathway.ConclusionCLD (PPT1+/− and Naglu+/−) boosted AD pathology and induced differential changes in circRNAs levels affecting amyloidogenic and autophagy pathways. There is a positive feedback loop between CLD and circRNAs in AD mouse models.
Identification of cis‐regulatory elements associated with MAPT expression in human induced pluripotent stem cell derived neural cells
Authors: Rogers Brianne B. , Anderson Ashlyn G , Lauzon Shelby N. , Davis M. Natalie , Hauser Rebecca M. , Roberts Sydney C. , Rodriguez‐Nunez Ivan , Trausch‐Lowther Katie , Roberts Brian S. , Barinaga Erin A. , Rizzardi Lindsay F. , Cooper Sara J. , Myers Richard M. , Cochran J. Nicholas 
Published: December 2023

AbstractBackgroundTau is encoded by MAPT and abnormal aggregates of tau are a hallmark of many neurodegenerative diseases. MAPT is highly expressed in neurons but much more lowly expressed in other cell types, including neural precursor cells (NPCs), suggesting that its expression may be controlled by neuron‐specific transcription factors and cis‐regulatory elements. Tau reduction, even of endogenous tau, is a current therapeutic strategy in both model systems and humans; therefore, understanding MAPT regulation may point to new strategies to achieve tau reduction. Additionally, genome sequencing studies continue to identify disease‐associated variants in non‐coding regions of the genome. These variants are likely located in regulatory regions and affect the expression of target genes whose function contributes to neurodegeneration. Therefore, an additional benefit of this study is that high confidence regulatory regions for MAPT may provide a way to identify important non‐coding variants associated with disease.MethodsThree‐dimensional chromatin conformation capture (Capture‐C), single‐cell multiomics (RNAseq + ATACseq), and chromatin marks including H3K27ac, H3K4me1, and DNase hypersensitivity were used to identify candidate enhancers of MAPT in human NPCs, NPCs differentiated to neurons, and pure inhibitory or excitatory neuron cultures (all lines were H1/H1). Approaches included nomination of elements with signals specific to neurons or neuronal subtypes. The nominated regions were then assessed using luciferase assays to test sufficiency for regulatory activity as well as CRISPR‐dCas9‐KRAB to assess the effect of nominated elements on MAPT expression.ResultsWe identified both proximal and distal regulatory elements for MAPT with function confirmed by up to four orthogonal approaches (chromatin capture, single cell multiomics, a reporter assay, and element inhibition using dCas9‐KRAB). Several of these elements were specific to neurons. One particularly important region was centromeric to MAPT beyond the H2 inversion breakpoint.ConclusionsOverall, these results indicate that MAPT regulation is likely controlled by neuron‐specific cis‐regulatory elements, including both proximal and distal elements. Next steps include study of the effect of trans‐regulatory elements (i.e., transcription factors) that may control recruitment of these cis‐regulatory elements for expression of MAPT and assessment of the effects of the disease‐associated genetic variation on cis‐regulatory element function and expression of MAPT.
Targeting hyperactive antiviral response to treat tauopathy
Authors: Gan Li 
Published: December 2023

AbstractBackgroundCyclic GMP‐AMP synthase (cGAS, Cgas), the major antiviral DNA sensor, binds double‐stranded DNA (dsDNA) and catalyzes cyclic GMP‐AMP (cGAMP) formation, which activates stimulator of interferon genes (STING). Activation of cGAS‐STING has been implicated in several neurodegenerative conditions. The role of cGAS in tauopathy remains unknown.MethodWe investigated cGAS‐STING‐IFN activation in microglia of tauopathy mice and human AD brains. We crossed cGAS knockout mice with P301S tauopathy mice and performed behavioral, immunohistochemistry, electrophysiology and single‐nuclei (sn) RNA‐seq.Resultwe demonstrated potent protective effects of Cgas genetic deletion against synaptic and cognitive deficits associated with induction of transcriptional network of MEF2C, a gene implicated in cognitive resilience against amyloid and tau pathology. SnRNA‐seq analyses of human AD brains revealed dysregulation of microglial IFN‐I genes and neuronal MEF2C transcriptional network.ConclusionOur current study linked a hyperactive cGAS‐IFN antiviral response with diminished MEF2C‐associated cognitive resilience. In diseased conditions, cGAS hyperactivation promoted microglial IFN‐I response, reduced neuronal MEF2C transactivation, and rendered loss of cognitive resilience. cGAS ablation diminished microglial IFN‐I response and enhanced neuronal MEF2C transcription network and associated cognitive resilience against tau pathology. Pharmacological inhibition of cGAS with TDI‐6570 enhanced MEF2C target genes and restored synaptic integrity and memory, supporting the therapeutic potential of targeting cGAS‐MEF2C axis to improve resilience against AD and related neurological disorders.
Consequences of neuromelanin‐like pigmentation on locus coeruleus integrity and function in mice
Authors: Weinshenker David 
Published: December 2023

AbstractBackgroundThe locus coeruleus (LC) is the first region of the brain to accumulate tau pathology in Alzheimer’s disease (AD) and subsequently undergoes catastrophic degeneration as disease progresses. It has been proposed that neuromelanin (NM), a dark cytoplasmic pigment that is a byproduct of catecholamine metabolism, may contribute to the selective vulnerability of the LC. However, causal relationships between NM and LC degeneration have been difficult to establish because, unlike primates, rodents do not produce appreciable amounts of NM.MethodWe adapted a viral‐mediated approach for expression of human tyrosinase (hTyr), the enzyme responsible for peripheral melanin production, to promote pigmentation in rodent LC neurons. Cre‐dependent AAV‐hTyr virus was infused bilaterally into the LC of 2‐month old TH‐Cre mice, and the LC and behavior was examined 1‐10 weeks later.ResultWe found that viral vector‐mediated hTyr expression drove pigment expression in the LC that recapitulated key features of endogenous NM found in primates, including eumelanin and pheomelanin, lipid droplets, and a double‐membrane encasement. Pigment accumulation resulted in mild neurodegeneration, altered catecholamine levels, transcriptional changes, and novelty‐induced anxiety phenotypes as early as 1 week post‐injection. By 6‐10 weeks, severe LC neurodegeneration and a robust neuroinflammatory response were observed.ConclusionThese results suggest that NM may contribute to the selective vulnerability of LC neurons in AD. The phenotypes of NM‐expressing mice were reminiscent of LC dysfunction and degeneration in AD, validating the utility of this model for studying the consequences of pigment accumulation in the LC as it relates to neurodegenerative disease.
Psychometric Validation and Prognostic Performance of the Bedford Alzheimer Nursing‐Severity Scale in community‐dwelling persons with severe dementia (PWSD)
Authors: Cheong Chin Yee , Yap Philip Lin Kiat , Malhotra Chetna 
Published: December 2023

AbstractBackgroundAssessment of disease severity and prognostication are germane to dementia care yet extant instruments are limited by floor effects and inadequate mortality prognostic performance. To date, the Advanced Dementia Prognostic Tool‐ADEPT(AUC = 0.68) is the best available but was validated in only nursing home residents. We aimed to investigate the psychometric properties of the 7‐item Bedford Alzheimer Nursing‐Severity Scale(BANS) in community‐dwelling people with severe dementia (PWSDs) and explore its prognostic utility.MethodPanel study Investigating Status of Cognitively impaired Elderly in Singapore is a multi‐centre prospective longitudinal study which recruited 215 PWSD, mean age 83.6±8.2 and median follow‐up 25 months. We evaluated the internal consistency reliability, factor, construct and predictive validity of BANS compared to FAST, a well‐established dementia severity tool. A 1‐year mortality prognostic index was derived from the adapted BANS and significant clinical variables.ResultFactor analysis revealed a two‐factor solution(variance 58.4%) with item‐2(sleep‐wake cycle) not loading onto any factor. Dropping item‐2(BANS‐6) revealed a single‐factor solution (variance 40.2%) and Cronbach’s α improved from 0.701(BANS) to 0.782(BANS‐6). FAST did not correlate with agitation(CMAI) and poor quality of life(QUALID), but BANS and BANS‐6 did. After adjusting for age, sex and comorbidities, BANS‐6 but not FAST was significantly associated with complications of severe dementia. A new index(comprising BANS‐6, malnourishment, age) was derived with superior mortality predictive performance (AUC = 0.68,95%CI = 0.60‐0.75) compared to BANS(AUC = 0.64,95%CI = 0.56‐0.71) and FAST(AUC = 0.52,95%CI = 0.44‐0.59).ConclusionThe 6‐item BANS(BANS‐6) outperformed FAST in predictive utility and was comparable to ADEPT’s previous mortality predictive performance (AUC = 0.68). BANS‐6 is psychometrically reliable and valid for assessing disease severity in community‐dwelling PWSD.
Implementation and dissemination of home and community‐based interventions for informal caregivers of people living with dementia: A systematic scoping review
Authors: Zhu Eden Meng , Buljac‐Samardžić Martina , Ahaus Kees , Sevdalis Nick , Huijsman Robbert 
Published: December 2023

AbstractBackgroundInformal caregivers of people with dementia (PwD) living at home are often the primary source of care, and, in their role, they often experience loss of quality of life. Implementation science knowledge is needed to optimize the real‐world outcomes of evidence‐based interventions (EBIs) for informal caregivers. This scoping review aims to systematically synthesize the literature that reports implementation strategies employed to deliver home‐ and community‐based EBIs for informal caregivers of PwD, implementation outcomes, and the barriers and facilitators to implementation of these EBIs.MethodsEmbase, MEDLINE, Web of Science and Cochrane Library were searched from inception to March 2021; included studies focused on “implementation science”, “home‐ and community‐based interventions” and “informal caregivers of people with dementia”. Titles and abstracts were screened using ASReview (an innovative AI‐based tool for evidence reviews) and data extraction was guided by the ERIC taxonomy, the Implementation Outcome Framework, and the Consolidated Framework for Implementation Science Research; each framework was used to examine a unique element of implementation.Results67 studies were included in the review. Multi‐component (26.9%) and eHealth (22.3%) interventions were most commonly reported, and 31.3% of included studies were guided by an implementation science framework. Training and education‐related strategies and provision of interactive assistance were the implementation strategy clusters of the ERIC taxonomy where most implementation strategies were reported across the reviewed studies. Acceptability (82.1%), penetration (77.6%) and appropriateness (73.1%) were the most frequently reported implementation outcomes. Design quality and packaging (intervention component suitability) and cosmopolitanism (partnerships) constructs, and patient’s needs and resources and available resources (infrastructure) constructs as per the CFIR framework, reflected the most frequently reported barriers and facilitators to implementation.ConclusionCurrent studies focused largely on intervention outcomes rather than implementation outcomes and lacked detailed insights on inner and outer setting determinants of implementation success or failure. Future dementia studies must prioritize implementation science for more contextually relevant findings and structurally examine the mechanisms through which implementation partners can strategically leverage existing resources and regional networks to streamline local implementation. Mapping local evidence ecosystems will facilitate structured implementation planning and support implementation‐focused theory‐building.
Diagnostic Performance of MRI‐based Alzheimer’s Disease Resemblance Atrophy Index and Plasma‐Based Biomarkers on Alzheimer’s Disease
Authors: Fu Siu Ting , Cai Yuan , Huang Junzhe , Liu Wanting , Shi Lin , Au Lisa Wing Chi , Ko Ho , Mok Vincent Chung Tong 
Published: December 2023

AbstractBackgroundAlthough positron emission tomography (PET) or cerebrospinal fluid measurements of amyloid and tau burden are available for the detection of Alzheimer’s disease pathology, such methods are invasive and not easily accessible. Recent studies show that Alzheimer’s Disease‐resemblance atrophy index (AD‐RAI), an MRI‐based machine learning‐derived biomarker, and plasma‐based biomarkers can be used as accurate biomarkers for Alzheimer’s disease pathology. We aim to evaluate the diagnostic metrics of AD‐RAI and plasma‐based biomarkers for detecting Alzheimer’s disease.MethodWe recruited 69 subjects from the CU‐SEEDS (The Chinese University of Hong Kong‐Screening for Early AlzhEimer’s DiseaSe) study who were stroke‐free and had different degrees of cognitive impairment: 8 cognitive unimpaired [CU], 26 with subjective cognitive decline [SCD], 21 with mild cognitive impairment [MCI] and 14 with dementia. All subjects underwent 11C‐ PIB and 18F‐T807 PET to measure pathological Aβ deposition (A+) and tau burden (T+). Subjects received structural MRI for deriving AD‐RAI. Plasma levels of Aβ40, Aβ42, total tau (t‐tau), phosphorylated tau at 181 (p‐tau181), and neurofilament light chain (NfL) were measured by Single Molecule Array (SiMoA) assays.ResultAmong 69 subjects (mean [SD] age, 67.7 [6.8] years; 28 men [40.6%]), 25 (36.23%) subjects were confirmed to be A+ and T+. AD‐RAI, plasma p‐tau 181, and plasma Aβ42 were associated with A+T+ after adjusting for age, gender, and education (p<0.01). AD‐RAI individually outperformed all plasma‐based biomarkers (AUC = 0.911; Sensitivity = 0.826; Specificity = 0.905). The combination of AD‐RAI, p‐tau181 and Aβ42 yielded the best diagnostic metrics for detecting A+T+ subjects (AUC = 0.957; Sensitivity = 0.870; Specificity = 0.929).ConclusionA panel of AD‐RAI, plasma p‐tau, and plasma Aβ42 might help with screening and diagnosis of Alzheimer’s disease.
Cerebrospinal fluid synaptic biomarkers in AT(N)‐based subgroups of Lewy body disease
Authors: Barba Lorenzo , Rumeileh Samir Abu , Halbgebauer Steffen , Bellomo Giovanni , Paoletti Federico Paolini , Gaetani Lorenzo , Oeckl Patrick , Massa Federico , Steinacker Petra , Parnetti Lucilla , Otto Markus 
Published: December 2023

AbstractBackgroundPatients with Lewy body disease (LBD) often show a co‐occurring Alzheimer’s disease (AD) pathology. Cerebrospinal fluid (CSF) biomarkers allow the detection in vivo of AD‐related pathological hallmarks included in the AT(N) classification system. Here, we aimed to investigate whether CSF biomarkers of synaptic and neuro‐axonal damage are correlated with the presence of AD co‐pathology in LBD and can be useful to differentiate LBD patients with different AT(N) profiles.MethodWe retrospectively measured CSF levels of AD core biomarkers (Aβ42/40 ratio, p‐tau, t‐tau) and of synaptic (β‐synuclein, α‐synuclein, SNAP‐25, neurogranin) and neuro‐axonal proteins (NfL) in 28 cognitively unimpaired participants with non‐degenerative neurological conditions and 161 participants with a diagnosis of either LBD or AD (at both mild cognitive impairment, AD‐MCI, and dementia stages, AD‐dem). We compared CSF biomarker levels in clinical and AT(N)‐based subgroups.ResultCSF β‐synuclein, α‐synuclein, SNAP‐25, neurogranin and NfL levels did not differ between LBD (n = 101, age: 67.2 ± 7.8 years, 27.7% females) and controls (age: 64.8 ± 8.6 years, 39.3% females) and were increased in AD (AD‐MCI n = 30, AD‐dem n = 30, age: 72.3 ± 6.0 years, 63.3% females) compared to both groups (p<0.001 for all comparisons). In LBD, we found increased levels of synaptic and neuro‐axonal degeneration biomarkers in patients with A+T+ (LBD/A+T+) than with A‐T‐ profiles (LBD/A‐T‐) (p<0.01 for all), and β‐synuclein showed the highest discriminative accuracy between the two groups (AUC = 0.938, 95%CI: 0.884‐0.991). CSF β‐synuclein (p = 0.0021), α‐synuclein (p = 0.0099) and SNAP‐25 concentrations (p = 0.013) were also higher in LBD/A+T+ than in LBD/A+T‐ cases, which had synaptic biomarkers levels within the normal range. CSF α‐synuclein was significantly decreased only in LBD patients with T‐ profiles compared to controls (p = 0.0448). Moreover, LBD/A+T+ and AD cases did not differ in any biomarker level.ConclusionLBD/A+T+ and AD cases showed significantly increased CSF levels of synaptic and neuro‐axonal biomarkers compared to LBD/A‐T‐ and control subjects. LBD patients with AD co‐pathology might, thus, experience similar degrees of synaptic dysfunction than pure AD cases.