bluuebunny/crossref_metadata_2025 huggingface dataset:
Interrogating the molecular interaction between apolipoprotein E and the beta‐amyloid peptide
Authors: Araujo Mateus V , Lourenco Mychael V , Torres Pedro H M
Published: January 2025

Background

The apolipoprotein ε4 (ApoE4) allele is a major risk factor for sporadic Alzheimer’s disease (AD) and was shown to promote amyloid‐β (Aβ) accumulation and mediate pathophysiological processes in AD. Although the molecular interaction between Aβ and ApoE is acknowledged, the precise nature of this interaction remains unclear. This study aims to explore the biophysical and biochemical nature of the interaction between Aβ and ApoE in the ε3 and ε4 isoforms.

Method

We initially reverted 5 point mutations to generate the original ApoE3 structure from its full‐length structure (PDB: 2L7B), by using the Swiss‐Model software. We then inserted the 112CtoR mutation to generate ApoE4. We further used a previously published open‐state structure of ApoE4. Three distinct Aβ42 structures (PDB: 1IYT, 6SZF, 1Z0Q) were used. Docking preparations were performed using ChimeraX with PDB2PQR and APBS used to generate electrostatic surfaces. ClusPro and Haddock software facilitated rigid and flexible molecular docking, respectively. This study performed nine dockings in total, selecting six suitable complexes for coarse‐grained molecular dynamics in triplicate using GROMACS.

Result

The Aβ42 structure that emulates a membrane‐associated environment (1IYT) provided the best fits in the molecular docking, followed by the pre‐transition to β‐sheet structure (1Z0Q). The “intermediate structure” (6SZF), a stage between the two other structures, resulted in unspecific docking. The molecular dynamics from the promising structures are being carried out to understand the different behavior and stability at pH 7.4. We are also undertaking additional dynamics experiments to investigate the influence of an acidic pH (5.5).

Conclusion

We initially confirmed the molecular interaction between Aβ42 and ApoE isoforms. This interaction is influenced by the local environment. Further results are expected to elucidate molecular details of this interaction hold potential to enhance our understanding of AD pathophysiology.
Targeting Endogenous Tau in a Human Tau Seeded Tauopathy Models Inhibits Tau Spread
Authors: Xu Hong
Published: January 2025

Background

Neurodegenerative diseases with the presence of tau pathology account for 90% of dementia in human patients, the most common of which is Alzheimer’s disease (AD). Although therapeutic approaches targeting tau and tau pathology are still under development, it remains unclear how tau targeting antibodies can inhibit the development of tau pathology.

Method

We hypothesize tau antibodies enter neurons and inhibit the seeding of tau pathology without direct interaction to the pathogenic tau seeds. To tackle this, we designed a study using the human tau seeds‐induced sporadic spreading model of tauopathy to evaluate the effect of a mouse tau‐specific antibody (mTau8) on tau spreading in vitro and in vivo.

Result

Our results show that mTau8 enters the cerebrospinal fluid by bypassing the blood‐brain barrier and effectively decreases AD‐tau‐seeded tau pathology in the wild‐type mouse and cell models. Moreover, the analysis of the spread of tau pathology in vivo and live imaging study in vitro suggest a mechanism that is independent of neutralizing the pathogenic tau seeds.

Conclusion

Our findings provide a mechanistic view of antibody‐based tau therapy for treating tauopathies.
Neuronal Cell‐Type Susceptibility in the Ventral Subiculum of 5xFAD Mice
Authors: Pachicano Maricarmen , Khanjani Neda , Hurtado Angela , Mehta Shrey , Smith Zion MK , Bienkowski Michael S
Published: January 2025

Background

Identification of cell‐type vulnerability in Alzheimer’s Disease (AD) is critical to the clinical development of targeted treatments. Neurodegeneration of the subiculum (SUB) is an early biomarker of AD, but it is unknown if specific SUB cell‐types are susceptible to AD neurodegeneration. In the 5xFAD mouse model, significant cell loss occurs within the SUB by 8 months of age. Our previous work creating the mouse Hippocampus Gene Expression Atlas (HGEA) has defined cell‐type specific gene markers that can identify cell‐types within the SUB (Bienkowski et al, 2018). Within the ventral SUB (SUBv), three relatively discrete layers of gene expression define cell‐type organization. Quantification of SUBv cells identified by these gene markers can be utilized to determine SUB cell‐type susceptibility across disease timepoints.

Method

To label SUBv gene expression patterns, we used RNAscope single molecule fluorescent in situ hybridization (smFISH) to label and quantify individual RNA transcript levels within SUB cell types. 5xFAD and wildtype (WT) mice (2, 6, 12, and 14 mo.) were perfused, dissected, and coronally sectioned into 20µm thick sections. SUBv tissue sections were hybridized with probes designed to target SUBv gene expression markers using RNAscope Multiplex Fluorescent V2 kit (Advanced Cell Diagnostics). Tissue sections were counterstained for DAPI cytoarchitecture, imaged at 40X with a spinning disk confocal microscope, and quantification was performed using QuPath (Quantitative Pathology and Bioimage Analysis) cell segmentation and SCAMPR analysis software (Ghoddousi et al, 2022).

Result

RNAscope labeling produced robust datasets enabling quantification of single RNA transcript levels for each gene expression marker within 10,000+ SUBv cells. At late disease timepoints, we found that the number of SUBv layer 3 cells were significantly diminished compared to WT controls suggesting that SUBv layer 3 cells are primarily susceptible to AD neurodegeneration. No significant difference was found between 5xFAD and WT mice at 2 mo. of age.

Conclusion

In the SUBv, layer 3 neurons are primarily susceptible to AD neurodegeneration in the 5xFAD mouse model. Future studies will investigate the transcriptomic changes that occur within SUBv layer 3 neurons that precede death.
Genomic landscape of RNA editing and genome regulatory signatures in aged human brains with Alzheimer’s disease
Authors: Gupta Amit Kumar , Martin William , Feng Yayan , Cheng Feixiong
Published: January 2025

Background

RNA editing represents one of the most common post‐transcriptional modifications that contribute to transcriptomic diversity, impacting RNA stability and regulations. To this end, we sought to investigate brain region‐specific RNA‐editing signatures (RNA‐editings) associated with Alzheimer’s disease (AD) and the human aged brain with regulatory elements.

Method

We investigated the genome‐wide landscape of RNA‐editings from 4,208 (1,364 AD case vs. 742 healthy controls [HC]) RNAseq samples across nine brain regions from three large biobanks (Mount Sinai, Mayo, ROSMAP) cohorts. We performed association and enrichment analysis of RNA‐editing enriched genes. We further identified sex‐specific and APOE4‐specific RNA‐editing. We inspected brain‐wide cis‐regulatory variants (RNA editing quantitative trait loci or cis‐edQTLs) considering two different cis‐distances (±100 KB and ±1 MB) utilizing matched whole‐genome genotyping data for 3,627 samples. Age, PMI, gender (sex), and APOE4 status are used as adjusting covariates. GWAS and cis‐edQTLs (1 MB) colocalization were performed with downstream functional and genome regulatory analysis.

Result

We have identified ∼14,687 significant RNA editing events across nine brain regions while comparing AD cases versus HC. We showed that two brain regions namely the parahippocampal gyrus (PHG), and cerebellum cortex (CBE) exhibit the highest editing abundance followed by the inferior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC). Overall, we pinpointed 127 genes harboring significant RNA editing loci (5*10‐3) shared by two or more brain regions. Further, we uncovered a large repertoire (9650‐30386) of cis‐edQTLs (distance ±100 KB) among distinct brain regions potentially influencing RNA editing sites. A total of 76 colocalized GWAS and cis‐edQTL (±1 MB) genomic variants in about 43 genes were identified. Some of these genomic loci (genes + variants) are CLU (rs867230), DGKQ (rs4690197, rs3733347), TRANK1 (rs7624498), BIN1 (rs1060743), PICALM (rs639012), FERMT2 (rs17125924), and TSPAN14 (rs7098414). Functional enrichment analysis shows these genes are allied to synaptic cycles, amyloid‐beta formation, neurofibrillary tangle, immune pathways, AD disease pathways, protein metabolism and signal transduction.

Conclusion

Our study offers brain‐wide region‐specific and common RNA editing signatures in AD. This underlying altered landscape of RNA‐editing and cis‐edQTLs may account for the genetic etiology and pathobiology of AD and other neurodegenerative diseases.
Feasibility of implementing time‐restricted eating in women with mild cognitive impairment
Authors: Thomas Matthew , Jicha Gregory A , Harp Jordan P. , Kern Philip A , Sears Dorothy D , James Dara L , Katsumata Yuriko , Pendergast Julie S
Published: January 2025

Background

Disruption of sleep and circadian rhythms are associated with cognitive decline, preclinical Alzheimer’s Disease (AD) pathology, and increased risk of dementia. Alleviating circadian rhythm and sleep disruption may improve cognition and reduce the progression of AD and related dementias (ADRD). Time‐restricted eating (TRE), a circadian behavioral intervention that corrects disrupted eating rhythms by aligning food intake to the daytime, has demonstrated improvements in metabolic dysfunction and sleep quality. Individuals who adhere to TRE are less likely to have cognitive impairment compared to those who consume meals with no time restrictions. To date, no studies have investigated the potential efficacy of a TRE intervention to improve cognition among individuals living with cognitive impairment. This study will determine the feasibility of TRE in women with mild cognitive impairment (MCI).

Method

Women diagnosed with MCI will be recruited from the University of Kentucky Sanders‐Brown Center on Aging cohort to participate in a pre‐post study. Data will be collected during a 2‐week baseline period and an 8‐week TRE intervention period. During baseline, measures of cognition, food timing, activity/sleep, and metabolic parameters will be collected. For the duration of the enrollment, first and last calorie intake times will be collected from participants with an SMS texting system. Participants with mean daily calorie durations of at least 12 hours and calorie intake after 8:00pm on the majority of nights during baseline will be eligible for the TRE intervention. During the TRE intervention, each participant will self‐select a 10‐h window (ending by 8:00pm) during which they will consume all daily calories during the 8‐week TRE intervention. At the end of the intervention, baseline measures will be repeated. Adherence to the TRE protocol is the primary outcome of this study.

Result

We anticipate enrolling 22 participants in a screening, baseline phase to enroll 15 eligible participants for the TRE intervention.

Conclusion

This pilot study will provide insight into the feasibility of conducting a TRE intervention among women living with MCI and provide preliminary data to calculate sample size for a future randomized controlled trial testing the efficacy of TRE in improving, or preventing further decline, in cognition.
Total neuron counts in vulnerable and resilient entorhinal subregions
Authors: Rosenblum Emma W , Augustinack Jean
Published: January 2025

Background

Neuron loss exceeds tau tangle formation (Gomez‐Isla et al. 1997) and p‐tau vulnerability differs by layer and subfield in entorhinal cortex (Llamas‐Rodriguez et al., 2022). Some subfields succumb to tau early and other subfields later in Alzheimer’s disease. Investigating neuron loss by subfield is pivotal for early diagnosis.

Method

We applied the optical fractionator to count neurons (West, 1991) using Stereoinvestigator (MicroBrightField Inc) in layer II subfields, ER, EI, and ECs, in n = 14 postmortem samples. The samples were preclinical controls, including 6 females, 8 males. A sampling grid (450 µm x 450 µm) with 75 µm x 75 µm counting frame was randomly overlaid. The neurons were counted using a 100x objective (Figure 1). The disector height was 10 µm; with guard zones 3 µm each. Counting inclusion criteria were 1) nucleolus in focus, 2) within inclusion lines, 3) did not touch exclusion lines. The tissue thickness was collected at each counting site (average 20.4 µm). The average coefficient of error was 0.08.

Result

Total neuron counts in EI was 172,429, with ER at 133,161 and EC lower at 103,493 (averaged across samples). Total neuron counts for EI were significantly different than ECs (one‐way ANOVA, p = 0.0033, Tukey’s multiple comparison test, p = 0.0023). Total neuron number from summed subfields did not correlate with age (r = ‐0.2816). Total neuron count for males and females differed but difference was not significant (t‐test, p = 0.5669). No significant differences between total neuron number and the preclinical stages (control, Braak stage I and II samples, averaged) (ANOVA, p = 0.8732).

Conclusion

These findings establish a baseline for total neuron number in specific entorhinal subregions of vulnerability (e.g., ECs) and resilience (e.g., ER, EI) at preclinical stage. These data support a previous report that total neuron number in frontal and temporal cortices does not decrease with age (Freeman et al.,2008). Related studies have applied the NvVref method (Gomez‐Isla et al. 1996, Gomez‐Isla et al. 1997, Freeman et al. 2008), but with varying tau pathology at this stage, optical fractionator is the ideal approach. The total neuron number was consistent with age, however, individual variability in the sample set was evident.
The SMOC1 proteomics network M42 controls multiple signaling modalities, brain homeostasis and toxicity in fly Alzheimer’s disease models
Authors: Li‐Kroeger David , Al‐Ramahi Ismael , Smith Nathaniel , Marella Aditi , Amoh Bismark K , Saladi Saathwik , Botas Juan , Seyfried Nicholas T , Levey Allan I. , Shulman Joshua M
Published: January 2025

Background

Alzheimer’s disease (AD) has a complex etiology where insults in multiple pathways conspire to disrupt neuronal function, yet molecular changes underlying AD remain poorly understood. Previously, we performed mass‐spectrometry on post‐mortem human brain tissue to identify >40 protein co‐expression modules correlated to AD pathological and clinical traits. Module 42 has the strongest correlation to AD pathology and consists of 32 proteins including SMOC1, a predicted driver of network behavior and potential biomarker for AD. SMOC1 is a matrisomal protein with conserved roles in modulating TGF‐Beta and wnt signaling during development, yet remains unstudied in the brain.

Methods

We evaluate M42 using a high‐throughput robotic screening platform and video assisted software, enabling quantitative assessments of neurological function to identify proteins that modify Aβ‐ or tau‐induced neurodegeneration. We then focus on dSMOC1 using Drosophila genetics and cell biological approaches to determine its role in the brain. Finally, we use Mass Spectrometry to identify protein changes in the brains of dSMOC1‐/‐ flies.

Results

Our screening assay identified 20 genes from M42 that modify tau toxicity and 5 for Aβ, including dSMOC1 and components of Wnt and TGF‐β signaling pathways. We find dSMOC1‐/‐ null flies suffer severely decreased survival and climbing defects upon aging. In the brain, dSMOC1 expression occurs primarily in glial cells while protein localizes around neuronal cell bodies, consistent with its role as a matrisomal protein. We show alteration of glypican levels in dSMOC1‐/‐ brains. Glypicans modulate Wnt and TGF‐β signaling further supporting a role connecting M42 in AD biology. Finally, we used mass spectrometry to determine protein changes in brains of dSMOC1‐/‐ flies and found perturbations in ECM/receptor interactions, proteostasis, KREBs/TCA cycle, and oxidative phosphorylation. Additional data suggests an age dependent shift from oxidative phosphorylation to glycolysis may compensate for reduced ATP levels in dSMOC1‐/‐ flies.

Conclusion

The M42 protein module contains multiple proteins with links to AD. Multiple M42 proteins interact with specific AD triggers including SMOC1, wnt and TGF‐β signaling components. The genetics, proteomics, and cell biological data combine to support a mechanistic hypothesis where changes in SMOC1 levels disrupt critical signaling pathways leading to disruptions in metabolism affecting neuronal function.
Single‐Microglia Transcriptomic Transition Network‐based Prediction and Real‐world Patient Data Validation Identifies Ketorolac as a Repurposable Drug for Alzheimer’s Disease
Authors: Xu Jielin , Danziger Michael , Xu Zhenxing , Zhang Chengxi , Zhou Yadi , Hou Yuan , Karavani Ehud , Shimoni Yishai , Pieper Andrew A. , Leverenz James B , Cummings Jeffrey L. , Hu Jianying , Wang Fei , Rosen‐Zvi Michal , Cheng Feixiong
Published: January 2025

Background

Microglia have been implicated as a key aspect of the pathology of Alzheimer’s disease (AD). However, high microglial heterogeneities, including disease‐associated microglia (DAM), tau microglia (tau‐pathology related), and neuroinflammation‐like microglia (NIM), hinder the development of microglia‐targeted treatment.

Method

In this study, we integrated ∼0.7 million single‐nuclei RNA (snRNA)‐seq transcriptomes derived from AD patient frozen brain samples using a variational autoencoder. We used trajectory analysis to identify microglial subtypes across AD progression, including DAM, tau microglia, and NIM. We conducted transition network analysis to identify putative molecular drivers of microglial subtypes across varying severities of AD and disease progression under the human protein‐protein interactome network. We prioritized candidate drugs by specifically targeting transition modules using drug‐gene signature enrichment analysis and we further validated drugs using two independent real‐world patient databases (MarketScan [172 million insured individuals] and INSIGHT Clinical Research Network [15 million patients]).

Result

We showed that tau microglia were significantly associated with synaptic processes. Compared to DAM, upregulated genes of NIM were significantly enriched with key immune pathways (e.g., toll‐like receptor). We identified potential AD pathobiological regulators (e.g., SYK, CTSB, PRKCA, INPP5D, and ADAM10) in transition networks between DAM and NIM. Via network‐based drug repurposing prediction by specifically targeting NIM subpopulations and real‐world patient data‐based validation, we identified that usage of ketorolac (anti‐inflammatory medicine) is significantly associated with reduced AD incidence in both MarketScan (hazard ratio [HR] = 0.81, 95% confidence interval [CI] 0.69‐0.91, p‐value = 0.002 after adjusting > 400 covariates) and INSIGHT (HR = 0.83, 95% CI 0.77‐0.92, p‐value = 0.004 after adjusting 267 covariates) patient databases.

Conclusion

This study offers insights into pathobiology of AD‐relevant microglial subtypes and identifies ketorolac as a potential anti‐inflammatory treatment for AD.
Investigating the neural ensembles underlying sundowning in an Alzheimer’s disease mouse model
Authors: Jin Michelle , Hunsberger Holly C , Whye Alicia R , Ogundare Simon , Alvarado Nicole , Sorid Sophia , Lanio Marcos , Denny Christine Ann
Published: January 2025

Background

As high as 50% of Alzheimer’s disease (AD) patients experience “sundowning”, which refers to an increased severity of neuropsychiatric symptoms (NPS), including agitation, confusion, and anxiety, selectively in the evening. Although sundowning significantly influences the decision to institutionalize patients, few preclinical models of this phenomenon exist and the underlying neural mechanisms are unknown. Here, we establish a model of sundowning by phenotyping the sleep‐wake cycle and anxiety and exploratory behavior at different times of day in an AD mouse model. We then investigate differences in brain‐wide activity patterns present at sundown and sunrise time in AD and control (Ctrl) mice.

Method

We recorded sleep‐wake activity in control (Ctrl) and APP/PS1de9 (AD) mice across 2‐, 6‐, 12‐, and 24‐month‐old male and female mice. Next, we measured anxiety/locomotion in 2‐, 12‐, and 24‐month‐old Ctrl and AD mice during the murine evening (ZT22‐0, sundown) and murine morning (ZT12‐14, sunrise) using the elevated‐plus maze (EPM) and open field (OF) assays. To identify brain‐wide ensemble patterns mediating sundowning, we bred the ArcCreERT2 x EYFP activity‐dependent tagging strategy with the AD line, which allows for temporally precise labelling of two active neural populations. We then applied a custom pipeline to label and map ensembles active during exposure to the EPM at sundown and sunrise.

Result

We found a degradation in strength of sleep‐wake rhythms with aging selectively in AD mice. We further found that older AD mice (24‐month‐old males and 12‐ and 24‐month‐old females) preferentially explore the open arms of the EPM and display hyperlocomotion in the OF (24‐month‐old males and 24‐month‐old females) selectively during sundown. Network analysis of mapping results showed selective decreases in topological measures of connectivity, such as degree, clustering, and efficiency, in AD mice at sundown but not sunrise time when compared with Ctrl mice.

Conclusion

We identified a striking behavioral abnormality in an AD mouse model resembling “nighttime wandering” and agitation seen in sundowning patients. Mapping of concurrent brain‐wide activity patterns showed global decreases in network connectivity at sundown time in contrast to sunrise time in AD mice, revealing novel insights about the neural patterns underlying this debilitating syndrome.
Neurocognitive Sequelae of COVID‐19 in Older African American Adults
Authors: Walker Tiffany A , Elchommali Jannah , Han Jenny E , Truong Alexander , Hajjar Ihab , Goldstein Felicia
Published: January 2025

Background

African Americans (AA) are disproportionately affected by Long COVID, highlighting the need for targeted research to understand the enduring consequences of COVID‐19 within this community. Among the array of symptoms associated with post‐acute sequelae of SARS‐CoV‐2 (PASC), cognitive impairments emerge as a significant concern affecting up to 19% of COVID survivors. In this study, our goal is to comprehensively characterize the specific cognitive domains impacted in older AA adults.

Method

This prospective, cohort study collected sociodemographic data and conducted a telephone‐based neurocognitive battery on AA adults aged ≥ 50 years with persistent symptoms ≥ 12 months following confirmed SARS‐CoV‐2 infection, measuring cognitive domains of global function (Blind Montreal Cognitive Assessment (MoCA)), attention (Blind MoCA Attention subscale, Number Span Forward), memory (Hopkins Verbal Learning Test (HVLT), Craft Story 21)), and executive function (Number Span Backward). Z‐scores were calculated based on the means and SDs of demographically comparable normative samples. Impaired performance was defined as z scores > ‐1.5.

Result

We enrolled 75 AAs with a median age of 58 years (range 51‐73); 65 (86%) were female, and 69 (92%) had a medium‐high social vulnerability index. Forty (53%) participants exhibited global impairment on Blind MOCA. 54 (72%) had impairment on ≥ 1 attention test, including 53 (70%) with impaired MoCA Attention subscale scores and 5 (6%) with impaired Number Span Forward testing. Fifty‐three (70%) had impairment on ≥ 1 memory test, including 42‐48% with impaired HVLT and 45‐48% with impaired Craft Story 21. Four (5%) had impaired executive function on Number Span Backwards testing.

Conclusion

We demonstrate persistent COVID‐19 cognitive impairments impacting memory, attention, executive function, and global function within a socioeconomically disadvantaged older AA adult population. Limited access to healthcare resources in medically underserved areas can lead to delayed or inadequate COVID‐19 treatment, potentially increasing the risk of neurological complications and cognitive deficits in African American populations.
Mutations in Tau’s Proline Rich Domain Affect its Protein Interactions
Authors: Koutures Anne , Katz Brittany , Hwang Kaylin , Cohn Whitaker , Addo‐Osafo Kwaku , Vossel Keith
Published: January 2025

Background

Epileptic activity is increasingly recognized as a contributor to Alzheimer’s Disease (AD) pathology. In AD models, endogenous tau contributes to epileptic activity and associated cognitive deficits through mechanisms that are not fully understood. Increased attention is being directed towards tau’s interactions with proteins that regulate neuronal activity, particularly tau’s proline rich domain and its binding to SH3‐containing proteins. However, the impact of mutations in tau’s proline‐rich region on other protein interactions remains unclear.

Method

We assessed mutations in tau’s proline rich domain in two mouse lines: AxxA6 (P‐to‐A substitutions in 6th PxxP motif in tau) and R221A (R‐to‐A substitution at amino acid corresponding to 221 in human 2N4R tau). These mutations block tau’s interactions with SH3‐containing proteins, including PLCγ1 and p85α/PI3K. Co‐immunoprecipitation (Co‐IP) of tau from cortical brain tissue was confirmed and analyzed by mass spectrometry. We compared protein abundance ratios to wild type tau mice within each mouse line. Significant (p<.05) tau‐baited protein interactions were further explored within literature and the String Database.

Result

The R221A line produced 143 and 120 significant proteins within the heterozygous and homozygous groups, respectively. Many identified proteins are strongly associated with processes such as microtubule organization, postsynaptic structure, and mitochondrial functions. The AxxA6 line produced 158 and 126 significant proteins within the heterozygous and homozygous groups, respectively. Many identified proteins are involved in cellular trafficking and are strongly associated with processes such as glutamate catabolic processes and microtubule protein localization. Notably, many proteins identified in both lines are involved in prion disease and vascular endothelial growth factor (VEGF) signaling pathways.

Conclusion

Co‐IP mass spectrometry of the R221A and AxxA6 mouse lines revealed that mutations in tau’s proline rich domain to affect tau’s interactions with multiple proteins. Of the significant proteins, multiple are related to microtubule, metabolic, synaptic, and mitochondrial activity, and many are found within prion disease pathways and VEGF signaling pathways. Interestingly, PLCγ1 and p85α/PI3K, are also implicated in VEGF signaling pathways. These findings highlight the importance of further investigating the possible relationships between noted cellular processes and biological pathways and tau‐protein interactions in familial AD.
Bi‐phasic Microtubule Defects in Tauopathy: Treatment Implications
Authors: Sun Xiaohuan , Baas Peter W , Karch Celeste M. , Qiang Liang
Published: January 2025

Background

In tauopathies, such as Frontotemporal Dementia (FTD), tau loses association with microtubules (MTs) and forms neurofibrillary tangles. Tau is an abundant MT‐associated protein in neurons, which essentially regulate MT properties. Because pathological tau binds less avidly to MTs, which was thought to reduce the levels and stability of axonal MTs. However, this idea is based on the dogma of functional tau as a MT stabilizer, which was challenged by some recent studies via tau‐knockdown strategies. The situation is further confounded in tauopathies because the pathological tau may elicit certain gain‐of‐toxicities on axonal MTs.

Method

To investigate this matter in a more disease‐relevant scenario, we used 1) cerebral organoids generated from an FTD‐patient derived induced pluripotent stem cells bearing a tau mutation (P301S/P301L/R406W) and their isogenic control corrected by CRISPR‐Cas9; and 2) postmortem brain tissues from a cohort of FTD patients, as our models.

Result

Elevated soluble tau was identified in tauP301S organoids during the early development with an increased ratio of mature/immature isoforms (4R‐tau/3R‐tau); whereas an overt reduction in soluble tau was identified in late‐stage developed organoids and postmortem FTD brains accompanied by increased aberrant PTM‐modifications of tau. Strikingly, MAP6, a bona fide MT stabilizer that competes with tau’s effects on MTs, presented opposite changes in its levels in tauP301S/R406W organoids at the early‐ and late‐developed stages also in the postmortem brain model as the late‐developed stage of disease. Such bi‐phasic changes in tau and MAP6 were consistently reflected by the predicted changes in MT dynamics. Interestingly, certain neurodegenerative features recapitulated in tauP301S organoids were ameliorated by novel corrective strategies such as tau antisense oligonucleotides in the early stage of disease.

Conclusion

We conclude that the biphasic changes in tau pathology with the subsequent MT defects may underlie the progressive neurodegeneration in tauopathy. Thus, therapies to correct tau and MT abnormalities in tauopathy must be vetted for the specific stages of the disease
Unraveling the interplay between tau seeding and autophagy processes
Authors: Deckert Annika , Böddrich Annett , Diez Lisa , Schmitt Matthias Jürgen , Nevado Juan Carlos Company , Beetz Stephanie , Brusendorf Lydia , Serresi Michela , Wegmann Susanne , Gargiulo Gaetano , Wanker Erich
Published: January 2025

Background

The microtubule‐associated protein tau is the most commonly misfolded protein in neurodegenerative disorders including Alzheimer’s disease and other related tauopathies. These neurological illnesses are hypothesized to share a common mechanism of disease progression, where pathogenic aggregates or ‘seeds’ of the tau protein function as templates promoting misfolding of functional, soluble tau protein. Under this premise, therapeutic strategies that modulate the seeding cascade, have high potential to interfere with the disease process.

Method

While increasing evidence is emerging that tau pathology progression is based on seeding and spreading mechanisms reminiscent of prion protein pathology, an in‐depth understanding of the cellular pathways and cofactors that drive disease progression is, however, still lacking. In order to identify tau seeding modulators, a previously described HEK293T biosensor cell line1 was applied, able to sensitively detect tau seeding. To understand the self‐propagation process, I exploited this cell model to performed a pooled genome‐wide loss‐of‐function CRISPR screen2, allowing the identification of proteins that robustly influence tau seeding.

Result

Amongst the top hits were many genes involved in autophagy and specifically autophagosome formation. Building on these insights, I am working towards a mechanistic understanding how the loss of function of the ATG genes impacts tau seeding in mammalian cells and in a Drosophila melanogaster model.

Conclusion

Together, my in vitro and in vivo studies are starting to unravel the molecular details of the interplay between tau seeding and autophagy. These studies have the ability to reveal novel strategies to reduce the toxicity of tau aggregates by stimulating the activity of the autophagic machinery. Research approaches addressing tau in general, and tau seeding more specifically, have enormous potential to provide highly innovative, disease‐modifying first‐in‐class therapeutics for AD.

References

1) Holmes BB et al. (2014) “Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci USA. 111: E4376‐E4385

2) Doench JG et al. (2016) “Optimized sgRNA design to maximise activity and minimise off‐target effects of CRISPR‐Cas9.” Nat. Biotechnol. 34: 184‐191
Neuronal hypofunction and network dysfunction in a mouse model at early stage of tauopathy
Authors: Ji Changyi , Yang Xiaofeng , Lin Yan , Eleish Mohamed , Sigurdsson Einar M.
Published: January 2025

Background

Abnormal neuronal activity was observed in awake and behaving tauopathy mice using two‐photon calcium imaging. Our previous study has revealed the relationship between tau pathology and altered neuronal calcium dynamics within the motor cortex of JNPL3 tauopathy mice at different stages of disease progression, specifically at 6 and 12 months of age (Wu Q et al, Neurobiol. Dis. 2021; Ji C et al, Alzheimers Dement 19, e074196; Ji C et al, Alzheimers Dement 18, e069415). However, network activity in tauopathy models remains less studied. Furthermore, the mechanisms responsible for the altered neuronal and network activity warrant further investigation.

Methods

Somatic calcium activity in the motor cortex of 6‐month‐old homozygous JNPL3 mice and age‐matched wild‐type controls was imaged using two‐photon microscopy, when the animals were resting versus running. Neuronal Ca2+ activity profiles and synchrony were analyzed. To explore the mechanisms underlying the altered neuronal and network activity, neuronal excitability and synaptic transmission were assessed by electrophysiological recordings in acute brain slices.

Results

We observed neuronal hypoactivity in the motor cortex of 6‐month‐old JNPL3 mice, when the animals were at rest or running on a treadmill. Neuronal Ca2+ activity exhibited enhanced synchrony and dysregulated responses to the running stimulus in JNPL3 mice. Furthermore, electrophysiological recordings in these motor cortical neurons of acute brain slices revealed a reduction in spontaneous excitatory synaptic transmission in pyramidal neurons and enhanced excitability of inhibitory neurons. These findings are likely linked to hypofunctional neurons and altered network activity in JNPL3 tauopathy mice.

Conclusion

In the JNPL3 tauopathy mouse model, a reduction in neuronal Ca2+ activity was observed in the motor cortex of awake and behaving animals during the early stage of tauopathy. This neuronal deficit was more pronounced under running conditions. The presence of tau pathology affected the local neuronal circuitry, as evidenced by an increased basal Ca2+ activity synchrony and altered profiles of running‐related neuronal responses in the motor cortex. Underlying mechanisms may be linked to impairments in excitatory synaptic transmission and altered excitatory/inhibitory balance in this region, resulting from the accumulation of pathological tau.
Mild parkinsonian signs and incidence of Motoric Cognitive Risk syndrome
Authors: Leroy Victoire , Emmeline Ayers , Verghese Joe
Published: January 2025

Background

Mild parkinsonian signs (MPS) are prevalent in older adults and linked to an increased risk of dementia. However, their association with Motoric Cognitive Risk syndrome (MCR), a pre‐dementia syndrome characterized by slow gait speed and cognitive complaints, is unclear. This study aims to examine the association of MPS with incident MCR.

Method

Non‐demented older adults without Parkinson’s disease were monitored annually (average follow‐up 30 months). We excluded participants with MCR at baseline and dementia incidence without previous MCR, as non‐cases. MPS were defined at baseline by the presence of bradykinesia, rigidity, or rest tremor rated by a study clinician using the Unified Parkinson’s Disease Rating Scale (UPDRS). MCR was diagnosed using established criteria at baseline and follow‐up. The association of baseline MPS and incident MCR was examined using survival analysis and reported as hazard ratio and 95% confidence intervals (CI).

Result

Of the 580 participants, 227 (39.1%) had MPS and 44 (7.5%) had MCR at baseline. Of the 513 initially MCR‐free participants, 46 (8.9%) developed incident MCR. Incident MCR cases had a higher prevalence of MPS at baseline compared to participants who did not develop MCR (OR adjusted for age, geriatric depression scale (GDS) score, and stroke history = 3.8, 95% CI 1.8‐8.2), particularly bradykinesia (52.3% vs. 19.0%; p<0.001) and rigidity (54.5% vs. 28.1%; p<0.001). They were older (p<0.001), more disabled (p<0.001), and had more strokes (p = 0.005), and depressive symptoms (p<0.001) compared to individuals who did not develop MCR. Participants with MPS at baseline had a greater risk of developing incident MCR (HR adjusted for age, GDS score, and stroke history = 3.7, 95% CI 1.8‐7.7).

Conclusion

MPS predicted the onset of MCR, suggesting a significant role in the pathogenesis and in improving early assessment of risk for MCR.
Exploring the coding rare variants in Alzheimer’s disease
Authors: Cheng Po‐Liang , Lee Wan‐Ping
Published: January 2025

Background

People leverage single‐variant association test to systematically evaluate common genetic variants (minor allele frequency 0.5% < [MAF) < 5%) for complex disease, such as Alzheimer’s disease (AD). Rare variants (MAF < 1%) could explain additional disease risk and are known to play an important role in the diseases. Unlike common variants, performing traditional single‐variant analysis on rare variants is often underpowered for general study sample sizes. A satisfied power for using single‐variants analysis on rare variants requires extremely large sample sizes that are often economically unaffordable. The alternative method to study the association between AD and rare variants was using aggregative testing that evaluate association for multiple variants in a biologically relevant region, such as a gene. However, the aggregative testing could only determine a set of variants instead of precisely determined the specific causal variant. Therefore, we try to use a new approach to identify coding AD causal variants.

Method

We first explored the case‐only coding rare variants in two independent datasets (ADSP with 16905 whole‐genome‐sequencing samples and ADGC with 38271 genotype samples that imputed by TOPMed). Then, we filtered variants that have at least two carriers in both datasets and CADD > 20. We further utilized STRING to build the protein‐protein interaction network for finding out the relation strength to known AD genes for those variants located in non‐conventional AD genes. Genes of the candidate rare variants were used to construct the protein‐protein interaction network with known AD genes. Non‐conventional AD genes that linked at least to five known AD genes, genes expressed in brain region, or neuron cells were selected and through literature searching to determine as potential novel AD genes.

Result

Through this approach, we identified seven coding rare variants in two known AD genes, SORL1 and CASP7, and in five novel AD genes, W LRP2, SPAG9, LEF1, PI4KA and USH2A. These potentially causal variants of AD could be further validated by biological functional assay in the future.

Conclusion

The new approach could help us to explore rare variants and discovered potential novel genes that might contribute large impact in causing AD.
Central auditory abilities are associated with cognitive and structural neuroimaging markers of Alzheimer’s disease dementia
Authors: Lad Meher , Griffiths Timothy , Taylor John‐Paul
Published: January 2025

Background

Hearing loss is associated with cognitive and neuroimaging markers of Alzheimer’s disease dementia but it is unclear how specific measures relate to these after accounting for a range of hearing abilities.

Method

200 participants (155 cognitively normal, 25 mild cognitively impaired and 20 Alzheimer’s disease dementia) underwent auditory testing (peripheral and central abilities), cognitive testing and MR scanning (structural and diffusion‐weighted sequences) to evaluate the relationship between hearing, cognition and imaging brain measures.

Result

Central auditory measures such as speech‐in‐noise perception and auditory memory for longer durations were associated with cognitive impairment across the Alzheimer’s disease continuum and specific auditory measures were independently associated with morphometric and diffusion‐weighted brain measures.

Conclusion

Auditory cognition could serve as a unique marker of cognition in Alzheimer’s disease dementia and reflects imaging‐derived brain changes potentially related to neurodegeneration.
Immunotherapy targeting toxic Tau reduces and mitigates cognitive decline, and senescence in a human Tau mouse model
Authors: Al‐Shaebi Fadhl , Senapati Sudipta , Sciortino Alessia , Farag Marina , Samples Madison , Xavier Rhea , Kayed Rakez
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized by the accumulation of tau protein in the brain, which forms neurofibrillary tangles and contributes to the gradual deterioration of brain function. As a consequence, cellular senescence occurs, leading to cognitive impairment and hastening the aging process. Immunotherapies targeting Aβ and other protein aggregates are also being developed in the meantime. This study looks at immunotherapy in a Mapt (hTau) mouse model. This could become a useful immunological treatment in the future by lowering inflammation and cellular senescence that come with getting older.

Method

Mapt (hTau) mice were inoculated in the hippocampus with 1 µg of brain‐derived Tau oligomers (BDTOs) from AD patients. After seven months, mice were injected in the tail vein with 120 µg of in‐house mouse monoclonal anti‐toxic tau antibodies (TTCM1‐2 and TOMA1‐4) or IgG isotype control. Mice were evaluated for cognitive and motor function before euthanasia, and brain neuropathology was investigated with immunohistochemistry, immunofluorescence, and western blot techniques.

Result

Treatment with anti‐toxic tau antibodies reduced total tau levels and tau phosphorylation in the brain. Furthermore, immunotherapy reduced inflammation and cellular senescence markers.

Conclusion

The observed decrease in tau aggregates following immunotherapy indicates that the mechanisms responsible for tau phosphorylation and/or aggregation may have been altered. Additionally, the decrease in senescence and inflammation markers suggests that immunotherapeutic strategies targeting tau are a promising approach in the management of tauopathies.
Meta‐analysis of NIH Alzheimer’s Disease‐Related Dementias (ADRD) programs responsive to the National Plan to Address Alzheimer’s Disease (AD)
Authors: McCartney Amber J , Astacio Herson , Shukla Arvind , Yin Xiling , Dodson Sara , Bryant Erin , Corriveau Roderick A
Published: January 2025

Background

AD/ADRD diseases currently impact more than 6 million people in the US. Rare forms of AD/ADRD are caused directly and unambiguously by genetic mutations. However, most AD/ADRD burden is complex in etiology and thought to result from an interplay among multiple incompletely understood genetic, biochemical, lifestyle, environmental and psychosocial risk factors. Moreover, risk factors interact with other health factors to impact AD/ADRD outcomes. For example, while the most common dementia diagnosis is AD, research over the past decade revealed most people with a diagnosis of AD have multiple brain pathologies, other comorbidities, and many people diagnosed with clinical AD do not have AD pathology at all. This new knowledge highlights the importance of better understanding dementia syndromes, and the relationships among them, to increase chances of developing effective interventions. The NINDS partners with the NIA, the NIH lead for AD/ADRD, in the NIH response to the National Plan. NINDS leads ADRD including frontotemporal dementia (FTD), Lewy body dementias (LBD), vascular contributions to cognitive impairment and dementia (VCID) and multiple etiology dementias (MED). This project aims to evaluate NIH and the ADRD field’s responsiveness to ADRD research milestones from triennial NINDS ADRD Summits by mapping NIH‐funded research activities to ADRD milestones.

Method

The approach used text‐based analysis/mining of grant titles, abstracts, and specific aims to map awards and activities to ADRD milestones. Mappings were vetted by expert concurrence. The ongoing study includes new or competitively renewed NIH ADRD awards starting from fiscal year 2017. Findings help NIH to better understand the state of the field, identify research gaps and opportunities for future efforts, and enable public communication of research activities with an accurate, accessible, compact, and updatable data visualizations.

Result

Results indicate the approach is feasible, and importantly the field and NIH have largely been responsive to the ADRD milestones in the National Plan to Address AD.

Conclusion

The analysis points to several cross‐cutting ADRD research areas that may benefit from increased attention going forward, including health equity, the multiple etiology hypothesis of common dementias, emerging risk factors for common dementias (e.g. COVID‐19, TBI, and TDP‐43 proteinopathy), and clinical trials.
Diminished learning rates in mnemonic discrimination of scenes but not objects are associated with beta‐amyloid positivity
Authors: Polk Sarah E. , Gellersen Helena M. , Lottes Yannik , Glanz Wenzel , Berron David
Published: January 2025

Background

The advent of remote and unsupervised digital cognitive assessment facilitates the use of frequent assessments only days apart to examine learning rates. Learning rates have been shown to differentiate patients with Mild Cognitive Impairment (MCI) and preclinical Alzheimer’s disease (AD) from healthy individuals across a variety of cognitive measures. Here, we investigated whether impairments in learning rates in a mnemonic discrimination task were domain specific, as object and scene memory have been found to rely on anatomically distinct neural pathways that are differentially affected by AD.

Methods

We examined learning rates over two weeks in the Mnemonic Discrimination Task for Objects and Scenes (MDT‐OS) in N = 54 older adults (age = 67.1 ± 5.68) recruited through a memory clinic who were clinically cognitively unimpaired (CU, n = 44, nAβ– = 28, nAβ+ = 6) or had MCI (n = 10, nAβ– = 3, nAβ+ = 7). Five identical stimuli sets were completed at three‐day intervals on participants’ own smartphone or tablet.

Results

Using linear mixed modeling, we found significant cognitive status‐by‐time interactions indicating that the MCI group showed reduced learning compared to the CU group in the Scene condition, though not the Object condition. However, a cognitive status‐by‐time‐by‐condition model indicated no significant effect of condition. We found no significant Aβ status‐by‐time interaction in either condition. However, an Aβ status‐by‐time‐by‐condition model revealed diminished learning in the Scene condition compared to the Object condition for the Aβ+ group but not the Aβ– group. In a sub‐group analysis including only CU individuals, this three‐way interaction effect remained significant.

Conclusion

The current results suggest that individuals with MCI show diminished learning rates in mnemonic discrimination of scenes, compared to CU individuals. We identified ceiling effects in the Object condition, which may have contributed to a null finding. Additionally, we found that Aβ positivity was associated with reduced learning of scenes but not objects, both in the overall sample and in individuals with no clinical indication of cognitive impairment. In conclusion, learning rates in the MDT‐OS may be a sensitive marker of AD in individuals who do not yet meet the clinical threshold for cognitive impairment.