bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical Characterisation of pre‐clinical progressive model of Alzheimer’s Disease
Authors: Iqbal Abdullah Asad , Almari Bushra
Published: January 2025

Background

Alzheimer’s Disease research lacks a suitable model to match the sporadic version of Alzheimer’s Disease (SAD). We a propose a model that will use 7PA2 cells which is a CHO modified to express the V717F mutation for APP (Indiana mutation). The 7PA2 cells will then be placed inside alginate microbeads to produce a factory that constantly produces amyloid species. Then the injected into the brains of rats. Generating pathological changes which can be compared against previous models and human data to test whether this model is more appropriate than current models.

Method

Alginate beads where produced of various different concentrations of alginate (Alg) and the gelling agent (calcium chloride ‐ CaCl2). 0.4 ‐ 8%Alg and 0.1M CaCl2 ‐ 1M CaCl2.

Stability measured as change in diameter using a Keynes microscope and comparing diameter for beads containing bv2 cells and no cells.

Stability also compared in aCSF.

Young Modulus was measured using a texture analyser and rheometer.

Inflammatory effects of alginate on BV‐2 cells characterised through TNF‐alpha.

Result

We found no changes in stability with changes in Alg or CaCl2 or if beads were in aCSF or distilled water for 4 weeks. (n = 50).

No significant effects of alginate on TNF‐alpha expression levels.

Young Modulus of Alg beads of 1.5% Alg and 0.3%M closely matches brain environment.

Conclusion

Alginate beads are stable over time in a brain‐like environment. Furthermore alginate beads of 1.5% Alg and 0.3%M closely match the brain environment. Alginate also causes no significant inflammatory response. Therefore alginate is a suitable carrier for 7PA2 further work must now be done in characterising 7PA2 cells and their amyloid species and the eventual effects in the brain.
sTREM2 mediates the correlation between BIN1 gene polymorphism and tau pathology in Alzheimer’s disease
Authors: Guo Fan , Sheng Ze‐Hu , Ou Ya‐nan , Wang Zuo‐teng , Zhao Qing‐Fei , Shan Tan Meng , Tan Lan ,   tanlan
Published: January 2025

Background

Bridging integrator 1 (BIN1), one of the most strongly associated gene with Alzheimer’s disease (AD). It has been reported to play a role in the pathological processes of AD; however, the exact mechanism has not yet been completely found.

Method

Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 495) was the discovery cohort, and the Chinese Alzheimer’s Biomarker and LifestylE (CABLE, N = 619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model was used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia‐soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Causal mediation analysis was conducted through 10,000 bootstrapped iterations to explore the mediating effect of sTREM2 on AD pathology.

Result

In the ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and the levels of CSF phosphorylated‐tau (P‐tau) (Pc = 0.017; 0.010, respectively) and total‐tau (T‐tau) (Pc = 0.011; 0.013, respectively). The BIN1 loci were also found to be correlated with the levels of CSF sTREM2 (Pc = 0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of the BIN1 loci with P‐tau (rs7561528: Prop = 20.9% of total effect; rs744373: Prop = 24.9% of total effect) and T‐tau (rs7561528: Prop = 36.6% of total effect; rs744373: Prop = 44.1% of total effect). The analysis in CABLE study replicated the mediation role of rs7561528.

Conclusion

This study demonstrated correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarker, particularly in preclinical AD. Additionally, the link between BIN1 loci and AD pathology was partially mediated by CSF sTREM2
An endolysosome pathway specific polygenic risk score for Alzheimer Disease predicts cell‐type specific transcriptomic and morphological phenotypes
Authors: Prater Katherine E , Rose Shannon , Johnson Corbin S.C. , Strohbehn Sam , Cochoit Alexandra J , Mamde Sainath , Sun Wei , Keene C. Dirk , Shojaie Ali , Garden Gwenn A , Blue Elizabeth E , Young Jessica E. , Jayadev Suman
Published: January 2025

Background

Late onset Alzheimer disease is a complex syndrome, genetically, clinically and pathogenetically heterogeneous. Genome Wide association studies have identified risk alleles for AD harboring genes in the endolysosomal network (ELN). We hypothesize that aggregate burden of these endolysosomal risk alleles impacts cell type specific ELN function, thus contributing to LOAD pathogenesis.

Method

To test this hypothesis, we first developed an endolysosomal polygenic risk score (ePRS) using a curated list of established GWAS AD risk loci. We identified a cohort in the top quartile (high) and bottom quartile (low) of ePRS scores within our LOAD biobank with rich clinical and pathological phenotype data, enabling brain tissue omics and cell based functional studies from the same donor. To explore cell type specific implications of ePRS burden, we studied frozen cortical brain tissue and primary cells derived from the same set of LOAD cases.

Result

We identified cell type‐specific gene expression and regulatory network shifts associated with ePRS burden. Immunohistochemistry revealed that high ePRS was associated with enlarged neuronal endosomes and microglial lysosomes. We explored whether ePRS itself predicted ELN changes in cells that are not exposed to pathologic protein deposition. Leptomeningeal cells isolated from the ePRS cohort also manifested changes to ELN morphology and bulk RNA sequencing revealed ePRS‐dependent gene expression changes, suggesting that ePRS directly influences ELN related transcriptomic phenotype.

Conclusion

Taken together, our data suggests that AD risk loci implicating genes within the endolysosomal system do in fact impact the cellular ELN, giving more confidence to the pathogenic relevance of “endolysosomal” risk loci. Dysfunction of endolysosomal pathways likely contributes to AD pathogenesis in LOAD and may highlight more specific points of intervention. Pathway‐specific polygenic risk scores can enhance our understanding of the complex mechanisms contributing to AD and pave the way for more specific targeted therapies in the clinic.
Five‐year Trajectory of Mild Behavioral Impairment in People with Subjective Cognitive Complaints
Authors: Creese Byron
Published: January 2025

Background

Mild Behavioral Impairment (MBI) describes a spectrum of late‐life onset, sustained neuropsychiatric symptoms grouped in five domains: mood/anxiety, apathy, impulse dyscontrol, social inappropriateness and psychosis. MBI is a well‐established correlated of incident dementia and is associated with PET amyloid and blood biomarker profiles consistent with early AD however little is known about the trajectory of MBI. This study set out to determine the course of MBI symptoms in a cohort of older adults with and without subjective cognitive complaints (SCC).

Method

Data from 3,428 adults aged over 50 were analysed. All had five years of annual follow up assessments. SCC was determined by self‐completed IQCODE scale at baseline(mean score <3.3: normal cognition (NC); >3.3: SCC). MBI was assessed using the MBI Checklist (MBI‐C) (higher scores indicating more severe symptoms). Change in MBI‐C score by SCC status was conducted using zero‐inflated negative binomial models. A random intercept was included to allow for correlations between repeated measurements on the same individual. Trajectories of mood/anxiety and apathy were also analysed. The other three domains were not due to low counts of non‐zero scores.

Result

The mean age at baseline was 64 and 78% of the sample were women. Fifteen percent (n = 514) had SCC. The SCC group had higher MBI scores than NC. For the SCC group, there was a statistically significant exponential increase in MBI‐C score over 5‐years. At baseline, total MBI‐C score was 3.5[3.1‐4], rising to 4.6[4.1‐5.2] in year 4 and 6[5.2‐7] in year 5 (Figure 1). For NC, the increase over 5 years was more modest, rising from 1 at baseline to 2.2 by year 5.

Conclusion

To our knowledge this is largest study of trajectories of MBI symptoms. We show that symptoms are not stable but show an exponential increase over time in those with SCC, while in those with normal cognition the overall trend was flat. These are population averaged estimates and there will be a degree of variability in the data which may warrant more individual‐level prediction modelling in future. As well as being a marker of cognitive risk, SCC may also represent a risk state for worsening neuropsychiatric symptoms.
Unusually young onset of spastic paraparesis in a carrier of both the A431E PSEN1 and A713T APP variants
Authors: Ringman John M , Sheikh‐Bahaei Nasim , Villareal Enrique Israel Velazquez , Craig David , Islas Miguel Angel Macias
Published: January 2025

Background

The ways in which diverse genetic variants interact to affect the phenotype of AD is poorly understood. The relatively consistent phenotype associated with specific mutations causing autosomal dominant AD (ADAD) provides the opportunity to study how other genetic variants contribute to disease manifestations.

Method

We performed an in‐depth case study of a patient with the A431E PSEN1 mutation who had onset of progressive spastic paraplegia at age 20.

Result

The proband was a Mexican woman known to be at 50% risk for inheriting the A431E PSEN1 mutation that commonly presents with cognitive changes and/or spastic paraplegia at age 40. At age 20 she began developing stiffness in her legs and difficulty walking. When seen at age 26 she had diffuse spasticity worse in the legs, slurred speech, and was cognitively intact. A flortaucipir PET scan at the time was negative as was a florbetaben scan 21 months later despite marked differences from controls in DTI measures in the corticospinal tract. Genetic screening demonstrated the presence of the A431E PSEN1 mutation and an A713T APP variant which was confirmed by WGS. The A713T APP variant was not present in her mother who had more typical disease nor in 62 other persons of Mexican origin.

Conclusion

The A713T variant in APP has been shown to affect APP processing and Abeta nucleation and is considered to be a risk factor for AD. We hypothesize that the presence of this variant led to the early onset of spastic paraparesis in our proband despite Abeta deposition in brain being undetectable on PET. This finding suggests spastic paraplegia may be related to aberrant APP processing in a manner distinct from plaque formation.

This study was funded by R01AG062007 and R01AG069013
P2RX7 deficiency prevents cognitive deficit, brain atrophy and tauopathy progression in PS19 mice via suppression of extracellular vesicle secretion and mitochondrial toxicity
Authors: Santos Victor B , Abdullah Mohammad , Ellison Justice , Ruan Zhi , Ikezu Tsuneya , Ikezu Seiko
Published: January 2025

Background

We previously identified the novel mechanism of pathological tau transfer via extracellular vesicles (EVs) in Alzheimer’s disease (AD). Targeting EV secretion to mitigate tau transfer is therefore a promising therapeutic approach for AD. P2X purinoreceptor 7 (P2RX7), an ATP‐gated cationic channel, regulates microvesicle shedding or secretion of multivesicular body‐derived exosomes. We aim to investigate the effect of P2rx7 deficiency on disease progression in PS19 tauopathy mouse model in vivo and by proteomic profiling of brain EVs.

Method

PS19:P2rx7–/– mice at 9 months of age were tested for the fear conditioning, and pathology assessment of the brain atrophy and tau using immunofluorescence against aggregated tau (Alz50) or phosphorylated tau (AT8) and ELISA. Mice were intracranially injected with viral vectors expressing mEmerald‐CD9 in microglia and P301L tau in neurons to visualize the secretion of microglial EV and extracellular tau in vivo. Brain EV samples were subjected to proteomic profiling by data independent acquisition mass‐spectrometry.

Result

PS19:P2rx7–/– mice showed significant improvement in contextual and cued memory compared to age‐matched PS19 mice, which was accompanied by preserved cortical and hippocampal volume, and significant reduction of hippocampal tau pathology and pS396 tau in sarkosyl‐insoluble fraction of brain tissues. The number of GFP+ microglial EVs were significantly reduced in P2rx7–/– compared to WT mice. Gene ontology pathway analysis of EV proteome showed significant enrichment of mitochondrial pathways in PS19 group compared to WT group, which was significantly downregulated in PS19:P2rx7–/– group.

Conclusion

Our study demonstrated that P2rx7 deficiency ameliorates cognitive dysfunction and tau pathology development in PS19 mice by dampening microglial EV secretion and EV‐mediated mitochondria transfer, further indicating the therapeutic potential of targeting P2RX7, an EV regulatory molecule, to ameliorate AD progression.
Human brain microglia responses to amyloid beta and tau pathology in high pathology controls and across disease stages
Authors: Melnik Mikhail , Mitri Vivianne , Atluri Swetha , Knitowski Nina , Kodavatikanti Achyutha , Bilousova Tina , Rexach Jessica E , Gylys Karen H
Published: January 2025

Background

Microglia responses to Aβ and tau pathology and the dysregulation of the microglial role in synaptic function may determine the onset and course of Alzheimer’s disease (AD). While significant work has been performed in mouse models, we still lack a complete understanding of physiological and pathological microglial states and functions in human AD brain.

Method

For immunoblotting of brain homogenates against multiple microglial markers, and flow cytometry (FC) analysis of synaptosomal fractions (SNAP25/CD47/Aβ(10G4)/phospho‐tau(AT8)), 49 cryopreserved human parietal cortex samples were categorized into four groups: low pathology control (LPC), high Aβ control (HAC), high pathology control (HPC), and AD. Selected microglia markers were assessed in the snRNAseq dataset (Rexach et al., 2023, bioRxiv) and validated by immunohistochemistry (IHC) analysis.

Result

In the LPC group, only 22.5% of Aβ‐positive (+)/p‐tau‐negative (‐) synaptosomes expressed CD47 on their surface, with a significant progressive increase in the percentage (%) of CD47+ events in the Aβ+/p‐tau‐ group across disease stages, reaching 53.4% in the AD group. Surprisingly, Aβ+/tau+ synaptosomes expressed the highest CD47 levels, suggesting protection from elimination. Higher levels of P2ry12 and CD206 were found in the LPC group compared to all other groups in brain homogenates. Interestingly, the levels of P2ry12, CD206, and Axl1 were significantly higher, and the level of Clec7a was significantly lower in the HPC group compared to the AD group. Linear regression modeling revealed a significant negative association between P2ry12 and synaptic tau pathology, as well as CD47 expression in p‐tau‐positive synaptosomes. Interestingly, in primary tauopathy microglia (but not AD microglia), IKFZ1‐regulated genes, including P2ry12, were upregulated according to snRNAseq and around p‐tau‐bearing neurons by IHC.

Conclusion

Our data suggest that in normal aging, synaptic Aβ accumulation leads to a diminishing of synaptic CD47 (‘don’t eat me’) signal, accelerating the clearance of malfunctioning Aβ but not p‐tau positive synapses. Upregulation of P2ry12 and CD206, accompanied by downregulation of Clec7a, may represent an early and potentially protective response to pre‐tangle tau pathology. Later in disease progression, P2ry12 reduction may drive a more reactive, phagocytic phenotype in response to tau pathology, leading to an increase in synaptic CD47 levels and synaptic pathology accumulation.
Depression Significantly Predicts Clinical Functioning Among Hispanic older adults
Authors: Duarte Andres , Padron Dilianna , Garcia Patricia , Mendoza Lisandra , Fiala Jacob , Marsiske Michael , Duara Ranjan , Rodriguez Miriam J.
Published: January 2025

Background

Hispanics are disproportionately affected by Alzheimer’s disease and related dementias (ADRD) when compared to non‐Hispanic Whites (NHW). Previous studies have shown that neuropsychiatric symptoms can further exacerbate clinical functioning among ADRD patients, leading to increase in caregiver burden and poorer quality of life. However, most studies in this area have focused on predominately Caucasian samples, and relationships between emotional and clinical functioning among Hispanic older adults at risk of ADRD are poorly understood. The aim of the current study was to examine predictive associations between emotional and clinical functioning among Hispanic ADRD older adults at risk of developing ADRD.

Methods

The Geriatric Depression Scale (GDS) and the modified Clinical Dementia Rating scale (mCDR) were administered to Hispanic (n = 159) and NHW (n = 101) participants from the 1Florida Alzheimer’s Disease Research Center (ADRC). Participants were aged 60‐90 years (Hispanics: M = 70.87, SD = 7.28; NHW: M = 73.24, SD = 7.72) and were either cognitive normal (n = 52) or diagnosed with Mild Cognitive Impairment (MCI, n = 208). Multiple linear regression analyses controlling for age and diagnosis were applied to examine predictive relationships between the emotional and functional measures for the two ethnic groups separately.

Results

Results showed significant positive relationship between the mCDR and the GDS (β = 0.01, SE = 0.00, t = 2.33, p > .05) among the Hispanic sample and interaction effects between diagnosis and GDS scores were not significant (β = 0.00, SE = 0.01, t = ‐0.41, p = 0.68). No significant associations were noted among the NHW group (β = 0.01, SE = 0.00, t = 1.13, p = 0.26).

Conclusion

Depression significantly predicted poorer clinical functioning among the Hispanic group only even when controlling for the effects of diagnosis. These findings indicate that the effect of emotional symptoms has a clinical impact on functioning among Hispanic older adults and may be related to increased risk of further decline and ADRD diagnosis. These results have important implications for dementia care. Future studies should examine these associations as they relate to ADRD risk and longitudinal clinical functioning.
X Ray Absorption Near Edge Spectroscopy (XANES) Shows Abnormal Iron Oxidation State in Alzheimer’s Hippocampi
Authors: Tran Dean , DiGiacomo Phillip , Nirschl Jeffrey , Edwards Nicholas , Bone Sharon , Webb Samuel , Georgiadis Marios , Zeineh Michael
Published: January 2025

Background

Recent studies suggest that iron and neuroinflammation are key components of Alzheimer’s Disease (AD) pathology. Ferrous Fe2+ can cause oxidative stress and cellular toxicity, but it is unknown to what extent Fe2+ is elevated in AD, in particular with the hippocampus. To answer this question, we quantified iron oxidation state in frozen human brain hippocampi.

Methods

22 fresh‐frozen human brain hippocampi from the Stanford Alzheimer’s Disease Research Center (high AD—n = 13, low AD—n = 7, non‐AD controls—n = 2) were imaged in beamline 7‐2 of Stanford’s Synchrotron Radiation Lightsource using X‐ray fluorescence imaging (XFI) to identify regions of interest (ROIs) with high iron concentration (Fig. 1A‐B). X‐ray absorption near‐edge structure (XANES) spectroscopy was performed on ROIs to determine the relative proportions of Fe2+ and Fe3+ in each deposit (Fig. 1B‐E). A Fischer’s exact test was performed to evaluate the association between AD stage and levels of Fe2+. Since Fe2+ proportion is a bounded measure with an excess of zeroes, a zero/one‐inflated beta (ZOIB) regression model was fitted.

In addition, to interrogate the effects of tissue thawing on iron oxidation state during the hours long scan times, a cryo‐chamber kept 3 hippocampal specimens frozen while their respective deposits were being scanned. These specimens were then allowed to thaw and their same deposits rescanned. The proportion of Fe2+ between the paired frozen/thawed deposits were compared using a Wilcoxon signed‐rank test.

Results

There was a statistically significant increase in Fe2+ in the AD specimens (p = 0.007). The ZOIB regression showed that low AD (z = 9.10, p<0.001) and high AD (z = 3.36, p = 0.001) hippocampi exhibit a significantly higher proportion of Fe2+ compared to controls.

Thawed deposits showed a statistically significant lower proportion of Fe2+ compared to their frozen state (p = 0.0145).

Conclusions

We found increased Fe2+ in thawed AD hippocampi compared to controls. Additionally, the thawing of frozen iron deposits resulted in a decrease of measured Fe2+. These findings may suggest actual differences are even higher between iron oxidation state in AD hippocampi versus controls.
Mitigation of Synaptic and Memory Impairments through F‐Actin Stabilization in an Alzheimer’s Disease Mouse Model
Authors: Haseena P A , Kommaddi Reddy Peera
Published: January 2025

Background

F‐actin plays crucial roles in establishment and maintenance of synapses including post synaptic density organization, facilitation of vesicle trafficking, anchoring of postsynaptic receptors, and involvement in translational machinery. Proteomic analysis of actin‐interacting proteins revealed the interaction of PSD‐95 with actin in synaptosomes from brain cortex of APP/PS1 mice. PSD‐95 functions as a critical scaffold for the assembly of neurotransmitter receptors at the synapse, playing a pivotal role in regulating synaptic strength and plasticity. PSD‐95 directly interacts with NMDA receptors, whereas its interaction with AMPA receptors occurs through an auxiliary subunit, TARPs. The disruption in PSD‐95 association with actin observed in nine‐month‐old APP/PS1 mice may contribute to the synaptic neurotransmission deficit evident in the AD mouse model. Our objective here is to stabilize the F‐actin using Jasplakinolide to examine the disrupted interaction and assess its impact on synaptic function and memory impairment.

Methods

Nine‐month‐old wildtype and APP/PS1 mice were injected intrathecally with vehicle or Jasplakinolide (0.5µg/mice) and contextual fear conditioning memory was assessed 24 hours later. Following behavioral analysis, synaptosomes were isolated and examined for synaptic F‐actin levels and PSD‐95‐ actin association. Additionally, primary cortical cultures were treated with Jasplakinolide and analyzed for F‐actin intensity, dendritic spine density and AMPA receptor subunit surface localization.

Results

Memory recall and PSD‐95 association with actin is dysregulated in nine‐month‐old APP/PS1 mice compared to wildtype mice. However, injection of Jasplakinolide in APP/PS1 mice rescued the memory recall deficit. Synaptic F‐actin levels and the association of PSD‐95 with actin were restored in APP/PS1 mice received the Jasplakinolide. Primary cortical neurons, DIV21, derived from APP/PS1 mice showed a significant reduction in surface localization of AMPA receptor, F‐actin levels and dendritic spine density while these molecular events are restored by stabilization of F‐actin by Jasplakinolide.

Conclusion

The compelling evidence supporting the stabilization of F‐actin suggests a promising strategy for alleviating synaptic impairments in AD, as it not only restores dendritic spines but also increases the surface localization of glutamate receptors. Our findings on complex interplay between cytoskeleton dynamics and synaptic functions may provide potential therapeutic targets aimed at preserving synaptic integrity and ameliorating cognitive decline in AD.
Theta band optogenetic stimulation of the septo‐hippocampal fibres in the fornix reduces interictal spikes and rescues memory performance in hAPP‐j20 mice
Authors: Varela Eva Vico , Carmichael James Eric , Manseau Frédéric , Choi Jisoo , Etter Guillaume , Williams Sylvain
Published: January 2025

Background

Altered neuronal timing and synchrony are biomarkers for Alzheimer’s disease (AD) and correlate with memory impairments. Electrical stimulation of the fornix, the main fibre bundle connecting the hippocampus to the septum, has emerged as a potential intervention to restore network synchrony and memory performance in human AD and mouse models. However, electrical stimulation is non‐specific and may partially explain why fornix stimulation in AD patients has yielded mixed results. We hypothesize that driving the specific circuits underlying rhythmicity within the fornix via optogenetics at the biologically relevant theta rhythm (5Hz) will stabilize septo‐hippocampal network timing in an AD mouse model (hAPP‐j20) to alleviate hypersynchronous interictal spikes (IS) and restore memory performance.

Methods

GABAergic neurons in the septum were transfected with the excitatory opsin ChETA (or eYFP controls) in J20+/+ or J20± littermate controls. An optical fibre was placed above the fornix to limit excitation to the projection fibres and recording electrodes were placed in CA1 to measure network oscillations. 5Hz stimulation was applied continuously for 4 hours following the encoding phase of either novel‐object‐location or passive contextual avoidance memory tasks. We also combined in vivo calcium imaging with electrical recordings in CA1 to monitor network activity to determine how IS shape hippocampal cell assemblies in J20+/+ mice without fornix stimulation.

Results

Interictal spikes were present in sleep in J20+/+ mice, and at a higher rate during REM (4.78/min) compared to slow‐wave (1.76/min; n = 11, p<0.001, one‐way ANOVA). J20+eYFP controls displayed a strong negative correlation between the rate of IS and memory recall score (n = 9, r = ‐0.62, p = 0.015). 5Hz optical fornix stimulation reduced the occurrence of IS in REM both during stimulation and 4hrs post‐stimulation (n = 11, p = 0.024, repeated measures ANOVA). Continuous 4‐hour theta stimulation between the encoding and recall phases of both memory tasks rescued J20+ChETA performance to levels comparable with healthy controls while J20+eYFP mice performed at the chance level (n = 9‐10 per group, p = 0.017, two‐way mixed ANOVA).

Conclusion

These data validate theta band optical stimulation as a viable method to pace the septo‐hippocampal network effectively reducing IS events and recovering memory performance in an APP mouse model.
Selective targeting free beta‐2 microglobulin as a promising therapeutic strategy for Alzheimer’s Disease
Authors: Cho Mi‐Hyang , Kim Min‐Seok , Han Seung‐Hwan , Mun Yeon‐Seon , Song Ha‐Lim , Kim Na‐Young , Shin Jung‐Su , Kim Dong‐Hou , Yoon Seung‐Yong
Published: January 2025

Background

Beta‐2 microglobulin (β2m) is a component of the major histocompatibility complex class I (MHC‐I) playing a crucial role in the immune system on cell surface, but it can be separated from the MHC‐I and exist in biological fluid independently. Numerous reports have shown that β2m is a systemic pro‐aging factor impairing cognitive function, and that it is increased in the blood and CSF of patients with Alzheimer’s disease (AD). While β2m in the body fluid has been recognized as a potential factor in AD and aging, the development of therapeutic agents, especially those directly targeting β2m using antibodies, may face challenges. As β2m is a protein normally expressed in most nucleated cells as heterodimer bound to MHC‐I, targeting β2m may indeed carry a risk of compromising immune responses and leading to side effects by inhibiting MHC‐I.

Method

To develop monoclonal antibody against free β2m, not complexed to MHC‐I, the hybridoma clones were obtained from mice injected with peptides containing epitopes targeting the adjacent region where β2m binds to heavy chain, another subunit of MHC‐I. One of these antibody clones, termed ADEL‐Y03, was selected by characterizing its binding affinity and specificity for free β2m, and mass‐produced for in vivo efficacy study against AD.

Result

The ADEL‐Y03 exhibit high affinity and specificity for free β2m, but not to β2m complexed with MHC‐ I. The in vivo activity of ADEL‐Y03 in blocking free β2m was validated by recovering β2m‐induced cognitive deficit in wild type mice. In addition, intraperitoneal injection of ADEL‐Y03 reduced free β2m levels in the brain and plasma, leading to a decrease of beta‐amyloid and inflammation, hallmarks of AD pathology, in 5XFAD mice brain. In vitro study demonstrates the role of free β2m in AD pathology, and these effects were ameliorated by ADEL‐Y03.

Conclusion

Specific targeting free β2m using ADEL‐Y03 antibody may be a promising approach to developing new therapies for AD without deleterious effects such as downregulating immune function of MHC‐I.
Clinicopathological mismatching in a patient presenting with clinical symptoms of Parkinson’s disease
Authors: Chung Eun Joo
Published: January 2025

Background

Because of clinically overlapping parkinsonian motor symptoms, it is hard to diagnose a specific disease in atypical parkinsonism or differentiate Parkinson’s disease (PD) from atypical parkinsonism. Herein, we report the clinicopathological mismatching of an autopsy‐confirmed PSP in a patient clinically diagnosed with PD.

Method Clinical history

We reviewed the brief clinical history of a 70‐year‐old man and neurologic examination. We investigated the findings of the Mini‐mental state examination (MMSE), Clinical dementia rating (CDR), and Montreal cognitive assessment (MoCA). He performed brain magnetic resonance imaging (b‐MRI) and fluoro‐propyl‐carbomethoxy‐iodophenyl‐tropane (FP‐CIT)‐positron emission tomography (PET).

Autopsy

The patient and his family gave antemortem consent for a postmortem examination. Autopsy was performed at the Inje University Brain Bank. The right brain was frozen and the left side was fixed into the 10% formalin. The fixed brain was photographed and coronally sliced at 1 cm intervals. After slicing, tissue block‐taking was done at 17 parts. Specimens were fixed with 10% buffered formalin at room temperature and embedded in paraffin. The hematoxylin‐eosin stain and immunohistochemical stains were performed.

Result

The UPDRS motor scale of off‐state was 18.5, and the HY stage of off‐state was 2.0. The first MMSE and MoCA were 28, and the CDR score was normal. The third MMSE was assessed at 76 years old, and the score was 25 which increased by 2 points compared to a year ago. These results are in the table. The b‐MRI revealed mild small vessel ischemic change in the corona radiata (CR). FP‐CIT PET revealed asymmetrically bilateral decreased FP‐CIT uptake in both the putamen and caudate nucleus. The total brain weight of this patient was 1270mg. The neuropathological findings did not show the Lewy body pathologies. Instead, PSP pathology based on the tufted astrocytes was observed.

Conclusion

His clinical symptoms were initially accordant with clinical diagnostic criteria for PD. However, neuropathological findings showed PSP pathology based on the tufted astrocytes. The patient had worse Parkinsonian motor symptoms, which pathologically suggested the brainstem‐predominant PSP rather than typical or cortical‐predominant.
Neuronal Calcium‐Sensing Receptor Is A Druggable Target To Treat Alzheimer’s Disease
Authors: Tu Chia‐Ling , Kurisu Kota , Cheng Zhiqiang , Miller Stephanie R , Mizuma Atushi , Liu Jialing , Palop Jorge J , Grinberg Lea T. , Yenari Midori A , Chang Wenhan
Published: January 2025

Background

Effective disease‐modifying regimens for Alzheimer’s Disease (AD) remain lacking due to insufficient understanding of its pathogenic drivers. It was shown previously that upregulation of the calcium‐sensing receptor (CaSR), an excitatory family C GPCR, induces neurodegeneration by interfering with the inhibitory γ‐aminobutyric acid (GABA) signaling following acute brain injuries (Ann_Clin_Transl_Neurol, 1:851‐66). Herein, we determined whether CaSR overexpression is causally associated with the AD.

Method

(1) Proteomic profiles of hippocampal CA1 neurons in postmortem brains of subjects at progressive AD Braak stages (0, 1, 2, 4 and 6) were compared using a NanoString GeoMx profiler. (2) Proximity ligation assays (PLA) were performed to assess interactions of neuronal CaSR with type B GABA receptors (GABAB1R and GABAB2R). (3) Y‐maze and new object recognition (NOR) tests were performed to assess the impact of neuronal ablation of the Casr gene by Camk2a‐Cre‐mediated gene recombination (Camk2aCaSRΔflox/Δflox) or pharmacological inhibition of neuronal CaSR activities by daily subcutaneous injections of a brain‐permeable calcilytic (NPS‐2143, 20 µmole/kg) on cognitive functions of aging C57/B6 mice and two mouse models of early‐onset AD, 5XFAD (MMRRC_034840‐JAX) and hAPPNL‐G‐F (Nature_Neuroscience, 5:661) mice.

Result

The abundance of CaSR protein was significantly (p<0.0001) increased from the Braak stage 2 to 4/6 (Fig. 1A, C) and positively correlated (r2 = 0.2448 ‐ 0.4655, p<0.0001) with the abundance of APP, Aβ1‐42, BACE1, PSEN1, and phospho‐tau proteins (Fig. 1E‐I) in the somas of CA1 neurons (Fig. 1B) of the human brains. PLA showed increases in heterodimerization of CaSR with the GABAB1R in human brain from the Braak 0 to 5 (Fig. 2A) and in cultured hippocampal neurons overexpressing the CaSR by lentiviruses along with reduced GABAB1R/GABAB2R heterodimerization (Fig. 2B). While the control mice showed significant (p<0.001) cognitive declines from 12 to 18/20 months of age (MOA), these defects were prevented in the age‐matched Camk2aCaSRΔflox/Δflox or NPS‐2143‐injected mice (Fig. 3A, B). Similarly, the early cognitive declines in the 5XFAD (Fig. 3C‐F) and hAPPNL‐G‐F (Fig. 3G, H) mice at 6 MOA were completely alleviated when the mice were bred into the Camk2aCaSRΔflox/Δflox background or injected with NPS‐2143.

Conclusion

The neuronal CaSR is a critical driver of dementia by interfering with GABABR signaling and a druggable target to prevent or treat AD.
Serial Imaging of Murine Brain Capillary Pericyte Dynamics in Hyperglycemia
Authors: El‐Ghazawi Kareem , Eyo Ukpong , Peirce‐Cottler Shayn
Published: January 2025

Background

The microvasculature of the central nervous system (CNS), which delivers oxygen and nutrients and forms a critical barrier protecting the CNS, is deleteriously affected by both Alzheimer’s Disease (AD) and Type 2 Diabetes (T2D). Previous studies have shown pericyte dropout and vessel constriction in brain capillaries in AD, while other studies have shown pericyte bridging and dropout in retinal capillaries in T2D. T2D patients have increased risk of AD, suggesting potentially related microvascular pathological mechanisms. Pericytes are an ideal cell type to study for functional links between AD and T2D. The purpose of this study was to evaluate the effects of T2D on the dynamics of brain capillaries and pericytes.

Method

Myh11‐CreERT2 ROSA floxed STOP tdTomato mice were fed a soft tamoxifen chow for 2 weeks. Cranial window surgery was performed in anesthetized mice, and mice underwent weekly serial live two‐photon imaging with retro‐orbitally injected FITC‐Dextran throughout a 3‐week period. Streptozotocin (STZ) (200mg/kg) was injected intraperitoneally, and mice were imaged 1‐week post‐injection. Z‐stack projections of brain tissue from the surface to 100mm deep (442um2 field of view) were collected, and capillary orientation and pericyte morphology were compared across timepoints and before and after STZ treatment.

Result

Quantitative assessment revealed that capillaries move closer to each other 1 week after STZ injection, as indicated by a 30% reduction in the average distance between capillaries. Moreover, wherever capillaries were in contact with pericyte soma, capillary diameter was reduced by 31% post‐STZ injection compared to pre‐STZ timepoints, suggesting a constrictive role of pericytes in a hyperglycemic environment.

Conclusion

Our study demonstrates how live, serial two‐photon imaging of the same fields of view of the mouse cortex can reveal dynamic capillary and pericyte morphological changes in response to a hyperglycemic environment. This experimental model system can be deployed to investigate how pericytes changes over time may link microvascular changes in T2D to those in AD. Future studies will include additional analysis time points, as well as studies in 5xFAD mice, a widely used model of AD.
Investigating Intranasal Olfactory Mucosa Progenitor Cells Administration in Compensating Hippocampal Atrophy in Alzheimer Disease: A Novel Perspective
Authors: Walid Mohammad , Ismail Youssef A. , El‐Satar Youssef M. Abd , Mohamed Hazim , Haitham Youssef
Published: January 2025

Background

The olfactory mucosa cells are capable of lifelong neurogenesis providing a viable source of progenitor cells. Olfactory mucosa progenitor cells (OMPCs) have alleviated several cerebral ischemia/reperfusion damage markers. OMPCs are safely obtainable from the upper nasal cavity. The aim is to investigate the potential of administering the OMPCs to achieve neurogenesis in regions of hippocampal atrophy in Alzheimer’s disease (AD)

Method

We reviewed database searches through December 2023 in MEDLINE, PsycINFO, and the Cochrane Central Register of Controlled Trials, and additional searches for ongoing trials through ClinicalTrials.gov and Current Controlled Trials (ISRCTN Register).

Result

Based on a trial conducted to assess the homing capacity of human OPMCs applied intranasally, the OPMCs migrated to the sites of soma atrophy and axonal swelling. Mapping the position of the applied cells, the mean distance (+SD) from OMPCs to regions of axonal damage indicated B‐APP+ (the same marker in CA1 hippocampal atrophy in AD) was 71.8+60.3 µm; OMPCs to atrophic cell bodies indicated p‐c‐jun+ (the same marker in CA2 hippocampal atrophy in AD) was 188.7 + 320 µm; OMPCs to random sites was 3929.3 + 2636.3 µm. Another trial was conducted on mice to confirm whether the OMPCs also exhibit high capacity of neurogenesis. The presence of relay neurons derived from the OMPCs differentiation was evident and traced by the Wheat germ agglutinin (WGA) expression in the injured regions in the spinal cords of the subjects. Based on the analysis of evidence and reviewing the literature related to the pathogenesis and markers of AD hippocampal atrophy, human OMPCs intranasal administration have high homing capacity which make them have a strong potential to safely migrate to the site of axonal damage (B‐APP+ region) and sites of soma atrophy (p‐c‐jun+ region) in hippocampus of AD patients. At the site of homing, OMPCs differentiate into trans‐synaptic relay neurons, expressing WGA protein, which reconstructs the neural pathways in the site of atrophy not only by acting as a scaffold, but also by differentiating into relay‐neurons

Conclusion

OMPCs intranasal administration is a novel technique which may have potential to restore neural pathways in subjects with AD presenting with hippocampal atrophy.
Optimizing Ultrasensitive RT‐QuiC assay on AD tau seed‐monomer reactions
Authors: Chen Junle , Lee Virginia M.‐Y. , Xu Hong
Published: January 2025

Background

Alzheimer’s disease (AD) is pathologically defined by the presence of extracellular Aβ plaque and intracellular tau inclusions. Emerging evidence shows that tau aggregates contain pathogenic bioactivities of templating monomeric tau into filamentous fibrils and propagating through cells. Based on these findings, assays have been developed to detect minute amounts of pathogenic tau in human samples. With great potential, it remains unclear about the sensitivity and fidelity of tau fibrillization due to the presence of pathogenic tau species.

Methods

To that end, our study focuses on optimizing the Real‐Time Quaking‐Induced Conversion (RT‐QuiC) assay for its potential of detecting and amplifying insoluble tau seeds derived from AD patient. To this end, we utilized recombinant tau monomers t306 and k12, 2R and 3R tau peptide respectively known for their rapid fibrillization and high amplification signals in previous studies. More specifically, we optimized the RT‐QuiC assay using both crude and purified brain lysates from AD and control cases.

Results

The specificity of the RT‐QuiC assay were successfully reproduced by multiple cases of AD and control brain lysates. Moreover, we tested the RT‐QuiC assay with purified AD tau seeds and assessed the sensitivity of the assays based on the amount of insoluble tau. To further interrogate the system, we also evaluated the impact of reaction buffer on the ThT‐based measurement of tau fibrillization. Our results show that the original RT‐QuiC assay can sensitively detect insoluble AD tau seeds at the nM level in our hands. The optimized RT‐QuiC assay could differentiate better between AD‐seeded reactions and controls with an improved sensitivity up to fM level, with a better separation between AD and control and faster reaction rate. The assay showed a clear dose‐dependent response till pM range.

Conclusion

Upon optimization, the RT‐QuiC assay is both ultrasensitive and specific to AD tau fibrillization. Our findings offer insights into the fibrillization mechanism of tau aggregates and expand our understanding of pathogenic tau seeds in AD. By optimizing the assay to more accessible patient samples in the future, namely CSF and plasma, the RT‐QuiC can serve as a potent diagnostic tool for AD tau progressions.
Synaptic proteasome is inhibited in Alzheimer’s disease models and associates with memory impairment in mice
Authors: Ribeiro Felipe C , Ferreira Danielle Cozachenco , Heimfarth Luana , Fortuna Juliana , de Freitas Guilherme B. , Souza Jorge M , Alves‐Leon Soniza , Leite Renata Elaine Paraizo , Suemoto Claudia Kimie , Grinberg Lea T. , De Felice Fernanda G , Lourenco Mychael V , Ferreira Sergio T
Published: January 2025

Background

The proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer’s disease (AD) post‐mortem brain tissue and in experimental models.

Method

We used primary hippocampal cultures, amyloid‐β oligomers (AβO)‐injected or transgenic animal models, and human brain tissue to determine brain proteasome function and subcellular localization. We further induced proteasome inhibition in vitro and in vivo to determine AD‐like phenotypes and memory in mice.

Result

We found a marked increase in ubiquitinylated proteins in post‐mortem AD hippocampi compared to controls. Using several experimental models, we show that AβO inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from APPswePS1ΔE9 mice. Reduced synaptic proteasome activity instigated by AβOs is corrected by treatment with rolipram, a phosphodiesterase‐4 inhibitor, in mice. Results further show that dynein inhibition blocks AβO‐induced reduction in dendritic proteasome content in hippocampal neurons. Finally, proteasome inhibition induces AD‐like pathological features, including reactive oxygen species and dendritic spine loss in hippocampal neurons, inhibition of hippocampal mRNA translation, and memory impairment in mice.

Conclusion

Results suggest that proteasome inhibition may contribute to synaptic and memory deficits in AD.
Correlation between Cognitive Function and Time‐Series Variation in Eyelid Opening and Closing from Facial Videos During Neuropsychological Tests
Authors: Umematsu Terumi , Tsugawa Akito , Takenoshita Naoto , Sato Tomohiko , Shimizu Soichiro
Published: January 2025

Background

The application of image recognition technology has been spreading to dementia screening. However, cognitive function fluctuates due to mental and physical conditions. Therefore, we believe that it may be necessary to evaluate facial information over time after considering these factors. This study evaluated the correlation between cognitive function and features acquired from facial videos during neuropsychological tests.

Method

Outpatients who complained of memory loss from a single memory clinic between March 2022 and April 2023 were recruited in the study. All patients underwent standard clinical tests, and facial videos were obtained during an approximately 1‐hour neuropsychological test. Cognitive function was evaluated by Mini‐Mental State Examination (MMSE). Facial feature points were calculated from the videos, then facial pose, gaze, and time‐series variation in eyelid opening and closing, such as the percentage of eyelid closure (PERCLOS), blink‐movement speed, number of blinks, eyelid time variability, and eyelid left‐right variability, were analyzed to evaluate their relationship to MMSE using the Pearson’s correlation coefficients. During neuropsychological tests, under concentration conditions, we evaluate a relationship between MMSE and the facial analysis results, particularly time‐series data of eyelid opening and closing.

Result

A total of 91 patients (31 males and 60 females, age: 80.5±5.7 years, years of education: 12.8±2.7years, MMSE: 22.2±4.9 points) were included in the study. The results showed a correlation between MMSE and the time‐series variation in eyelid opening and closing, with a correlation of 0.17 with PERCLOS, 0.26 with blink‐movement speed, and 0.15 with blink counts. The correlation coefficient between blink‐movement speed and MMSE was significant, with a 95% confidence interval.

Conclusion

This study showed a weak correlation between MMSE and some features of eyelid opening and closing. These results suggest that, during neuropsychological tests, when subjects are considered to be concentrating on their answers, i.e., not drowsy, an increase in the PERCLOS may be seen as one of the physical responses due to cognitive function decline.
Lung function and plasma biomarkers: Unraveling the interplay with Alzheimer’s Disease and Related Dementias
Authors: Vivek Sithara , Crimmins Eileen M. , Guan Weihua , Faul Jessica D , Thyagarajan Bharat
Published: January 2025

Background

With the emerging role of the blood biomarkers in Alzheimer’s Disease (AD) clinical practice and trials, it is crucial to identify and address factors influencing the concentrations of these biomarkers in circulation for enhanced clinical utility. We aim to assess the impact of lung function on plasma AD biomarker levels and elucidate the relationship between lung function and Alzheimer’s Disease and Related Dementias (ADRD).

Method

We used the Peak Expiratory Flow (PEF), plasma biomarkers of AD (Amyloid beta 42/40 (Aβ42/40) ratio, phosphorylated‐tau181 (p‐tau181), Neurofilament light chain (NfL) and Glial fibrillary acidic protein (GFAP)) measured in the Health and Retirement Study (HRS) 2016 survey participants (n = 3801) and incident dementia (n = 142) over 4 years. Participants were categorized into sex‐specific standardized residual percentiles (SRP) of PEF adjusted for age and height based on previously published method. We created 3 categories using SRP with cut points at: ≥50%, 10%–50%, and <10% (poor lung function). Multiple linear regressions assessed the association between PEF and AD biomarkers, adjusting for sample weights, age, race, education, body mass index, smoking status, comorbidity index, composite inflammatory score, estimated glomerular filtration rate and APOE ε4 allele. Separate analysis were conducted for men and women. We applied causal mediation analysis to determine how plasma biomarkers mediate the association between PEF and incident dementia.

Result

In models adjusted for covariates, men (β = 0.11 p = 0.09) and women ( = 0.06, p = 0.09) in SRP <10% show elevated GFAP levels compared to those in SRP ≥50%. Women in SRP <10% exhibit higher NfL levels (β = 0.13, p = 0.001) compared to those in SRP ≥50%. PEF showed no association with plasma levels of Aβ42/40 and p‐tau 181 in both sexes. In women, the association between lung function and incident dementia was mediated by plasma levels of NfL (proportion mediated = 20%, 95% CI = [1.2, 39], p = 0.04).

Conclusion

Individuals with poor lung function exhibit elevated levels of NfL and GFAP in their blood, with discernible sex‐specific variations in the association. These findings suggest a potential connection between lung health and cognitive function in older women, and providing a basis for future hypotheses to explore the pathological mechanisms of AD/ADRD.