bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tau pathology induced alteration in neuronal activity disrupt sleep and cerebral metabolic rhythms in the P301S PS19 mouse model of tauopathy
Authors: Irmen Riley E , Carroll Caitlin M , Constnantino Nicholas J , Snipes James A , Macauley Shannon L 
Published: January 2025

AbstractBackgroundAlzheimer’s disease is defined by the pathological aggregation of amyloid‐beta and hyperphosphorylated tau. AD patients often exhibit other symptoms like metabolic and sleep dysfunction. Currently, it is unclear if impairments are a cause or consequence of Aβ or tau aggregation. Previously, we demonstrated cerebral and peripheral changes in glucose elevate brain lactate levels stimulating wake. Further, previous work showed tau pathology corresponds with decreased sleep. Currently, it’s unclear what mechanisms drive sleep changes or if it relates to metabolic dysfunction. Therefore, we investigated how tau pathology impacts sleep and metabolism in P301S mice.MethodsTo examine peripheral metabolism, glucose tolerance tests were conducted on P301S and wild‐type mice(female). Recordings of indirect calorimetry over 3 days further explored peripheral metabolism. Paired glucose and lactate biosensors in the hippocampi tracked sub‐second fluctuations of brain interstitial fluid (ISF) to observe cerebral metabolic changes. EEG and EMG recorded cortical activity over a 3‐day period and spectral analysis investigated sleep/wake architecture.ResultTau aggregation preserves peripheral glucose tolerance and diurnal rhythms of brain glucose/lactate, normally lost in aged controls, suggesting increased glucose utilization. Similarly, P301S mice show increased respiratory exchange ratio suggesting heightened carbohydrate utilization. Conversely, they exhibit diminished energy expenditure. EEG spectral analysis revealed increased delta, increased theta, and decreased beta with pathology, suggesting disrupted GABA activity and sleep drive. Starting early in pathology, mice display increased wake and decreased NREM/REM. Effects on total sleep depend heavily on decreased REM bout number and duration.ConclusionBlood glucose levels in P301S mice fail to rise in response to glucose injection. Brain glucose/lactate fluctuations are maintained suggesting tau pathology preserves glucose utilization. Conversely, decreased NREM and REM and increased wake were exhibited with tau pathology. EEG spectral analysis indicates decreased beta activity, suggesting diminished GABA activity. Increased theta during NREM suggests increased pressure to transition to REM sleep. Reduced sleep drive is illustrated by increased delta in wake. Together, tau pathology reduces sleep drive and ability to switch between vigilant states despite increased sleep need. These results suggest that tau pathology causes excitatory/inhibitory imbalance and sleep impairment but does not contribute to profound effects on cerebral metabolic rhythms.
The role of TGFbeta signals in Lead (Pb)‐induced Cerebral Amyloid Angiopathy
Authors: Gu Huiying , Luo Alexandria , Zheng Wei , Du Yansheng 
Published: January 2025

AbstractBackgroundMounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) results in longitudinal decline in cognitive function and brain atrophy. In animals, chronic Pb exposure can increase brain Aβ deposition. However, it remains unclear how Pb induces different natures of amyloid depositions and underlying mechanisms to contribute to the pathogenesis of AD and related dementia.MethodFemale APP/PS1 mice at 8 weeks old were administered with either 50 mg/kg Pb‐acetate (PbAc) (i.e., 27 mg Pb/kg) via oral gavage or an equivalent molar concentration of Na‐acetate (NaAc) once daily for additional 3 days or 8 weeks, in the presence or absence of an PAI‐1 inhibitor (12mg/kg). Parenchymal plaques and vascular amyloid deposition were quantitated by double staining with Thioflavin S and anti‐collagen IV antibody. Brain sections were also stained with anti‐NeuN (for neurons), anti‐myelin basic protein (for myelination) and anti‐rabbit FITC (for reactive astrocytes) antibodies. Assays for perivascular drainage as well as in vitro vascular binding with Aβ and microglial endocytosis were also performed.Result2‐month Pb exposure increased vascular Aβ deposits in neocortex of female APP/PS1 mice at the 4‐month of age by almost 300% (p<0.01). In contrast, Pb only increased parenchymal amyloid in the same brain areas by 86.7% (p<0.05). Demyelination, but not neuronal loss was observed in Pb‐treated AD mice that had significantly cognitive deficits detected by Y‐maze. Following Pb treatments, the ratios of Aβ1‐40/Aβ1‐42 in Pb‐treated groups increased to 0.58 ± 0.21 in the cortical parenchyma and 0.50 ± 0.10 in the brain vasculature, as compared to those in the control group (0.39 ± 0.09 and 0.11 ± 0.02). Additionally, TGF‐β1, Smad2, PAI‐1 and fibronectin were significantly induced in cerebrovasculature isolated from mice treated with 27 mg/kg of Pb for 3 days, accompanied by dramatic inhibition of perivascular drainage and vascular binding with Aβ1‐40. Furthermore, Pb exposure induced microglial TGF‐β1 and inhibited clearance of Aβ40 and LRP‐1 expression. Interestingly enough, all of these alterations induced by Pb exposure could be markedly ameliorated by a PAI‐1 inhibitor.ConclusionTGF‐β signals play distinct roles in Pb‐induced amyloid pathology.
Brain arteriolosclerosis is linked to lower gray matter volume in community‐based older adults
Authors: Tomash Ana , Tazwar Mahir , Yasar Md Tahmid , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos 
Published: January 2025

AbstractBackgroundBrain arteriolosclerosis is characterized by the thickening of vessel walls and arteriolar stenosis and is one of the primary pathologies of cerebral small vessel disease. Arteriolosclerosis is linked to lower cognitive and motor function, as well as an elevated risk of dementia. This study aimed to investigate the association of brain arteriolosclerosis with regional gray matter volumes in a large number of community‐based older adults.MethodData from ex‐vivo MRI and detailed neuropathological evaluation were collected from older adults (N = 882) participating in four longitudinal, clinical‐pathologic cohort studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Fig. 1A). Cerebral hemispheres from all participants were obtained at autopsy and imaged ex‐vivo with a multi‐echo spin‐echo sequence (ME‐SE) on 3T clinical MRI scanners approximately one month postmortem. The acquired voxel size was 0.6mm × 0.6mm × 1.5mm, and the scan time was approximately 30 minutes. The gray and white matter were segmented in the ex‐vivo MRI data. Subsequently, the gray matter underwent further division into 42 cortical and subcortical regions using multi‐atlas segmentation. The volume of each region was measured and normalized by the participant’s cerebral hemisphere volume. Following ex‐vivo MRI, a detailed neuropathologic assessment was performed on pathologies including arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts, Alzheimer’s pathology, Lewy bodies, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), and hippocampal sclerosis (Fig. 1B). For statistical analysis, linear regression was employed to explore the association of brain arteriolosclerosis with regional gray matter volumes (normalized by cerebral hemisphere volume) controlling for all other neuropathologies (Fig. 1B), demographics (age at death, sex, years of education), postmortem intervals, and scanner (Fig. 1A).ResultMore severe brain arteriolosclerosis was associated with lower volume in several gray matter regions, including medial orbitofrontal, superior frontal, pericalcarine, cuneus, and lateral occipital areas, independently of the effects of other neuropathologies (Figs. 2, 3).ConclusionThis study demonstrated that brain arteriolosclerosis is associated with lower volume in multiple gray matter regions independently of the effects of other vascular or neurodegenerative pathologies.
GWAS of neuropsychiatric symptoms in Mild Cognitive Impairment and Alzheimer’s Disease/Related Disorders
Authors: Wingo Aliza P. , Vattathil Selina M. , Wingo Thomas S. 
Published: January 2025

AbstractBackgroundApproximately 85% of individuals living with MCI or ADRD experience one or more neuropsychiatric symptoms (NPS), referred to as ADRD‐NPS. They include depression, anxiety, irritability, apathy, agitation, delusions, hallucinations, and sleep disturbances. ADRD‐NPS are associated with greater functional impairment, higher caregiver burden, and earlier institutionalization. However, we have limited insight into mechanisms underlying ADRD‐NPS to develop effective treatments. Here, we conducted a GWAS of ADRD‐NPS to investigate genetic loci contributing to ADRD‐NPS.MethodWe included only participants with MCI or ADRD in the GWAS of ADRD‐NPS. A total of 12,728 participants of European ancestry recruited by the U.S. Alzheimer’s Disease Research Centers were included. Among them, 23% had MCI and 77% had ADRD. ADRD‐NPS were assessed with the NPI‐Q. We conducted a GWAS for each of the ADRD‐NPS domains. Additionally, we performed a multivariate GWAS of all ADRD‐NPS domains simultaneously using a linear mixed model.ResultBoth the GWAS of anxiety and the GWAS of delusion identified several genome‐wide significant SNPs (p < 5 × 10‐8) located in a 41 Kb region of chr19q13.32 after adjusting for sex, MCI/ADRD status, genotyping batch, and 10 PCs. Since this region overlaps the APOE gene and thus these signals may be related to severity of cognitive impairment (MCI or ADRD), we performed a stratified GWAS in MCI and ADRD separately. The stratified GWAS found that some of these signals remained genome‐wide significant in ADRD participants (n = 9766) for both anxiety and delusion, respectively. Furthermore, we found that APOE e4 allele was strongly associated with ADRD‐NPS in the domain of anxiety (p = 1.9 × 10‐10), hallucinations (p = 1.6 × 10‐5) and delusions (p = 4.0 × 10‐12) after adjusting for sex, MCI/ADRD status, genotyping batch, and 10 PCs. Lastly, the multivariate GWAS of ADRD‐NPS identified genome‐wide significant SNPs on chromosome 14 (KIF26A) and 19 (APOE) after adjusting for sex, MCI/ADRD status, genotyping batch, and 10 PCs.ConclusionAPOE e4 and genetic variants in chr19q13.32 are associated with anxiety and delusion experienced by individuals with MCI or ADRD. We plan to integrate the GWAS findings with human brain proteomic data to identify brain proteins contributing to ADRD‐NPS to nominate targets for therapeutic investigation.
Senescent cells, a promising target for Alzheimer's Disease
Authors: Guerrero Ana 
Published: January 2025

AbstractBackgroundSenescence is a cellular response to stress or damage leading to a state of irreversible growth arrest. As we age, the number of senescent cells increases and directly contributes to age‐related conditions including cancer and neurodegenerative diseases. As a result, there is a growing interest to therapeutically target senescence either with drugs eliminating senescent cells (senolytics) or with strategies to modulate their secretory phenotype among others. Importantly, even though the accumulation of senescent cells is a key hallmark of ageing, and ageing the biggest risk factor for Alzheimer´s Disease (AD), the extent of senescence in the brain during AD remains elusive.MethodWe have developed a new preclinical model combining a mouse model of amyloid pathology (App NL‐G‐F knock‐in) with both a senescence transgenic reporter and a conditional targeted cell ablation lines based on p16Ink4a expression, a well‐known senescence marker. This model allows to track the onset of cellular senescence in response to amyloid deposits and to evaluate the therapeutic potential of the selective elimination of senescent cells.ResultIn this Presentation, I will give an overview on the available strategies to therapeutically target senescence and share some preliminary data obtained with our new preclinical model.ConclusionThere is an urgent need to explore new therapeutic avenues to improve the lives of those affected by AD, either by delaying the onset and progression of the pathology, or by ameliorating the symptoms of this devastating disease. Cellular senescence constitutes a promising target that warrants further investigation.
Defects in the signaling lipid PI3P may contribute to dendritic spine loss in Alzheimer’s disease
Authors: Rivero‐Rios Pilar , Uygun Tunahan , Chavis Garrett D. , Sutton Michael A. , Weisman Lois S. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of dementia worldwide. The recent announcement that lecanemab, a monoclonal antibody targeting amyloid‐b, can slow down cognitive decline in AD is a great step forward in the battle against the disease. However, the modest success achieved in the clinical trial speak to the need for developing additional pharmaceutical approaches to target other key features of AD. Notably, dendritic spine loss correlates more strongly to cognitive decline in AD than amyloid pathology, but the molecular causes remain poorly understood.MethodWe performed immufluorescence studies in cultured primary hippocampal neurons to evaluate endosomal defects and dendritic spine loss.ResultWe discovered that endocytic recycling of cell surface receptors from endosomes to the plasma membrane is key to maintain dendritic spine density in cultured hippocampal neurons. There are two major pathways for endocytic recycling: SNX27‐Retromer and SNX17‐Retriever. Our unpublished data show that both pathways contribute to dendritic spine maintenance by promoting the recycling of different sets of surface proteins at synapses. Moreover, alterations in either pathway result in a loss of dendritic spines.In addition, we found that the recruitment of SNX17 and SNX27 to synapses is dependent on the signaling lipid phosphatidylinositol‐3‐phosphate (PI3P). Notably, a lipidomic study revealed that PI3P levels are decreased in postmortem brain tissue from AD patients as well as in AD‐related mouse models. Thus, the observed decrease in PI3P levels may contribute to spine loss in AD and act in part by dysregulating endocytic recycling at synapses.ConclusionContinued studies of the connections between PI3P, spine density and AD may ultimately open avenues for new therapeutic approaches for this devastating disease.
Harbingers of Disease: Decoding Shared Multi‐Omic Changes in Human and Mouse Models of Alzheimer’s Disease
Authors: Swarup Vivek , Morabito Samuel , Miyoshi Emily , Head Elizabeth , Green Kim N. 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) presents a significant challenge in understanding its complex pathophysiology, owing to its multifaceted genetic and environmental factors. Despite extensive research, the translatability of findings from animal models to human conditions remains a critical hurdle. This study addresses the need to uncover shared molecular changes in AD by comparing human and mouse models, thereby enhancing our understanding of the disease’s underlying mechanisms and improving the prospects for effective treatments.MethodThe study employed a comprehensive multi‐omic approach, integrating spatial transcriptomics (ST) and single‐nucleus RNA‐sequencing (snRNA‐seq) data from postmortem human prefrontal cortical tissue and 5xFAD mouse brains across various stages of AD pathology, including AD in Down Syndrome (DS). An unbiased clustering algorithm, BayesSpace, was used to identify distinct clusters in both human and mouse datasets. Cross‐species differential expression analysis and multi‐scale co‐expression network analysis using hdWGCNA were conducted. These analyses were complemented with fluorescent amyloid imaging to correlate gene expression changes with amyloid pathology.ResultThe analysis revealed evolutionary‐conserved AD transcriptional changes, particularly in genes associated with amyloid‐beta response and microglial activation. The study identified upregulated genes with age in the mouse model, with variances across different brain regions. Co‐expression network analysis exposed amyloid‐associated gene modules that were consistent across species. Additionally, the integration of spatial and single‐cell data elucidated cellular diversity and transcriptomic alterations within the AD brain, providing a spatial context to the observed molecular changes.ConclusionThis study successfully decodes shared multi‐omic changes in human and mouse models of Alzheimer’s Disease, highlighting key molecular similarities and differences across species. The findings underscore the significance of a multi‐faceted, integrated omic approach in understanding AD pathogenesis. This cross‐species analysis not only advances our knowledge of the molecular underpinnings of AD but also opens avenues for developing more accurate and translatable AD models, ultimately guiding the discovery of potential therapeutic targets.
BIN1 regulation of brain region‐specific tau pathogenesis and propagation
Authors: Ponnusamy Moorthi , Wang Shuai , Yuksel Melike , Patel Om , Hansen Mitchell , Collier Lisa , Thinakaran Gopal 
Published: January 2025

AbstractBackgroundBIN1, the second strongest GWAS risk factor for late‐onset Alzheimer’s disease (AD), encodes a nucleocytoplasmic adaptor protein that plays many roles in multiple tissue and cell types. It is known that BIN1 can directly bind to tau in vitro, and neuronal BIN1 expression decreases in patients with AD. Accumulation of intracellular hyperphosphorylated tau is a hallmark pathogenic feature of AD and related tauopathies. Neuronal BIN1 localizes to presynaptic terminals and influences excitatory synaptic transmission, however, the molecular events underpinning neuronal BIN1 function in disease progression in vivo has remained unclear.MethodTo mimic the decrease in neuronal BIN1 expression in Alzheimer’s patients, we recently generated and characterized tau pathology in novel conditional Bin1 knock‐out (tau P301S transgenic mice lacking BIN1 expression in the forebrain excitatory neurons; PS19:Bin1‐cKO) and examined tau pathogenesis. In order to establish a direct connection between neuronal BIN1 and the degree of neurofibrillary tangle pathology, we injected tau seeds into the brains of PS19:Bin1‐cKO mice and investigated tau propagation and spreading.ResultsWe observed that the loss of excitatory neuronal BIN1 expression attenuates tau accumulation and neurodegeneration selectively in the hippocampus, entorhinal/piriform cortex, and amygdala. Furthermore, the knock‐out mice had significantly reduced neuroinflammation, preservation of hippocampal synapses, and complex transcriptomic changes in the neurons and glial cells. In addition, we observed reduced brain‐derived tau seed propagation from the site of injection in the hippocampus into connected cortical regions. Instead, there is an accumulation of Ser202/Thr205 phosphorylated tau and MC1+ tau in hippocampal CA1 pyramidal neurons. Thus, our findings reveal an interesting region‐specificity in neuronal BIN1 regulation of tau pathogenesis and propagation.ConclusionOverall, our findings reveal that excitatory neuronal BIN1 promotes region‐specific tau pathogenesis and tau propagation through neuroanatomically connected brain regions. These findings add to our understanding of in vivo BIN1 function in the context of tau pathogenesis, revealing cell‐autonomous and non‐cell‐autonomous mechanisms involved in BIN1 modulation of tau burden in AD.
Differential alterations of lateral entorhinal cortex impact on CA1 pyramidal neuron subpopulations in PS19 mouse model of tauopathy
Authors: Tian Chengju , Reyes Isabel , Thangavel Mohankumar , Masurkar Arjun V. 
Published: January 2025

AbstractBackgroundThe lateral entorhinal cortex (LEC), followed by area CA1 of hippocampus, are interconnected brain areas implicated early in Alzheimer’s disease (AD). Processing of LEC input by CA1 pyramidal neurons (PNs) is critical for non‐spatial memory, in which deficits are seen in early AD. How this process is affected by tauopathy is unclear. Furthermore, CA1 PNs are divided into molecularly and functionally distinct superficial (sPN) and deep (dPN) subpopulations. It is additionally unclear if and how LEC input processing by these subpopulations are differentially impacted.MethodLEC of female PS19 and WT mice (8‐10 month old) were injected with an AAV expressing channelrhodopsin ChrR2. After two weeks, acute hippocampal slices were prepared and whole cell patch clamp recordings were performed on dPNs/sPNs of distal CA1 in current clamp and voltage clamp mode using a potassium‐ or cesium‐based intracellular solution, respectively. Synaptic responses were measured in current clamp and voltage clamp mode, with LEC axons optogenetically activated by blue LED light. In current clamp, excitatory postsynaptic potentials (EPSPs) were measured with inhibition blocked. In voltage clamp, excitatory postsynaptic currents (EPSCs) were evaluated by holding membrane potential at ‐70mV, and inhibitory postsynaptic currents (IPSCs) were evaluated by holding at 0mV.ResultAll data is n = 3‐8/group. Compared to WT, LEC‐driven EPSCs showed significant reductions in PS19 sPNs (18.7pA vs. 8.4pA, p = 0.0016) but were unchanged in dPNs (12.4pA vs. 13.6pA, p = 0.2841). Measurements of LEC‐driven EPSPs showed analogous findings. There was no change in paired pulse ratio, ruling out presynaptic changes. There was no change in EPSP decay time constant or temporal summation of the EPSP, ruling out changes in postsynaptic excitability. In contrast to excitation, LEC‐driven IPSCs were unchanged in PS19 versus WT mice in both sPNs (45.7pA vs. 51.9pA, p = 0.62) and dPNs (25.46pA vs. 22.3pA, p = 0.22).ConclusionLEC drive of CA1 PNs exhibits a cell type‐specific vulnerability to tauopathy, with sPNs differentially susceptible to a reduction of excitation, without changes in feedforward inhibition. Our results further support a postsynaptic mechanism that may be due to spine loss, changes in spine morphology, or shifts in glutamate receptor expression.