bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct cerebrovascular pathways underlying Alzheimer’s disease‐related neurodegeneration
Authors: Mohanty Rosaleena , Marseglia Anna , Westman Eric 
Published: January 2025

AbstractBackgroundCerebrovascular pathology is an emerging key contributor to neurodegeneration in both non‐pathological and pathological aging. Cerebrovascular pathology manifests as different markers in the brain (gross‐ vs micro‐infarcts, chronic vs acute infarcts, etc.). The relative association or dissociation of these markers with Alzheimer’s disease (AD) pathologies, copathologies and neurodegeneration remains poorly understood. Thus, we investigated how distinct cerebrovascular markers relate to AD pathology, copathologies, and neurodegeneration.MethodWe included 77 individuals with postmortem neuropathologic examination and in vivo MRI (antemortem‐to‐postmortem interval = 5±3 years) from the Alzheimer’s Disease Neuroimaging Initiative. We investigated eight markers of cerebrovascular burden at postmortem including atherosclerosis of the circle of Willis, cerebral amyloid angiopathy (CAA), gross chronic infarcts, gross chronic hemorrhages, chronic microinfarcts, arteriolosclerosis in subcortical white or gray matter, white matter (WM) rarefaction and other vascular changes (acute infarcts, vascular malformation, etc.). Using multiple correspondence analysis, we identified a lower dimensional representation and assessed contributions of these eight markers. Further, we correlated the identified dimensions with other neuropathologic changes (Aβ, tau, neuritic plaques, Lewy body, TDP‐43, hippocampal sclerosis, and atrophy) and antemortem MRI measures (total gray matter volume and white matter hypointensity volume).ResultIndividuals were 83±7 years‐old at death and included 26% women, 56% APOE‐ε4 carriers and 75% individuals with confirmed AD neuropathologic change. Multiple correspondence analysis on the eight cerebrovascular markers resulted in two dimensions (Fig. 1). Dimension 1 was characterized by presence of gross chronic infarcts, chronic microinfarcts, mild WM rarefaction, severe arteriosclerosis, and severe atherosclerosis. Dimension 1 was significantly associated with higher postmortem cortical atrophy (r = 0.2), hippocampal atrophy (r = 0.4), hippocampal sclerosis (r = 0.3) and antemortem WM hypointensity volume (r = 0.3). Dimension 2 was characterized by moderate atherosclerosis, moderate arteriosclerosis, moderate WM rarefaction, severe CAA, presence of chronic hemorrhages and other vascular changes (acute gross‐/micro‐infarcts, microhemorrhage, vasculitis, blood vessel mineralization). Dimension 2 was significantly associated with higher postmortem Aβ (r = ‐0.4), tau (r = ‐0.3), neuritic plaques (r = ‐0.3) and hence, AD neuropathologic change (r = ‐0.3).ConclusionWe identified two data‐driven cerebrovascular pathways, one AD‐unspecific (dimension 1) and one AD‐specific (dimension 2). Cerebrovascular burden may differentially manifest in individuals depending on the underlying cause of neurodegeneration.
Evaluation of the functional activity in synaptic genes related to polygenic risk for Alzheimer’s disease using a Massively Parallel Reporter Assay
Authors: Perlaza Danna , Gil Laia Lidón , Cervantes‐González Alba , Serrano‐Requena Sara , Tamayo Natalia Valle , Sánchez‐Aced Érika , Álvarez‐Sánchez Esther , Escabias Joaquim Aumatell , Muñoz Laia , Dolcet Sonia Sirisi , Dols‐Icardo Oriol , Lleo Alberto , Belbin Olivia 
Published: January 2025

AbstractBackgroundSynaptic degeneration is a primary neuropathological factor associated with cognitive decline in Alzheimer’s disease (AD). In 2021, we generated a synaptic Polygenic Risk Score (PRS) that comprised only 8 variants within 6 synaptic genes (APOE, PICALM, BIN1, PTK2B, DLG2 and MINK1) that predicted AD with 72% accuracy in two neuropathological cohorts. This supports the hypothesis that genetic variants that regulate an individual’s vulnerability to AD‐related synapse degeneration could be used to identify individuals at‐risk for AD prior to the appearance of clinical symptoms. The aim of this study was to determine whether the constituent variants of the linkage disequilibrium (LD) blocks represented by the PRS have regulatory activity in vitro.MethodWe cloned an oligonucleotide library of 137 putative regulatory variants each represented by 5 barcodes per allele into pMPRA1 vector. Then we transfected the plasmids into HEK293 cells (n = 5). We extracted DNA and RNA from the cells and sequenced on an Illumina MiSeq. Using the mpra package in R, we normalized the tag counts to a common size of 10 million reads and computed paired log ratios of RNA/DNA counts for each barcode. We used weighted linear models to test for differential activity of the minor versus the major allele of each SNP using the mpralm function, adjusting for multiple testing using the Benjamini‐Hochberg method.ResultWe acquired approximately 15 million reads of DNA and RNA from 5 independent experiments. We found that 35 out of the 137 SNPs tested had differential activity between alleles (adj. p <0.05, Figure 1A). Three of the SNPs that showed regulatory activity were included in the PRS (BIN1: rs17014923 and rs35114168; DLG2: rs286043) and the remaining 32 are captured on LD blocks within the synaptic PRS.ConclusionAll LD captured by the synaptic PRS contain SNPs that impact on regulatory activity, thus supporting a potential mechanism by which changes in the expression of these specific loci that encode synaptic proteins could lead to a modified cumulative risk for AD. Further studies to determine the precise mechanism involved in this regulatory activity at the synapse could guide future therapeutic strategies for AD.
Synapse‐enriched miRNA expression in Alzheimer’s disease cortex tissue
Authors: Gil Laia Lidón , Núñez‐Llaves Raúl , Serrano‐Requena Sara , Perlaza Danna , Cervantes‐González Alba , Tamayo Natalia Valle , Álvarez‐Sánchez Esther , Sánchez‐Aced Érika , Dolcet Sonia Sirisi , Dols‐Icardo Oriol , Lleo Alberto , Pérez‐González Rocío , Belbin Olivia 
Published: January 2025

AbstractBackgroundSynapse degeneration is one of the earliest changes in Alzheimer’s disease (AD) and is the major neuropathologic correlate of cognitive impairment. The aim of this study was to characterize microRNA (miRNA) dysregulation at AD synapses post‐mortem brain tissue and explore the specificity for AD.MethodWe prepared synaptosomes (SYN) by serial ultracentrifugation of 10 AD (mean age = 77.4±13.3) and 10 control (CN; mean age = 72.3±18.8) temporal cortex samples over a sucrose gradient and saved the homogenates (H). We extracted and quantified miRNA from SYN and H fractions by TaqMan Advanced miRNA Assay‐Openarray system. We calculated deltaCt and performed linear regression to identify differentially expressed (DE) miRNA across AD and CN SYN, adjusting for multiple testing using Benjamini‐Hochberg method (α<0.05). We identified gene targets of the DE miRNA using two predictive databases (TargetScan and miRDB) and performed pathway analysis using the Panther database. We selected miRNA candidates that are DE in AD synapses and performed a follow‐up study in 4 different brain regions of 10 CN (mean age = 80.7±12.9), 10 AD (mean age = 77.4±13.3) and 10 non‐AD tauopathy (mean age = 70.6±6.4) cases to determine the regional distribution and the AD specificity.ResultSynapse fractions were isolated demonstrating a 3.2‐fold enrichment in the synaptic protein VAMP‐2 (p<0.001) compared to homogenates. We detected 411 miRNA in H and 432 in SYN of the total in the panel with 89% overlap between AD and CN in SYN. Three miRNA from the same family (miR‐132‐3p, miR‐132‐5p and miR‐212‐3p) were under‐expressed and 2 miRNA (miR‐181a‐3p and miR‐1260a) were over‐expressed in AD compared to CN SYN. The gene targets of these miRNA were overrepresented in pathways regulating synaptic and mitochondrial function. In addition, targets of miR‐132 also were overrepresented in pathways related to tau pathology, Aβ production, interleukin production, apoptosis and oxidative stress. We will describe the regional distribution in AD brains post‐mortem and the specificity of the changes to AD by comparing to non‐pathological controls and non‐AD tauopathies.ConclusionmiRNA that are dysregulated in AD synapses target genes that are involved in pathways related to AD pathogenesis. Future studies will focus on the use of these miRNA as therapeutic targets.
Unraveling the role of Microglia in triggering High Fat Diet‐Induced Cognitive Decline
Authors: de Bem Andreza Fabro , Da Rosa Priscila Batista , Rodrigues Matheus Scarpatto , Engel Daiane F , Lazzarino Gisela Paola , de Oliveira Jade , Engblom David 
Published: January 2025

AbstractBackgroundExcessive dietary fat is not only a risk factor for metabolic disorders but also for premature cognitive decline and Alzheimer’s disease. Recent findings from our study revealed that even a few days of a high‐fat diet (HFD) are sufficient to disrupt hippocampal bioenergetics, activate microglia, and induce cognitive decline in mice. We hypothesize that microglia, rather than merely responding to diet‐induced damage, play a critical role in disrupting synaptic homeostasis.MethodTo investigate this hypothesis, we first assessed the effects of a HFD over time on cognitive impairment and hippocampal microglia activation in C57Bl6J male mice. Subsequently, we employed a chemogenetic approach using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) to conditionally inhibit microglia and evaluate the metabolic and behavioral outcomes induced by HFD.ResultRemarkably, only 10 days of HFD led to changes in hippocampal‐dependent behavioral tasks, such as the novel object recognition test, in 3‐month‐old male C57Bl6J mice, which persisted for 4 and 8 weeks. Sholl analysis and stereology confirmed morphological alterations and reactivation of microglia in the hippocampal CA1 region after 10 days of HFD, while metabolic parameters (adiposity and weight gain) were increased only after 4 and 8 weeks of HFD in C57Bl6J mice. Interestingly, sub‐chronic chemogenetic microglial inhibition (by DREADD) prevented memory impairment, evaluated by novel object recognition and object reallocation tests, in mice submitted to HDF for 7 days.ConclusionTogether our data support the notion that microglia play a critical role in triggering mechanisms of hippocampal damage induced by HFD.
Novel microglial markers that are specifically increased in early clinical AD stages
Authors: Blujdea Elena Raluca , Vermunt Lisa , Chen‐Plotkin Alice , Irwin David J , Boiten Walter , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Van Bokhoven Pieter , del Campo Marta , Teunissen Charlotte 
Published: January 2025

AbstractBackgroundTranscriptomic and pathological studies indicate that microglia play a key role in the progression of Alzheimer’s disease (AD). Throughout the stages of the AD continuum, there may be varying microglia phenotypes, such as the disease‐associated microglia (DAM). Microglia proteins have been detected in cerebrospinal‐fluid (CSF), providing a quantifiable avenue for potential stage‐detection. This study aims to find CSF microglial biomarkers to stage early‐ versus late‐AD.MethodIn total, 637 proteins were measured with proximity extension assay in 564 samples from the Amsterdam Dementia Cohort and from University of Pennsylvania. We defined four clinical groups spanning the AD continuum, as follows: 1) cognitively normal or subjective cognitive decline with negative AD‐ratio of CSF t‐tau/amyloid‐beta42 as controls, and positive AD‐ratio 2) subjective cognitive decline, 3) mild cognitive impairment, and 4) AD‐dementia. We selected 176 microglia‐enriched proteins based on human‐derived single‐cell RNA‐sequencing data and compared the groups by ANCOVA and Tukey’s HSD. Functional characterisation was done by associating proteins of interest to a list of microglial markers per state, such as DAM‐like proteins, that were identified through single‐cell Hierarchical Poisson Factorization.ResultsOverall, proteins showed distinct wave‐like patterns of dysregulation, presented in figure 1. 21 of the 176 microglial proteins were specifically upregulated in the early stages, while 20 were specific to the dementia stage. The proteins increased specifically in early stages consisted of receptors, possibly reflecting increased cellular recruitment, with an increase in DAM‐like proteins, particularly ones associated to MHC class II binding, such as CD4 and CD74, which are related to adaptive innate immune response.ConclusionIn conclusion, we identify varying microglial protein signatures spanning the AD stages, which may provide a basis for early‐staging biomarkers. Independent cohort and cross‐method validations are ongoing, and are necessary for the understanding of the hypothesized dynamicity of AD inflammation driven by microglia.
Sexual dimorphic synaptic dysfunction and cognition in a mouse model of Alzheimer’s disease
Authors: Findley Caleigh A. , McFadden Samuel A , Hill Tiarra , Peck Mackenzie R. , Quinn Kathleen , Hascup Kevin N. , Hascup Erin R. 
Published: January 2025

AbstractBackgroundGlutamatergic neurotransmission plays an essential role in learning and memory. Previous studies support a dynamic shift in excitatory signaling with Alzheimer’s disease (AD) progression, contributing to negative cognitive outcomes. The majority of previous studies have relied heavily on male physiology when determining these alterations in AD mouse models. Here, we examine sex differences in neurotransmission and cognition using the APPNL‐F mouse model of AD.MethodMale and female APPNL‐F and control C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR) at 2‐4 and 18+ months of age. Afterwards, mice were anesthetized with isoflurane while determining basal, stimulus‐evoked, and clearance rates of extracellular glutamate measures in the dentate gyrus (DG), CA3, and CA1 hippocampal subregions.ResultOur data support impaired spatial cognition in aged male and female APPNL‐F mice, but only aged females displayed recognition memory deficits compared to age‐matched control mice. Evoked glutamate release was elevated in the DG and CA3 of young APPNL‐F male mice that declined with age compared to age‐matched control mice. Young female APPNL‐F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age‐matched control mice. Both sexes of APPNL‐F mice exhibited decreased CA1 basal glutamate levels, but only males also showed CA3 reductions.ConclusionOur findings confirm a sex‐dependent hyper‐to‐hypoactivation glutamatergic paradigm in APPNL‐F mice. Additionally, we observed a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APPNL‐F mice than males. This research mirrors that of human AD pathology and provides further evidence of divergent AD pathogenesis between sexes.
The Effect of a Mediterranean and Western Diet on Cognitive Performance in Middle‐Aged Rats
Authors: Solch‐Ottaiano Rebecca J , Prats Madison , Engler‐Chiurazzi Elizabeth , Bix Gregory J , Maraganore Demetrius M 
Published: January 2025

AbstractBackgroundClinical studies indicate that mid‐life dietary patterns are a risk factor for cognitive decline. Adherence to a Mediterranean diet (MeDi) may promote healthy brain aging in contrast to a Western diet (WD), yet these diets have not been examined in pre‐clinical models. We hypothesized that consumption of the MeDi would have better cognitive performance compared to the Western diet in middle‐aged rats.MethodA subset of animals that provided diet‐specific fecal samples were used in this pilot study. Four‐month‐old male Fischer 344 rats were randomly assigned to a MeDi (n = 13) or WD (n = 7) for approximately one year. Animals then underwent neurobehavioral assessments including the Y‐maze, Morris water maze, and water radial arm maze to assess aspects of short‐ and long‐term memory. Data were analyzed via Student’s T‐test or Two‐Way Repeated Measures ANOVA where appropriate.ResultFor the Y‐maze, there was no difference in percent correct alternations between diet groups (p = 0.24), but the MeDi group had more total alternations compared to the WD group (p = 0.04). For the Morris Water Maze, the MeDi group had a decreased latency compared to the WD group (p = 0.03). Additionally, there was a Day x Diet Effect where the MeDi group had a decreased latency on days 3‐5 (p ≤ 0.01) compared to the WD group. There was no difference between diet groups for platform probe testing (p = 0.80). For the water radial arm maze, there was no difference in total (p = 0.56), working memory correct (p = 0.73), or working memory incorrect (p = 0.33) errors between diet groups. However, the WD group committed more reference memory errors compared to the MeDi group (p = 0.01).ConclusionMiddle‐aged animals consuming a MeDi demonstrated better aspects of learning and memory compared to animals consuming a WD. This data helps support clinical data suggesting that mid‐life dietary patterns impact cognitive function.
Role of mTORC1 signaling during memory consolidation in Alzheimer’s disease
Authors: Pereyra Magdalena , Schmidt‐Hieber Christoph , Bathellier Brice 
Published: January 2025

AbstractBackgroundMemory consolidation is an essential process for our everyday lives that is severely disrupted in Alzheimer’s Disease (AD). Memories are initially encoded in the hippocampus before being consolidated in the neocortex by synaptic plasticity processes that depend on protein synthesis. However, how molecular pathways affect synaptic signalling during memory consolidation in health and disease is unclear. We hypothesize that mechanistic Target Of Rapamycin Complex 1 (mTORC1), a central regulator of protein synthesis, plays an essential role in the communication between the hippocampus and the prefrontal cortex (PFC), and that mTORC1 dysregulation contributes to memory dysfunction in AD.MethodWe evaluated the role of mTORC1 in memory consolidation using a PFC‐dependent spatial object recognition (SOR) task. We used a mouse model of AD where mice express a human variant of the amyloid precursor protein (hAPP). We extend our results to another amyloid‐based mouse model (5XFAD 6,5 months old). Furthermore, we have evaluated mTORC1 pathway‐associated protein levels by Western Blot in both AD mice models.ResultFirst, we found that infusion of rapamycin, a selective mTORC1 inhibitor, into the PFC of WT animals immediately but not 3 hours after training disrupted long‐term memory expression.We observed that hAPP‐injected animals exhibited impaired long‐term memory expression in the SOR task (tested 6 weeks after hAPP injections in PFC) as well in the novel object recognition task compared to control mice. We evaluated mTORC1 pathway‐associated protein levels by Western Blot in hAPP‐expressing or control mice (1,5 months after viral injections) and found no differences in PFC or hippocampal samples. We repeated biochemical measurements in untrained hAPP or control mice 4 months after injections and found a trend towards downregulation of mTORC1 pathway‐associated protein levels in PFC.Finally we also observed great memory retention deficits in 5XFAD mice(6,5 months old) as well as a significant downregulation of mTORC1 pathway‐associated protein levels in PFC and hippocampal samples.ConclusionOur preliminary data suggest a downregulation of mTORC1 activation in two different AD mice models. Taken together, our results point to a key role of mTORC1 during memory consolidation in PFC that might be disrupted during AD.
Neuroprotective mechanism of syringic acid against traumatic brain injury induced cognitive dysfunction
Authors: Banderwal Rittu 
Published: January 2025

AbstractBackgroundTraumatic brain injury (TBI) due to external forces is a major cause of morbidity and mortality among people of all age groups, worldwide. Multiple biological processes like neuroinflammation, mitochondrial dysfunction, oxidative stress, amyloid β (Aβ) production, and tau hyperphosphorylation are involved in the pathogenesis of TBI. The role of neuroinflammation and oxidative stress has been suggested in the pathophysiology of brain injury‐induced cognitive dysfunction. Therefore, the present study was designed to explore the neuroprotective potential of syringic Acid (SA) against TBI.MethodSprague‐Dawley male rats were exposed to brain injury using a weight drop model and kept for a rehabilitation period of 14 days after injury. Afterwards, animals were administered with SA (25 and 50 mg/kg; per oral) daily, for 14 days. Further, various behavior parameters (NOR and MWM, locomotor activity and motor coordination), biochemicals (oxidants and antioxidants markers), activities of mitochondrial enzyme complexes and acetylcholinesterase (AChE), proinflammatory markers (TNF‐α, IL‐6) were evaluated in specific brain regions.ResultTraumatized rats followed by treatment with SA (25 and 50 mg/kg, per oral) for 14 days had significantly improved memory performance (increased time spent in the target quadrant, shortened escape latency to access the platform, and increased discrimination index) in Morris water maze and novel object recognition test when compared to control (TBI) groups. Further, SA treatment significantly restored antioxidant levels, attenuated increased AChE activity, and TNF‐ α levels, and regained mitochondrial capacities. The results of the present study show that the therapeutic effect of syringic acid might involve the inhibition of inflammatory reactions against brain injury‐induced cognitive dysfunction and neuroinflammation in rats.ConclusionThe current work demonstrates the neuroprotective effect of syringic acid in an experimental model of TBI. The study further suggests that the neuroprotective impacts of syringic acid may be related to its effects on TNF‐α, IL‐6 levels, oxidative stress pathways, and mitochondrial complex capabilities.
Mechanisms underlying AD‐sleep interactions: Recent insight from animal models
Authors: Veasey Sigrid C 
Published: January 2025

AbstractEpidemiologic studies have revealed a relationship between chronic persistent short sleep and the risk of dementia, yet whether short sleep is an early symptom of dementia or a contributor to dementia in humans has not been resolved. A rapidly growing body of research in animal models, however, strongly supports the concept that chronic disruption of sleep can impart significant injury in the brain consistent with some of the important pathology evident in Alzheimer’s disease (AD), the most common form of age‐related dementia. Transgenic models of AD pathology develop an increased density of amyloid plaques in response to chronic sleep loss, and this response is independent of significant stress. Studies in animal models without a genetic predisposition to AD pathology have identified late‐in‐life neural injury with many features observed in AD, including increased amyloid‐beta in the hippocampus, gliosis, memory impairment and loss of AD‐vulnerable neurons. Moreover, sleep loss impairs microglial capacity to clear amyloid fibrils. The chronically sleep‐deprived brain shows a unique proteomic profile in response to sleep loss, in cerebrospinal fluid (CSF) independent of plaque. Can we now identify who is at risk for AD‐like injury from a sleep disorder by assessing CSF, or identify subtypes of AD based on CSF findings? Noradrenergic locus coeruleus neurons are susceptible to loss in AD and sleep loss, where noradrenaline reuptake and lysosomal dysfunction in the neurons may contribute to injury. We should now determine whether chronic sleep loss in humans increases specific lysosomal markers in the blood or cerebral spinal fluid, and if so, these biomarkers may be used to identify individuals at risk and for early AD. As locus coeruleus activity can now be monitored non‐invasively in humans, this work also highlights novel avenues to detect early neural injury in Alzheimer’s and assess the effectiveness of early therapies. Thus, the time is right to integrate new findings in humans and in animal models of sleep disruption to effectively advance diagnostics and therapies for AD and related dementias.