bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reactive astrocytes with reduced function of glutamate transporters in the AppNL‐G‐F knock‐in mice
Authors: Loera‐Valencia Raúl , Srivastava Ipsit , Goikolea Julen , Kaya Tamer Ayberk , Leal Maria Latorre , Iglesias Marta Pereira , Alvarez‐Jimenez Laura , Arroyo‐García Luis Enrique , Shimozawa Makoto , Nilsson Per , Fisahn André , Lindskog Maria , Maioli Silvia 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is associated with synaptic and memory dysfunction. A pathological hallmark of the disease is reactive astrogliosis, with reactive astrocytes surrounding amyloid plaques in the brain. Astrocytes have also been shown to be actively involved in disease progression, nevertheless, mechanistic information about their role in synaptic transmission during AD pathology is lacking. Astrocytes maintain synaptic transmission by taking up extracellular glutamate during synaptic activity through astrocytic glutamate transporter GLT‐1, but its function has been difficult to measure in real‐time in AD pathology.MethodIn this study, we used an App knock‐in AD model (AppNL‐G‐F) carrying the Swedish, Arctic and Beyreuther mutations associated with AD and exhibiting AD‐like Aβ plaque deposition and memory impairment. Using immunohistochemistry, patch‐clamp of astrocytes, and western blot from tissue and FACS isolated astrocytes.ResultWe found that AppNL‐G‐F mice at 6‐8 months of age have astrocytes with clearly altered morphology compared to wild‐type (WT). Moreover, astrocyte glutamate clearance function in AppNL‐G‐F mice, measured as electrophysiological recordings of glutamate transporter currents, was severely impaired compared to WT animals. We suggest that the loss of function of GLT‐1 is not related to altered protein levels since no changes in GLT‐1 levels in synaptosomes nor FACS‐isolated astrocytes from AppNL‐G‐F mice were found. This phenotype can potentially alter synaptic transmission and/or contribute to glutamate excitotoxicity.ConclusionOur data suggest that astrocytic glutamate transporters are affected by excess Aβ42 in the brain contributing to synaptic dysfunction in the hippocampus. Thus, our data indicate that restoring astrocyte synaptic function could be a potential therapeutic strategy to treat AD.
Isoform‐dependent regulation of Tau function by phosphorylation
Authors: Naseri Nima N , Tomlinson Taylor L , Shimogawa Marie , Shalem Ophir , Petersson E. James , Rhoades Elizabeth 
Published: January 2025

AbstractBackgroundTau is a neuronal microtubule associated protein whose interactions with microtubules are regulated by phosphorylation. Tau has numerous putative phosphorylation sites, but it is unclear which combinations of Tau phosphorylation co‐occur in the normal state and precisely how they impact Tau function. Adding further complexity, there are six major Tau isoforms arising from alternative splicing. These isoforms are expressed in an age‐dependent manner: only 3R (3‐repeats in the microtubule‐binding domain) Tau is expressed in development, while both 3R and 4R (4‐repeats in the microtubule‐binding domain) Tau isoforms are present in adult brain.MethodWe applied time course studies in mice, sub‐cellular MT fractionation from human iPSC‐derived neurons as well as biophysical assays using recombinant Tau phospho‐mimics and purified tubulin to investigate the isoform‐specific impacts of phosphorylation to Tau‐tubulin/MT interactions. Significantly, we semi‐synthesized Tau, modified with bonafide site‐specific phosphorylation and a fluorescently labeled unnatural amino acid, to measure the impact of phosphorylation in the proline‐rich region to tau‐tubulin binding at the single molecule level.ResultOur data reveal that in each of the platforms investigated, 3R Tau function is more dramatically altered by phosphorylation as compared to 4R Tau upon modification at the same residues. These isoform‐specific differences were most pronounced at phosphorylation sites in the proline‐rich region of Tau, and significantly less so in the C‐terminal tail.ConclusionOur findings highlight the possibility of differential regulation of Tau isoforms that reflect different roles for Tau in the developing and adult brains. Overall, our findings provide insight into functional regulation of Tau‐tubulin/MT interactions by phosphorylation, which is critical for ultimately understanding the significant increase in phosphorylated Tau found in pathology and whether specific phospho‐Tau forms can be targeted for therapeutic intervention.
Maintaining Brain Resilience with prevents disease in rat and mouse models of Alzheimer’s disease and restores brain health and cognition in chronic traumatic brain injury
Authors: Pieper Andrew A. 
Published: January 2025

AbstractBackgroundEven when patients carry disease‐causing mutations their entire lives, they do not develop Alzheimer’s disease (AD) until later in life. The reason for this loss of brain resilience is not known, and two of the greatest risk factors for developing AD are aging and traumatic brain injury (TBI). Unfortunately, there are currently no protective treatments for patients that prevent the development of AD.MethodWe assessed the ability of early treatment with the NAD+/NADH‐normalizing P7C3 compounds to prevent disease in the 5xFAD mouse and TgF344 AD rat amyloid‐based preclinical models of AD. We also assessed the therapeutic efficacy of delayed treatment with P7C3 compounds in a mouse model of chronic TBI. Lastly, we examined the ability of P7C3 compounds to protect human brain microvascular endothelial cells (HBMVECs) of the blood brain barrier (BBB) from oxidative stress, such as occurs in human AD.ResultEarly administration of P7C3‐A20 to presymptomatic 5xFAD mice prevented plaque accumulation, tau phosphorylation, blood‐brain barrier deterioration, oxidative stress, DNA damage, neuroinflammation, impaired hippocampal neurogenesis, deficient synaptic plasticity, neurodegeneration, and neuropsychiatric and cognitive impairment. Similar protective efficacy was noted in TgF344 AD rats, and delayed treatment with P7C3 compounds in chronic TBI restored the BBB, arrested chronic neurodegeneration, and fully normalized cognitive function one year after injury. Lastly, treatment of HBMVECs with P7C3‐A20 protected them from the deleterious effects of exposure to otherwise overwhelming oxidative stress.ConclusionOur results offer a first proof of principle for maintaining brain resilience to protect from developing AD, as well as the ability to reverse pathology and cognitive impairment in chronic TBI.
A Dual‐Color Fluorescent Reporting System for Dynamic Monitoring of Microglial Phagocytosis of Amyloid β Oligomers
Authors: Huang Xin 
Published: January 2025

AbstractBackgroundThe reduced phagocytosis of amyloid β (Aβ) by microglia is linked to increased cognitive decline in Alzheimer’s disease (AD) patients. Previous methods utilized anti‐Aβ antibodies and flow cytometry to reveal Aβ surface binding without internalization. This study introduces a “Two‐Color Fluorescent Reporting System” to overcome limitations, allowing differentiation between intra‐ and extracellular Aβ.MethodThis novel system utilizes AF647‐conjugated Aducanumab to visualize the surface‐bound amyloid β oligomers (Aβo), while pHrodo red serves to delineate intra‐lysosomal Aβo. Initial investigations focused on pHrodo‐Aβo phagocytosis by neuronal (HT22) and glial (U251) cells, comparing them with microglial cells (BV2). Subsequent examinations assessed the impact of glatiramer acetate (GA), a phagocytosis‐promoting peptide, on BV2 phagocytosis of Aβo in comparison to control without GA (basal) and oxidized ATP (oxATP), a P2X receptor antagonist. Flow cytometry was employed for temporal observations at 0.5, 1, 2, 4, and 24 hours, complemented by real‐time fluorescent microscopy for continuous monitoring of the entire process.ResultIn the initial study, BV2 cells exhibited Aβo surface adhesion and subsequent internalization after 2 hours, with the majority phagocytosed into lysosomes by 24 hours. Conversely, HT22 cells displayed surface adhesion of pHrodo‐Aβo without internalization, and after 24 hours, a modest internalization was observed. U251 cells demonstrated weak internalization after 2 hours and more apparent internalization after 24 hours, distinct from BV2. In the second study, the intralysosomal Aβo vs. surface Aβo ratio revealed significant differences between the basal, GA, and oxATP groups after two and 24 hours. Notably, the GA group exhibited increased pHrodo red‐Aβo in a completely acidified state after 24 hours.ConclusionThis study introduces an innovative dual‐color fluorescent reporter system, showcasing its potential for standardization in elucidating the intricate dynamics of microglial phagocytosis of Aβo. The results underscore the utility of this system, offering promise for advancing research and enhancing our understanding of Alzheimer’s disease pathology.
Links Between Microvascular and AD‐related pathology in the Medial Temporal Lobe
Authors: Perosa Valentina 
Published: January 2025

AbstractBackgroundCerebral small vessel disease (CSVD), which includes cerebral amyloid angiopathy (CAA) and arteriolosclerosis, often co‐occurs with Alzheimer’s disease (AD) pathology. The medial temporal lobe (MTL) is susceptible to hosting multiple AD pathologies, such as neurofibrillary tangles (NFTs), amyloid‐β plaques, phospho‐Tar‐DNA‐Binding‐Protein‐43 (pTDP‐43), as well as CSVD. Whether a causal relationship between these pathologies exists remains largely unknown, but one potential linking mechanism is the dysfunction of perivascular clearance. Our objective was to examine the burden of CSVD in the MTL of a pathological AD cohort and to establish the associations between CSVD and AD‐related pathologies, as well as between CSVD and enlarged perivascular spaces (EPVS), a potential indicator of clearance dysfunction.MethodThe study included 156 autopsy cases (mean age at death 79.4±10.9 years, 90 females) from the Massachusetts Alzheimer’s Disease Research Center (MADRC). One hemisphere was preserved in formalin, and 5 µm‐thick sections were cut from predefined regions of the hippocampal body and entorhinal cortex. These sections were subsequently stained using luxol fast blue with hematoxylin&eosin (LHE), and antibodies against amyloid‐β, hyperphosphorylated tau (At8), and pTDP‐43, following standard histological and immunohistochemical protocols. Utilizing deep‐learning models (Aiforia®), we computed the burden of CAA, amyloid‐β plaques, NFTs, and pTDP‐43 inclusions (Figure 1). Additionally, the severity of arteriolosclerosis and the % area of EPVS were evaluated on the LHE sections.ResultIn linear mixed effects models CAA was positively associated with the density of NFTs (Est = 7.21; p = 0.024; R2 = 69%) and amyloid‐β plaque burden (Est = 3.01; p<0.001; R2 = 61%) in all regions of interest. Arteriolosclerosis had no direct effect on parenchymal AD‐related pathologies but showed a positive interaction with CAA in the association with PVS enlargement. There was no relationship between pTDP‐43 inclusions and arteriolosclerosis.ConclusionThese results point towards an association between microvascular pathology and AD‐related pathology, possibly mediated by clearance dysfunction.
Arteriolosclerosis and LATE‐NC: two common and inter‐related contributors to Alzheimer’s‐type dementia
Authors: Nelson Peter T , Katsumata Yuriko 
Published: January 2025

AbstractBackgroundBrain arteriolosclerosis (B‐ASC) is a pathologic hallmark characterized by dysmorphic brain arteriolar wall thickening. B‐ASC is a common finding at autopsy in aged persons – some degree of B‐ASC is seen in >80% of brains beyond age 80 years – and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B‐ASC. We and others have also found that B‐ASC is associated with limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) and hippocampal sclerosis of aging (HS‐A). Here we re‐test this association using updated data from the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data set.MethodParticipants were assessed using the standardized NACC Uniform Data Set (UDS) at their local ADRC approximately annually, including participant demographics. Participants over 60 years of age at death (last seen during or after 2010) who met the study’s eligibility criteria were selected from the June 2023 (NACC62) data freeze. TDP‐43 neuropathologies were specified in three brain regions: amygdala, entorhinal/inferior temporal cortex and/or hippocampus, and neocortex. For cerebrovascular pathologies, data were available on arteriolosclerosis (none, mild, moderate, and severe), cerebral amyloid angiopathy (none, mild, moderate, and severe), infarcts and lacunes (no and yes), and microinfarcts (no and yes).ResultFollowing exclusions, the final analytic sample included 2558 participants, including brains with none (n = 370), mild (n = 909), moderate (n = 884), and severe (n = 395) B‐ASC severity. The mean age at death was 82.3 years and half were females. More than half of the participants had severe ADNC (Braak NFT stages V or VI). Over 28% of included participants had TDP‐43 pathology in hippocampus, whereas 16.4% had HS‐A. The associations between B‐ASC and both LATE‐NC and HS‐A were strong and specific when controlling for other factors such as age (P<0.001). This association remained robust when a subset analysis was performed only analyzing results from individuals who died after 2014.ConclusionThere is a strong, replicable association between B‐ASC and LATE‐NC/HS‐A in the NACC Neuropathology Data Set. Microvasculopathy appears to be a component of the LATE‐NC/HS‐A brain condition, which is remarkable because both B‐ASC and LATE‐NC are strongly associated with “Alzheimer’s‐type” amnestic dementia.
Using three‐dimensional histology to visualize vascular tau accumulation in Alzheimer’s disease
Authors: Hoglund Zachary T , Ruiz‐Uribe Nancy E , del Sastre Eric , Woost Benjamin , Bailey Joshua J , Zwang Theodore J , Bennett Rachel E 
Published: January 2025

AbstractBackgroundIn cerebral amyloid angiopathy, amyloid beta accumulates within the walls of blood vessels and contributes to impaired vascular integrity and function. In this work, we observe that tau protein similarly builds up along blood vessels in Alzheimer’s disease brain.MethodWe obtained frozen inferior temporal cortex from the Massachusetts Alzheimer’s Disease Research Center from n = 7 neuropathological confirmed Alzheimer’s disease donors and n = 6 normal aging controls. Three‐dimensional histology was carried out by cutting thick tissue sections (0.5 ‐ 1 mm) on a vibratome, clearing them using a modified CLARITY protocol, and immunolabeling for blood vessels, tau, neurons, and smooth muscle cells. Whole images were collected on a confocal or light sheet microscope and quantitatively examined using a combination of virtual reality tracing, MATLAB and Imaris. Adjacent tissues and isolated blood vessels were also measured for tau and phospho‐tau species using capillary western blotting to confirm imaging results.ResultIn total, n = 107 Alzheimer’s disease and n = 127 control blood vessels were examined using three‐dimensional histology. Nearly all measured blood vessels in AD brain had regions of enhanced tau accumulation at the vascular surface (within 3 microns). Tau associated with blood vessels was found throughout cortical layers I‐V and was observed to be primarily located on arterioles. Further, isolated blood vessels were significantly enriched for the tau N‐terminus and phospho‐tau 181 and 217.ConclusionThese data indicate that tau accumulates on blood vessels in the Alzheimer’s disease brain to a greater extent than previously appreciated. Further, they highlight the utility of three‐dimensional histology methods for visualizing and quantifying novel relationships between features in the brain.
Interconnected Dynamics of ‘Obesageing’: Intricate Relationship Between Obesity and Ageing Processes
Authors: Ghosh Shampa , Singh Krishna Kumar , Jha Suchita , Raghunath Manchala , Sinha Jitendra Kumar 
Published: January 2025

AbstractBackgroundObesity and ageing individually pose significant challenges to global public health, leading to preventable deaths. With an increasing geriatric population due to improved medical interventions, the intersection of these health issues becomes a critical concern worldwide. Both developed and developing countries grapple with the consequences of obesity, a major risk factor for various conditions like cardiovascular diseases, hypertension, type 2 diabetes, dementia, and neuropsychiatric diseases. Ageing, a natural process involving the gradual decline in physiological functions, shares similar comorbidities with obesity.MethodThis paper explores the concept of ‘Obesageing,’ highlighting the commonalities between the pathological aspects of obesity and the normal physiological processes of ageing. A unique rodent model, WNIN/Ob, has been established to mimic Obesageing, embodying traits of morbid obesity and premature ageing.ResultThe WNIN/Ob rodent model provides a platform to unravel the intricate interplay of mechanisms shared between obesity and ageing. This novel approach enhances our understanding of the complex relationship, paving the way for future strategies to address the escalating challenges posed by the simultaneous rise of obesity and ageing.ConclusionThe development of the WNIN/Ob rodent model signifies a breakthrough in comprehending the interconnected dynamics of obesity and ageing. This model serves as a valuable tool for investigating shared mechanisms, enabling the formulation of targeted strategies to mitigate the dual burden of obesity and ageing in the global population.
Unveiling and mapping the immune compartment in human Alzheimer’s disease
Authors: Buss Suzanne , Couper Kevin , Haley Michael , Brookes Emily , Gomez‐Nicola Diego 
Published: January 2025

AbstractBackgroundThe neuroimmune response, characterised by the proliferation and activation of microglial cells, is a driver of Alzheimer’s disease (AD). However, the extent of immune cell infiltration and interactions in the human AD brain are yet to be established in detail. While microglial cells are at the centre of this neuroimmune response, recent research has explored the possibility of peripheral immune cell involvement, typically focusing on T‐cell infiltration. There is currently a scarcity of studies using human tissues, with most of our understanding being derived from the study of animal models of AD‐like pathology, which lack the complexity and diversity of the human condition. Our study aims to advance our understanding of the complex interplay of immune cells and signals, helping to define how the neuroimmune response plays a role in driving AD pathogenesis.MethodsWe used two complementary techniques that provide a comprehensive map of the immune compartment through providing data rich results and spatial context. Samples were derived from human fresh‐frozen and FFPE post‐mortem tissues at all Braak stages, obtained from UK brain banks. We used fluorescence activated nuclei sorting to isolate the key cellular populations in the brain, as well as other non‐resident immune cells. Single‐nuclei RNA sequencing is used to establish not only the microglial transcriptional diversity in AD but also what other immune populations we see residing in the AD brain. Imaging mass cytometry, a highly quantitative technique that utilises up to 40 metal conjugated antibodies simultaneously, has also been deployed to provide spatial context of the main microglial phenotypes and immune cell interactions via single‐cell bioinformatic analysis.ResultsPreliminary data suggests that there are populations of peripheral immune cells infiltrating into the brain during AD which could be impacting disease outcome. Distinct microglial phenotypes have also been detected which reflect results of recent human single‐cell RNA sequencing studies. Future work includes increasing the sample number to further support our preliminary findings.ConclusionBy understanding the complex interplay of immune cells, not only with one another but with pathological and physical hallmarks, we could significantly advance our comprehension of AD pathogenesis and steer research into preventative and/or treatment options.
Primary progressive aphasia in Italian and English: a cross‐linguistic cohort study
Authors: Mazzeo Salvatore , Hardy Chris JD , Jiang Jessica , Morinelli Carmen , Moschini Valentina , Johnson Jeremy , Chokesuwattanaskul Anthipa , Volkmer Anna , Rohrer Jonathan D. , Ingannato Assunta , Bagnoli Silvia , Padiglioni Sonia , Nacmias Benedetta , Sorbi Sandro , Bessi Valentina , Warren Jason D 
Published: January 2025

AbstractBackgroundPrimary Progressive Aphasia (PPA) is a neurodegenerative disorder primarily affecting language abilities, with clinical variants (nonfluent/agrammatic variant [nfvPPA], semantic variant [svPPA], logopenic variant [lvPPA], and mixed‐PPA [mPPA]) categorized based on linguistic features. This study aims to compare PPA cohorts of native speakers of two different languages: English (an analytic language with deep orthography) and Italian (a synthetic language with shallow orthography).MethodsWe considered 166 English participants (70 nfvPPA, 45 svPPA, 42 lvPPA, 9 mPPA) and 106 Italian participants (14 nfvPPA, 20 svPPA, 42 lvPPA, 31 mPPA). Starting from the neuropsychological battery used to assess patients, we extracted one test for each cognitive and linguistic function that can be compared between cohorts. Comparisons were adjusted for symptom duration and Mini‐mental State Examination scores.ResultsThe English cohort included a higher proportion of nfvPPA patients (42% vs. 13%, p<0.001), while the Italian cohort showed higher proportions of lvPPA (25% vs. 38%, p = 0.019) and mPPA (5% vs. 29%, p<0.001). English nfvPPA patients were more frequently impaired in single‐word comprehension (60% vs. 8%, p = 0.013), while Italian nfvPPA patients exhibited more agrammatism (46% vs. 93%, p = 0.015). English svPPA had a higher proportion of surface dyslexia (68% vs. 30%, p = 0.046) and spelling impairment (38% vs. 10%, p = 0.021). English lvPPA had broader impairments, including single‐word comprehension (89% vs. 29%, p<0.001), repetition of words (61% vs. 26%, p = 0.03), nonverbal working memory (69% vs. 36%, p = 0.005), and visuospatial perception (89% vs. 25%, p<0.001).ConclusionsThis study reveals linguistic and cognitive distinctions between English and Italian PPA cohorts, emphasizing the impact of language‐specific characteristics on symptomatology. Cultural and linguistic nuances should be considered in PPA diagnosis and management, calling for more tailored assessments and criteria.