bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carbonic anhydrase inhibitors improves cognitive functions in Tg2576 AD mice
Authors: Vazquez‐Torres Rafael , Parodi‐Rullan Rebecca M , Carey Ashley M , Fossati Silvia 
Published: January 2025

AbstractBackgroundOver the years, Alzheimer’s Disease (AD) has been identified as a multifactorial disease, with cerebral vascular dysfunction being one of the most common and early pathological features. Vascular risk factors (VRF) are thought to further increase AD risk and pathology. Cerebral Amyloid Angiopathy (CAA) is defined as the accumulation of amyloid‐beta (Aβ) on the vascular wall. CAA occurs progressively with age in human AD brains, vascular dementias, and the Tg2576 AD mouse model. The Tg2576 develops significant amounts of parenchymal Aβ plaques and vascular amyloid deposits making it a valuable model to study CAA and AD. To study the contribution of VRF to CAA and AD pathology, we induced hyperhomocysteinemia (HHcy) and hypertension (HP) in Tg2576 mice. We have shown that carbonic anhydrase inhibitors (CAi) decreased vascular amyloid accumulation and neuroinflammation and prevented cognitive impairment in TgSwDI mice. Here, we evaluated the effects of HP and HHcy in AD and CAA pathology. In addition, we assessed the beneficial effects of CAi in the Tg2576 with/without the presence of VRF.MethodsTo induce VRF, male and female WT and Tg2576 mice were fed a HHcy inducing diet and/or were given L‐NAME (NO inhibitor to induce HP) in the water starting at 5 months of age. To test the effects of CAi, the FDA‐approved CAi (Acetazolamide) was added to the diet starting at 5 months of age. Animals were then tested in a battery of behavioral measures including spatial learning and memory (barnes maze, fear conditioning, novel object recognition, open field, and rotarod), at 12 months of age.ResultThe presence of HHcy or HT worsens spatial learning and memory in the WT and Tg2576 mice. Preliminary results may suggest that treatment with CAi improved spatial learning and memory in the WT and Tg2576 mice, in the presence or absence of VRFs.ConclusionTaken together, our results suggest that VRF affect learning and memory in AD/CAA and non‐AD/CAA animal models. Importantly, we demonstrate that CAi is a promising treatment for treating mixed AD and CAA pathology.
Mitochondria as Sensors of Amyloid‐Beta Toxicity and Regulators of Inflammation in Cerebrovascular Endothelial Cells
Authors: Parodi‐Rullan Rebecca M , Carey Ashley M , Fossati Silvia 
Published: January 2025

AbstractBackgroundThe blood‐brain barrier (BBB) is a crucial regulator of cerebral homeostasis and function. Cerebrovascular endothelial cells (EC) are important components of the BBB, and EC damage and/or dysfunction may result in defects in brain clearance and perfusion, microhemorrhages, inflammation, and neurodegeneration. In addition to EC damage resulting from the presence of amyloid‐beta (Aβ) in Alzheimer’s Disease (AD) and Cerebral Amyloid Angiopathy (CAA), the presence of cardiovascular risk factors (CVRF) may further exacerbate cerebrovascular function and neurodegeneration. Particularly, ECs may be the most susceptible to Aβ and CVRF damage leading to the initiation and/or perpetuation of an inflammatory cascade in neurodegenerative diseases. Brain ECs are highly dependent on glycolysis and their mitochondria have important roles as signaling organelles, sensing cellular damage and mediating downstream pathways such as inflammation. Here, we aim to understand the mechanistic nature of endothelial mitochondrial dysfunction and its elicited pathways in Aβ and mixed (Aβ+CVRF) vascular pathologies. Understanding the mechanisms by which the mitochondria may mediate EC inflammation could pave the way to new roads for therapeutic advancements in the field.MethodHuman brain microvascular ECs were challenged with Aβ, Homocysteine (Hcy, a CVRF), or the combination. Mitochondrial ultrastructure, metabolic function, and inflammatory cascades were assessed.ResultThe presence of Aβ, but not Hcy, increased mitochondrial ROS production (mtROS) and induced deficits in mitochondrial respiration concomitant with a decrease in mitochondrial ATP production. Deficits in mitochondrial respiration were accompanied by an increase in glycolytic ATP production and, to some extent, the expression of proteins involved in glycolytic regulation. Mitochondrial fragmentation, as an indicator of mitochondrial damage, was assessed ultrastructually and by the analysis of the expression of fission proteins. Markers of EC activation were assessed to link mitochondrial dysfunction to EC inflammation.ConclusionDeficits in mitochondrial function and metabolism were associated with Aβ but not Hcy, and accompanied by the release of mtROS, a mitochondria damage associated molecular patterns (mtDAMP). This, in turn, was associated to an increase in EC inflammatory markers and barrier permeability. Overall, our results reveal a novel role for mtDAMPs in vascular dysfunction in the presence of Aβ and/or Hcy.
Comprehensive Clinical and Neuropathological Analysis of Down Syndrome Over Seven Decades of Life
Authors: Sukreet Sonal , Goodwill Vanessa , Ngolab Jennifer , Kim H Y. , Leisher Solana , Salehi Sahar N , Rafii Michael , Hiniker Annie , Rissman Robert A. 
Published: January 2025

AbstractBackgroundIndividuals with Down Syndrome (DS) exhibit a unique aging profile and have early‐onset Alzheimer’s Disease (AD) due to a triplication of the amyloid precursor protein (APP) gene on chromosome 21.MethodHere, we present a study of a 73‐year‐old non‐Hispanic White female with DS who underwent extensive clinical assessments for several decades. She had a cognitive and functional impairment consistent with DS and AD‐like symptoms. Post‐autopsy we did neuropathological and immunohistochemical analysis of the brain and retina.ResultNeuropathological and immunohistochemical analysis of the brain and retina revealed age and disease‐related changes. Numerous senile plaques, neurofibrillary tangles, Lewy bodies, and cerebral amyloid angiopathy were found throughout cortical and subcortical regions of the brain. Additionally, aberrant TAR DNA‐protein (TDP) 43 accumulation was observed in the amygdala and hippocampus. Immunofluorescent analysis of retinal tissue revealed the presence of amyloid deposits and phosphorylated tau in the ganglion cell and inner plexiform layer of the retina. Whole‐genome sequencing identified two SNPs, rs2802292 and rs4977756 (p < 0.05), linked to longer lifespans.ConclusionThis case report provides a comprehensive look into the clinical and neuropathological correlates of DS and documents unique clinical and pathological changes over 7 decades of life. We also explored hypotheses and potential mechanisms underlying increased lifespan in certain DS individuals despite progressive intellectual impairment and neurodegenerative pathologies.
Linkage analyses identifiy novel loci for Alzheimer’s disease in non‐Hispanic white families
Authors: Gomez Nicholas , Jean‐Francois Melissa , Hamilton‐Nelson Kara L. , Slifer Susan H. , Kunkle Brian W. , Cuccaro Michael L. , Martin Eden R. , Haines Jonathan L. , Reitz Christiane , Pericak‐Vance Margaret A , Vardarajan Badri N. , Beecham Gary 
Published: January 2025

AbstractBackgroundAlzheimer disease (AD) is a progressive dementia with high heritability. While genome‐wide association studies have identified common variation associated with AD, most of these loci have effects too small to explain the segregation of disease within multiplex families. As such, these multiplex families likely harbor novel genetic variants with strong effects, and thus still play an important role in assessing the genetic etiology of AD.MethodLinkage analyses were conducted on 670 individuals across 70 non‐Hispanic white (NHW) multiplex families for AD or mild cognitive impairment (MCI). A combination of genome wide array data and imputed data was used for the analyses. Rare variants, and low‐quality variants were excluded; remaining variants were LD pruned. Linkage analyses included both multipoint (MPT) and two‐point (2PT) approaches, with non‐parametric, parametric (affected only; AO), and parametric (age‐penetrance; AP) models. Primary analyses included (1) all AD+MCI individuals and (2) all AD+MCI individuals with age at onset 65 or lower (early‐onset AD). Sensitivity analyses included the same models but excluding MCI.ResultWe identified three primary linkage regions (HLOD > 3). For the MPT‐parametric‐AO model (AD+MCI) we identified chromosome 5q33 (HLOD = 3.017; 149MB‐156MB). A region on 8p11‐p21 (20MB‐37MB) was identified using the MPT‐parametric‐AO model (AD and early‐onset models; HLOD = 3.09, 3.27). Finally, chromosome 14q22‐24 (57MB‐70MB) was identified using the MPT‐parametric‐AP model (AD+MCI; HLOD = 3.56). The 5q33 region contains IL12B and ADAM19 genes. IL12B is an inflammatory cytokine that has been associated with amyloid burden and AD affection status. ADAM19 has been associated with AD progression and has functional links to APP. The 8p locus houses the CLU locus, first identified in large AD GWAS, while the 14q locus is near the PSEN1 gene. Further analyses of whole genome sequence data in these regions are ongoing.ConclusionThese analyses highlighted three regions and several genes connected with Alzheimer’s disease. These new loci, along with the established loci identified, may give more insight into the causes of AD for multiplex families.
Progranulin acts in lysosomes to promote neuronal survival and growth
Authors: Kaplelach Azariah K , Hall Justin A , Davis Skylar E. , Roth Jonathan R , Aljabi Qays , Hakim Ahmad R. , Savell Katherine , Day Jeremy J , Arrant Andrew E. 
Published: January 2025

AbstractProgranulin is a secreted pro‐protein that is necessary for maintaining lysosomal function and exerts anti‐inflammatory and neurotrophic effects in the brain. Loss‐of‐function GRN mutations, most of which cause progranulin haploinsufficiency, are a major autosomal dominant cause of frontotemporal dementia (FTD). Other GRN variants are associated with risk for FTD, Alzheimer’s disease (AD) and Parkinson’s disease. A common AD‐ and FTD‐associated GRN variant is also associated with mild reduction of progranulin levels. Thus, loss of progranulin’s lysosomal, anti‐inflammatory, and/or neurotrophic effects may underlie the association of GRN with neurodegenerative disease. Restoring progranulin is a promising treatment strategy for people with GRN mutations and perhaps for a broader group of patients. Understanding progranulin’s mechanism of action could enable design of optimal progranulin‐based therapies. Progranulin is constitutively secreted and can interact with several signaling receptors before being taken up and trafficked to lysosomes. It is not clear if progranulin’s anti‐inflammatory and neurotrophic effects are mediated by extracellular signaling or actions in lysosomes. To distinguish between these mechanisms, we developed lentiviral vectors expressing human progranulin (PGRN) fused to the transmembrane domain and cytosolic tail of LAMP‐1 (L‐PGRN). We used these vectors in mixed primary neuron/astrocyte cultures to test the hypothesis that progranulin’s neurotrophic effects are mediated in lysosomes. L‐PGRN was not secreted, but was trafficked to lysosomes, cleaved into granulins, and able to normalize lysosomal enzyme activity in Grn–/– neurons. L‐PGRN mimicked the protective effects of PGRN against NMDA excitotoxicity in primary cortical neurons. Delivery of L‐PGRN with neuron‐specific vectors confirmed that this effect was mediated directly in neuronal lysosomes. Further investigation revealed that L‐PGRN blocked the contribution of autophagy to excitotoxic cell death. L‐PGRN was also as effective as PGRN at promoting dendritic outgrowth in primary hippocampal neurons. A neuron‐specific L‐PGRN vector failed to promote neuronal outgrowth, but an astrocyte‐specific L‐PGRN vector promoted neuronal outgrowth similarly to the non‐specific L‐PGRN vector. Progranulin may therefore promote dendritic outgrowth through a non‐cell–autonomous mechanism involving astrocytes. We are currently investigating how progranulin may act in astrocytic lysosomes to change reactive and/or neurotrophic phenotypes.
Multi‐ancestry Genome‐wide Gene‐Vascular Risk Factors Interaction Analyses in Alzheimer’s Disease
Authors: Lee Annie J. , Cui Zuoqiao , Song Zhengwei , Reyes‐Dumeyer Dolly , De Jager Philip L. , Bennett David A. , Schneider Julie A. , Menon Vilas , Wang Yanling , Lantigua Rafael A. , Medrano Martin , Mejia Diones Rivera , Jiménez‐Velázquez Ivonne Z. , Kukull Walter A. , Biber Sarah A , Brickman Adam M. , Tosto Giuseppe , Kizil Caghan , Farrer Lindsay A. , Mez Jesse , Chung Jaeyoon , Vardarajan Badri N. , Mayeux Richard 
Published: January 2025

AbstractBackgroundCardio and cerebrovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and clinical Alzheimer’s Disease (AD), and over 70% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with a burden score of hypertension, diabetes, heart disease, and body mass index (BMI) by altering the normal astroglial‐vascular mechanisms that underly amyloid clearance. Stroke, defined by history of a clinical stroke or brain imaging, is a moderately robust risk factor for AD and dementia. The goal here was to identify genes that interact with CVRFs, incorporating stroke as an additional factor, on AD in multi‐ethnic cohorts.MethodWe conducted a genome‐wide gene‐CVRF score interaction analysis for AD, in 7,939 AD patients and 9,631 controls from eight multi‐ethnic cohorts of non‐Hispanic Whites, African Americans, and Hispanics including ADNI, NACC, NOMAS, WHICAP, EFIGA, and ROSMAP. A CVRF score was created from the first principal component of history of clinical stroke, hypertension, diabetes, and heart disease, and measured BMI. Gene‐based interaction test was performed with the adaptive gene‐environment interaction test. Results were summarized using a meta‐analysis. We investigated the association of pathological AD, amyloid‐β, or brain infarcts with gene expression and protein expression from the frontal cortex in ROSMAP using a generalized linear model. Age, sex, and the first three principal components were adjusted in the models.ResultThe interaction of CVRF score with FMNL2 on AD (p = 1.02E‐05) was identified and additional genes were identified to interact with CVRF score, including SLC22A14 (p = 1.44E‐06), AMMECR1L (p = 2.74E‐06), PRG3 (p = 2.76E‐06), CFAP99 (p = 5.22E‐06), ADPGK‐AS1 (p = 8.58E‐06) and BRINP1 (p = 6.29E‐06). ADPGK‐AS1 and FMNL2 gene expressions were associated with pathological AD (p = 0.004 and p = 0.0002). FMNL2 and BRINP1 gene expressions were higher in the brains of patients with brain infarcts (p = 0.025 and p = 0.006). BRINP1 protein expression was associated with pathological AD (p = 0.0002) and was higher in the brains of patients with brain infarcts (p = 0.022).ConclusionWe identified novel candidate genes that interact with CVRFs on AD in multi‐ethnic cohorts. Understanding the interplay between genes, CVRFs, and AD has the potential to reveal novel molecular targets for prevention and treatment for AD.
Carbonic Anhydrase Inhibitors rescue microvascular impairment and neuroinflammation in 3xTg AD mice
Authors: Canepa Elisa , Lemon Nicole L , Alves Micaelly , Vazquez‐Torres Rafael , Abyaneh Maryam H. , Fossati Silvia 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized‐ at both early and late stages‐ by neurovascular impairment. In AD, dysfunctional cerebral microvasculature is accompanied by an inflammatory response, contributing to Aβ and tau accumulation, brain cell stress and death, impaired clearance of metabolic waste, BBB permeability, and ultimately leading to neuronal demise and cognitive impairment. We previously showed that Aβ peptides induce mitochondrial dysregulation and caspase‐mediated apoptosis in brain cells, including endothelial, glial, and smooth muscle cells. Moreover, we found FDA‐approved carbonic anhydrase inhibitors (CAIs), acetazolamide (ATZ) and methazolamide (MTZ), clinically used for non‐AD related conditions, effectively rescue these pathological events, and ameliorate cognitive impairment, brain amyloidosis, and vascular and glial fitness, in an AD/CAA (Cerebral Amyloid Angiopathy) in vivo model. We unveiled a mitochondrial isoform, Carbonic Anhydrase (CA‐VB), as a major player in Aβ‐mediated toxicity, with increased CA‐VB levels in AD/CAA mouse and human brains.Method3xTg mice express three familial AD mutations: Swedish APP mutation (KM670/671NL), PSEN1 M146V mutation, and MAPT P301L mutation. Following 10 month‐CAI‐diet, mice were sacrificed at 16 months of age,. Brains were harvested and processed for biochemical and immunohistochemistry analysis.ResultCAIs ameliorate cognitive dysfunction, and significantly reduce hippocampal and cortical Aβ deposition and Thioflavin S positive deposits in 3xTg mice. Specifically in the hippocampus, CAIs rescue OXPHOS complexes dysregulated expression, reduce mitochondrial CA‐VB expression, and prevent caspase‐3 activation. In hippocampus and cortex, 3xTg present loss of PDGFRβ (microvascular marker) and increased gliosis (GFAP and IBA1), which are rescued by CAIs.ConclusionCAIs show positive behavioral outcomes in 16‐month‐old 3xTg mice, and reduce brain amyloidosis, compared to untreated animals. In the hippocampus, CAIs foster microvascular health and reduce inflammatory state, and in the cortex, MTZ decreases microgliosis, unveiling cell specific CAI effects underlying Aβ deposition reduction observed in both areas. This work points to CAIs as a potential therapeutic strategy to treat brain microvascular impairment and neuroinflammation, preventing mitochondria‐mediated cell stress and death.
Astrocytic induction of triglyceride lipolysis in AD‐associated pathology and neuroinflammation
Authors: Zimmer Till S , Barnett Daniel , Orr Adam L , Orr Anna G. 
Published: January 2025

AbstractBackgroundMultiple AD risk genes are implicated in lipid metabolism, and plasma and brain lipid levels are altered in AD. Astrocytes are enriched in key lipid‐related factors and are likely contributors to altered lipid homeostasis in AD. We hypothesize that APP/Aβ‐related pathology and neuroimmune factors modulate astrocytic gene transcription that promote maladaptive changes in lipid pathways, including aberrant astrocytic production and release of lipids that could affect Aβ pathology and neuronal deficits.MethodTo investigate the effects of APP/Aβ and neuroinflammation on astrocytic lipid metabolism, we used homozygous mutant APP knock‐in mice (APPSAA‐KI) that have progressive Aβ proteinopathy and gliosis, as well as mice injected systemically with lipopolysaccharide (LPS) to induce acute neuroinflammatory responses. Astrocyte‐specific analyses were performed in vivo by either FACS‐sorting astrocytes for downstream lipidomic profiling or by ribosome‐tagging astrocytes in mouse models (Ribotag) for astrocyte‐specific RNA sequencing. We also performed lipidomic, RNA, and protein‐based analyses in primary murine astrocytes stimulated with oligomeric Aβ (oAβ) or interleukin‐1 (IL‐1α/β).ResultLipidomics in acutely sorted cortical astrocytes from APPSAA‐KI or LPS‐injected mice revealed decreased levels of triglycerides and cholesterol esters. In LPS‐injected mice, cortical astrocytes also had increased expression of enzymes involved in lipolysis, most notably adipose triglyceride lipase (Atgl), the principal triglyceride hydrolase. Similarly, primary astrocytes had increased levels of triglyceride lipolysis upon IL‐1α/β or oAβ stimulation, leading to increased liberation of free fatty acids (FFAs) in an NF‐κB and ERK1/2‐dependent manner. Astrocytic FFAs generated from triglyceride lipolysis were not used for energy production via β‐oxidation but instead utilized by astrocytes to produce prostaglandins (PGE2) and to facilitate secretion of extracellular vesicular bodies (EVB). Inhibiting ATGL decreased PGE2 production, revealing an essential role of astrocyte triglyceride lipolysis in neuroinflammatory processes.ConclusionOur findings suggest that Aβ pathology and neuroinflammatory factors cause astrocytic triglyceride lipolysis, a process that liberates fatty acids to be utilized for various potentially pathogenic cascades in disease. We conclude that amyloid pathology and neuroimmune factors converge to alter astrocytic lipid‐related gene transcription and lipid‐based signaling.
Mild Behavioral Impairment in individuals with subjective cognitive decline and mild cognitive impairment in Southern Brazil
Authors: Souza Victória Tizeli , da Mota Simone Sieben , Paz Gabriela Raquel Rivas , De Marchi Bruno De Oliveira , Carvalho Guilherme Da Silva , De Souza Haniel Bispo , Beltrami Lucas Bastos , Santos Rhaná Carolina , Carnevalli Sarah Vitoria Bristot , de Albuquerque Ana Letícia Amorim , de Paula Leonardo Martins , Giordani Manuella Edler Zandoná , Borelli Wyllians Vendramini , Carello‐Collar Giovanna , Chaves Marcia L Fagundes , Zimmer Eduardo R. , Castilhos Raphael Machado 
Published: January 2025

AbstractBackgroundMild Behavioral Impairment (MBI) is a construct developed to capture neuropsychiatric symptoms in individuals in early stages of neurodegenerative diseases. The assessment of MBI in individuals with preclinical cognitive manifestations in Brazil is still quite limited. The aim of this study is to evaluate the MBI‐Checklist (MBI‐C) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) in the Brazilian Subjective Cognitive Decline (BRASCODE) cohort in southern Brazil.MethodBRASCODE cohort is currently following cognitive unimpaired individuals with > 60 years with cognitive complaints and without severe clinical or neuropsychiatric illness. In this analysis we included the individuals evaluated in the 12 months follow‐up. We performed the following scales: MBI‐C (participant and informant), Neuropsychiatric Inventory–Questionnaire (NPI‐Q), Memory Complaint Scale (MCS) (participant and informant), Geriatric Anxiety Inventory (GAI), Geriatric Depression Scale (GDS), and Mini Mental State Examination (MMSE). A correlation analysis was conducted among these variables.ResultUntil December 2023, 47 individuals performed the 12‐month evaluation. Table 1 described the characteristics of the participants. The MBI‐C of the patient and informant had medians (IQR) of 3(0.75‐6) and 3(1‐9), respectively. The MBI‐C‐informant showed a strong positive correlation with the NPI (p‐value<0.0001, rho = 0.827) and also correlated with the SCD‐informant (p‐value = 0.006, rho = 0.404). The MBI‐C‐patient correlated positively with GDS (p‐value<0.0001, rho = 0.604) and with GAI (p‐value = 0.049, rho = 0.314), and negatively with their education (p‐value = 0.009, rho ‐0.387), but it was not with NPI, MCS‐patient and MCS‐informant Particularly, MBI‐C of the participant and informant did not correlate.ConclusionOur partial analyses showed that informant perceptions of neuropsychiatric and memory manifestations were correlated in participants with SCD and MCI. In addition, MBI‐C of the participants was correlated with anxiety and depression symptoms. Studies with a larger sample size may provide additional information about MBI in individuals with SCD and MCI.