The adapter protein KINDLIN2, encoded by the Alzheimer's disease (AD) genetic risk factor FERMT2, was identified as a modulator of APP processing. KINDLIN2 directly interacts with APP to modulate its metabolism, and KINDLIN2 underexpression impairs long-term potentiation in an APP-dependent manner. Altogether, these data suggest that loss of KINDLIN2 could have a detrimental effect on synaptic function and promote AD pathophysiological process. In this study, we identified KINDLIN2 as a novel substrate of caspases and calpain I, two well-characterized cysteine proteases involved in the regulation of synaptic plasticity. These cleavages resulted in the dissociation of the F0 and F1 domains of KINDLIN2 that are necessary for it to function as an adapter protein. Furthermore, we demonstrate that these cleavages lead to a decrease in KINDLIN2’s ability to control APP processing. Overall, these KINDLIN2 cleavages appear as potential new mechanisms in the regulation of KINDLIN2 functions at the synapse and could be of interest for the pathophysiology of AD.
{"title":"Calpain and caspase regulate Aβ peptide production via cleavage of KINDLIN2 encoded by the AD-associated gene FERMT2","authors":"Chloé Najdek , Pauline Walle , Amandine Flaig, Anne-Marie Ayral, Florie Demiautte, Audrey Coulon, Valérie Buiche, Neuro-CEB Brain Bank, Erwan Lambert , Philippe Amouyel, Carla Gelle, Dolores Siedlecki-Wullich, Julie Dumont, Devrim Kilinc, Fanny Eysert , Jean-Charles Lambert, Julien Chapuis","doi":"10.1016/j.neurobiolaging.2025.04.009","DOIUrl":"10.1016/j.neurobiolaging.2025.04.009","url":null,"abstract":"<div><div>The adapter protein KINDLIN2, encoded by the Alzheimer's disease (AD) genetic risk factor <em>FERMT2</em>, was identified as a modulator of APP processing. KINDLIN2 directly interacts with APP to modulate its metabolism, and KINDLIN2 underexpression impairs long-term potentiation in an APP-dependent manner. Altogether, these data suggest that loss of KINDLIN2 could have a detrimental effect on synaptic function and promote AD pathophysiological process. In this study, we identified KINDLIN2 as a novel substrate of caspases and calpain I, two well-characterized cysteine proteases involved in the regulation of synaptic plasticity. These cleavages resulted in the dissociation of the F0 and F1 domains of KINDLIN2 that are necessary for it to function as an adapter protein. Furthermore, we demonstrate that these cleavages lead to a decrease in KINDLIN2’s ability to control APP processing. Overall, these KINDLIN2 cleavages appear as potential new mechanisms in the regulation of KINDLIN2 functions at the synapse and could be of interest for the pathophysiology of AD.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"151 ","pages":"Pages 117-125"},"PeriodicalIF":3.7,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-19DOI: 10.1016/j.neurobiolaging.2025.04.008
Hannah R. Maybrier , Joshua J. Jackson , Cristina D. Toedebusch , Brendan P. Lucey , Denise Head
Age-related changes in sleep have been associated with cognitive decline, yet causal pathways have not been identified. Evidence suggests reduced cardiovascular health may be a consequence of poor sleep and a precursor to cognitive decline. This observational cohort study used path analyses to determine whether cardiovascular disease risk mediated or moderated effects of sleep on yearly longitudinal change in cognition, estimated with linear growth models. Total sleep time (TST), sleep efficiency (SE), and relative spectral power of slow wave activity (SWA; 1–4 Hz) and slow oscillations (SO; 0.5–1 Hz), were measured with single-channel home EEG. Cardiovascular disease risk (CVR) was estimated as 10-year Framingham Risk Score 1-year post-sleep. Outcomes were yearly change in executive function (EF), episodic memory (EM), and processing speed (PS) over 2–5 years post-sleep. 342 participants (mean age 73.5 +/- 5.6 years, 51 % female) were included. Shorter TST was linearly associated with increased CVR across all models (βs = -0.18(0.058) – -0.19(0.059), ps< 0.002). TST was indirectly associated with EF and PS decline through CVR, such that associations between short TST and cognitive decline were partially due to higher CVR. All other mediating and moderating effects were nonsignificant after multiple comparisons. Indirect associations between short sleep duration and greater decline in executive function and processing speed were found through higher CVR, suggesting a potential mechanism by which sleep leads to cognitive decline. Findings support the prioritization of adequate sleep duration to preserve both cardiovascular and cognitive health in later life.
{"title":"Influence of sleep and cardiovascular health on cognitive trajectories in older adults","authors":"Hannah R. Maybrier , Joshua J. Jackson , Cristina D. Toedebusch , Brendan P. Lucey , Denise Head","doi":"10.1016/j.neurobiolaging.2025.04.008","DOIUrl":"10.1016/j.neurobiolaging.2025.04.008","url":null,"abstract":"<div><div>Age-related changes in sleep have been associated with cognitive decline, yet causal pathways have not been identified. Evidence suggests reduced cardiovascular health may be a consequence of poor sleep and a precursor to cognitive decline. This observational cohort study used path analyses to determine whether cardiovascular disease risk mediated or moderated effects of sleep on yearly longitudinal change in cognition, estimated with linear growth models. Total sleep time (TST), sleep efficiency (SE), and relative spectral power of slow wave activity (SWA; 1–4 Hz) and slow oscillations (SO; 0.5–1 Hz), were measured with single-channel home EEG. Cardiovascular disease risk (CVR) was estimated as 10-year Framingham Risk Score 1-year post-sleep. Outcomes were yearly change in executive function (EF), episodic memory (EM), and processing speed (PS) over 2–5 years post-sleep. 342 participants (mean age 73.5 +/- 5.6 years, 51 % female) were included. Shorter TST was linearly associated with increased CVR across all models (βs = -0.18(0.058) – -0.19(0.059), ps< 0.002). TST was indirectly associated with EF and PS decline through CVR, such that associations between short TST and cognitive decline were partially due to higher CVR. All other mediating and moderating effects were nonsignificant after multiple comparisons. Indirect associations between short sleep duration and greater decline in executive function and processing speed were found through higher CVR, suggesting a potential mechanism by which sleep leads to cognitive decline. Findings support the prioritization of adequate sleep duration to preserve both cardiovascular and cognitive health in later life.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"152 ","pages":"Pages 34-42"},"PeriodicalIF":3.7,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-18DOI: 10.1016/j.neurobiolaging.2025.04.005
Elizabeth R. Paitel , Corinne Pettigrew , Abhay Moghekar , Michael I. Miller , Andreia V. Faria , Marilyn Albert , Anja Soldan
Recent research suggests that hippocampal-cerebellar (Hp-CB) functional connectivity may be altered early in the course of Alzheimer’s disease (AD), given the early accumulation of AD pathology in the hippocampi and emerging evidence of cerebellar changes in early AD. This study analyzed the role of AD genetic risk (via APOE ε4 carrier status) and cerebrospinal fluid (CSF) biomarkers of AD pathology (ratio of phosphorylated tau (p-tau181) to amyloid beta (Aβ42/Aβ40)) on the relationship between age and functional Hp-CB resting state fMRI connectivity in 161 cognitively unimpaired older adults (M age =67.3; SD =9.0; 37 % APOE ε4 +). In multiple regression analyses with Hp-CB connectivity as the outcome, there were significant interactions between age and APOE ε4 status, and between age and CSF AD biomarkers. Older age was associated with greater Hp-CB connectivity in APOE ε4 non-carriers and participants with less abnormal CSF AD biomarkers. In contrast, Hp-CB connectivity was marginally lower with older age in ε4 carriers and those with more abnormal AD biomarkers. Furthermore, greater Hp-CB connectivity was associated with better episodic memory performance across all groups. These findings suggest that age-related increases in Hp-CB connectivity among APOE ε4 non-carriers and those with low AD biomarker levels reflect age-related changes that are largely unrelated to AD, while age-related decreases in Hp-CB connectivity in APOE ε4 carriers may reflect AD-related alterations. These findings also highlight the importance of cerebellar contributions to cognitive performance among older adults and suggest that Hp-CB connectivity may be altered in preclinical AD.
{"title":"Alzheimer’s disease cerebrospinal fluid biomarker levels and APOE genetic status are associated with hippocampal-cerebellar functional connectivity","authors":"Elizabeth R. Paitel , Corinne Pettigrew , Abhay Moghekar , Michael I. Miller , Andreia V. Faria , Marilyn Albert , Anja Soldan","doi":"10.1016/j.neurobiolaging.2025.04.005","DOIUrl":"10.1016/j.neurobiolaging.2025.04.005","url":null,"abstract":"<div><div>Recent research suggests that hippocampal-cerebellar (Hp-CB) functional connectivity may be altered early in the course of Alzheimer’s disease (AD), given the early accumulation of AD pathology in the hippocampi and emerging evidence of cerebellar changes in early AD. This study analyzed the role of AD genetic risk (via <em>APOE</em> ε4 carrier status) and cerebrospinal fluid (CSF) biomarkers of AD pathology (ratio of phosphorylated tau (p-tau<sub>181</sub>) to amyloid beta (Aβ<sub>42</sub>/Aβ<sub>40</sub>)) on the relationship between age and functional Hp-CB resting state fMRI connectivity in 161 cognitively unimpaired older adults (<em>M</em> age =67.3; <em>SD</em> =9.0; 37 % <em>APOE</em> ε4 +). In multiple regression analyses with Hp-CB connectivity as the outcome, there were significant interactions between age and <em>APOE</em> ε4 status, and between age and CSF AD biomarkers. Older age was associated with greater Hp-CB connectivity in <em>APOE</em> ε4 non-carriers and participants with less abnormal CSF AD biomarkers. In contrast, Hp-CB connectivity was marginally lower with older age in ε4 carriers and those with more abnormal AD biomarkers. Furthermore, greater Hp-CB connectivity was associated with better episodic memory performance across all groups. These findings suggest that age-related increases in Hp-CB connectivity among <em>APOE</em> ε4 non-carriers and those with low AD biomarker levels reflect age-related changes that are largely unrelated to AD, while age-related decreases in Hp-CB connectivity in <em>APOE</em> ε4 carriers may reflect AD-related alterations. These findings also highlight the importance of cerebellar contributions to cognitive performance among older adults and suggest that Hp-CB connectivity may be altered in preclinical AD.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"151 ","pages":"Pages 107-116"},"PeriodicalIF":3.7,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-17DOI: 10.1016/j.neurobiolaging.2025.04.007
Laura M. Wright , Paul C. Donaghy , David J. Burn , John-Paul Taylor , John T. O’Brien , Alison J. Yarnall , Fiona E. Matthews , Michael J. Firbank , Hilmar P. Sigurdsson , Julia Schumacher , Alan J. Thomas , Rachael A. Lawson
Neuropsychiatric symptoms (NPS) are prevalent, emerge early, and are associated with poorer outcomes in Lewy body dementia (LBD). Research suggests NPS may reflect LBD-related dysfunction in distributed neuronal networks. This study investigated NPS neural correlates in prodromal LBD using resting-state functional MRI. Fifty-seven participants were included with mild cognitive impairment (MCI) with Lewy bodies (MCI-LB, n = 28) or Parkinson’s disease (PD-MCI, n = 29). Functional MRI assessed connectivity within five resting-state networks: primary visual, dorsal attention, salience, limbic, and default mode networks. NPS were measured using the Neuropsychiatric Inventory. Principal component analyses identified three neuropsychiatric factors: affective disorder (apathy, depression), psychosis (delusions, hallucinations) and anxiety. Seed-to-voxel connectivity maps were analysed to determine associations between NPS and network connectivity. In PD-MCI, affective symptoms and anxiety were associated with greater connectivity between limbic orbitofrontal cortex and default mode areas, including medial prefrontal cortex, subgenual cingulate and precuneus, and weaker connectivity between limbic orbitofrontal cortex and the brainstem and between the salience network and medial prefrontal cortex (all pFWE<0.001). Psychosis severity in PD-MCI correlated with connectivity across multiple networks (all pFWE<0.001). In MCI-LB, no significant correlations were found between NPS severity and network connectivity. However, participants with anxiety demonstrated a trend towards greater connectivity within medial prefrontal areas than those without (pFWE=0.046). Altered connectivity within and between networks associated with mood disorders may explain affective and anxiety symptoms in PD-MCI. Neural correlates of NPS in MCI-LB, however, remain unclear, highlighting the need for research in larger, more diverse LBD populations to identify symptomatic treatment targets.
神经精神症状（NPS）在路易体痴呆（LBD）中普遍存在，出现较早，并且与预后较差相关。研究表明，NPS可能反映了分布式神经网络中与lbd相关的功能障碍。本研究利用静息状态功能MRI研究了前驱LBD的NPS神经相关。57名受试者被纳入轻度认知障碍（MCI）伴路易体（MCI- lb, n = 28）或帕金森病（PD-MCI, n = 29）。功能性MRI评估了五个静息状态网络的连通性：初级视觉网络、背侧注意网络、显著性网络、边缘网络和默认模式网络。使用神经精神量表测量NPS。主成分分析确定了三种神经精神因素：情感障碍（冷漠、抑郁）、精神病（妄想、幻觉）和焦虑。分析种子到体素的连接图，以确定NPS和网络连接之间的关联。在PD-MCI中，情感症状和焦虑与边缘眼窝前额皮质与默认模式区域（包括内侧前额皮质、亚属扣带和楔前叶）之间的连通性更强有关，与边缘眼窝前额皮质与脑干以及突出网络与内侧前额皮质之间的连通性较弱有关（所有pFWE<；0.001）。PD-MCI患者的精神病严重程度与跨多个网络的连通性相关（所有pFWE<；0.001）。在MCI-LB中，NPS严重程度与网络连通性之间没有显著相关性。然而，焦虑的参与者比没有焦虑的参与者表现出内侧前额叶区域更大的连通性（pFWE=0.046）。与情绪障碍相关的网络内部和网络之间连接的改变可以解释PD-MCI的情感和焦虑症状。然而，NPS在MCI-LB中的神经相关性仍不清楚，这表明需要在更大、更多样化的LBD人群中进行研究，以确定对症治疗靶点。
{"title":"Brain network connectivity underlying neuropsychiatric symptoms in prodromal Lewy body dementia","authors":"Laura M. Wright , Paul C. Donaghy , David J. Burn , John-Paul Taylor , John T. O’Brien , Alison J. Yarnall , Fiona E. Matthews , Michael J. Firbank , Hilmar P. Sigurdsson , Julia Schumacher , Alan J. Thomas , Rachael A. Lawson","doi":"10.1016/j.neurobiolaging.2025.04.007","DOIUrl":"10.1016/j.neurobiolaging.2025.04.007","url":null,"abstract":"<div><div>Neuropsychiatric symptoms (NPS) are prevalent, emerge early, and are associated with poorer outcomes in Lewy body dementia (LBD). Research suggests NPS may reflect LBD-related dysfunction in distributed neuronal networks. This study investigated NPS neural correlates in prodromal LBD using resting-state functional MRI. Fifty-seven participants were included with mild cognitive impairment (MCI) with Lewy bodies (MCI-LB, n = 28) or Parkinson’s disease (PD-MCI, n = 29). Functional MRI assessed connectivity within five resting-state networks: primary visual, dorsal attention, salience, limbic, and default mode networks. NPS were measured using the Neuropsychiatric Inventory. Principal component analyses identified three neuropsychiatric factors: affective disorder (apathy, depression), psychosis (delusions, hallucinations) and anxiety. Seed-to-voxel connectivity maps were analysed to determine associations between NPS and network connectivity. In PD-MCI, affective symptoms and anxiety were associated with greater connectivity between limbic orbitofrontal cortex and default mode areas, including medial prefrontal cortex, subgenual cingulate and precuneus, and weaker connectivity between limbic orbitofrontal cortex and the brainstem and between the salience network and medial prefrontal cortex (all <em>pFWE</em><0.001). Psychosis severity in PD-MCI correlated with connectivity across multiple networks (all <em>pFWE</em><0.001). In MCI-LB, no significant correlations were found between NPS severity and network connectivity. However, participants with anxiety demonstrated a trend towards greater connectivity within medial prefrontal areas than those without (<em>pFWE</em>=0.046). Altered connectivity within and between networks associated with mood disorders may explain affective and anxiety symptoms in PD-MCI. Neural correlates of NPS in MCI-LB, however, remain unclear, highlighting the need for research in larger, more diverse LBD populations to identify symptomatic treatment targets.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"151 ","pages":"Pages 95-106"},"PeriodicalIF":3.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-12DOI: 10.1016/j.neurobiolaging.2025.03.012
Isabelle L. Moore, Devyn E. Smith, Nicole M. Long
Healthy older adults typically show impaired episodic memory – memory for when and where an event occurred. This selective episodic memory deficit may arise from differential engagement in the retrieval state, a brain state in which attention is focused internally in an attempt to access prior knowledge, and the encoding state, a brain state which supports the formation of new memories and that trades off with the retrieval state. We hypothesize that older adults are biased toward a retrieval state. We recorded scalp electroencephalography while young, middle-aged and older adults performed a memory task in which they were explicitly directed to either encode or retrieve on a given trial. We used multivariate pattern analysis of spectral activity to decode retrieval vs. encoding state engagement. We find that whereas all age groups can follow task demands to selectively engage in encoding or retrieval, mnemonic brain state engagement is diminished for older adults relative to young and middle-aged adults. These findings suggest that differential mnemonic state engagement may underlie age-related memory changes.
{"title":"Mnemonic brain state engagement is diminished in healthy aging","authors":"Isabelle L. Moore, Devyn E. Smith, Nicole M. Long","doi":"10.1016/j.neurobiolaging.2025.03.012","DOIUrl":"10.1016/j.neurobiolaging.2025.03.012","url":null,"abstract":"<div><div>Healthy older adults typically show impaired episodic memory – memory for when and where an event occurred. This selective episodic memory deficit may arise from differential engagement in the retrieval state, a brain state in which attention is focused internally in an attempt to access prior knowledge, and the encoding state, a brain state which supports the formation of new memories and that trades off with the retrieval state. We hypothesize that older adults are biased toward a retrieval state. We recorded scalp electroencephalography while young, middle-aged and older adults performed a memory task in which they were explicitly directed to either encode or retrieve on a given trial. We used multivariate pattern analysis of spectral activity to decode retrieval vs. encoding state engagement. We find that whereas all age groups can follow task demands to selectively engage in encoding or retrieval, mnemonic brain state engagement is diminished for older adults relative to young and middle-aged adults. These findings suggest that differential mnemonic state engagement may underlie age-related memory changes.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"151 ","pages":"Pages 76-88"},"PeriodicalIF":3.7,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzheimer's disease (AD) is an age-associated disorder characterized by cognitive decline, with dementia representing the final stage of a complex clinical-biological process rather than simply a more severe form of cognitive decline. Circular RNAs (circRNAs), novel non-coding RNAs, have emerged as key regulators of brain function and associated disorders. This study explores the role of circRNAs in AD by reviewing experimentally validated circRNAs in human and animal models. We identified 10 human (seven pathogenic, three protective) and six animal (three pathogenic, three protective) AD-related circRNAs. Experimental studies have confirmed that human protective circRNAs are predominantly downregulated in AD, where they function by sequestering specific miRNAs within cells, particularly miR-7, miR-142–5p, and miR-217, which have well-recognized neuroinflammatory functions. In-silico analysis revealed that circLPAR1 (pathogenic), circHUWE1 (pathogenic), and circHOMER1 (protective) interact with miRNAs that mainly control AD-related genes. Notably, circHOMER1 plays a key role in regulating multiple AD-related pathways, including autophagy, apoptosis, and PI3K-AKT and amyloid fiber formation. Furthermore, circRNA/protein interaction analysis revealed that circHUWE1 predominantly associates with RNA transport proteins, whereas circHOMER1 interacts with proteins involved in mRNA surveillance pathways. Remarkably, docking analysis demonstrated that circAβ-a (pathogenic) exhibits a strong affinity for eukaryotic translation initiation factor 4A3 protein, while circHOMER1 shows a higher binding affinity for DGCR8 microprocessor complex subunit protein. Our study presents a concise list of circRNAs as potential key targets for further investigation in AD research. Future experimental research is essential to uncover their precise mechanisms and assess their potential as biomarkers, offering promising avenues for developing interventions to alleviate cognitive decline in AD.
{"title":"Dynamics and role of covalently-closed circular RNAs in Alzheimer's disease: A review of experimental and bioinformatics studies","authors":"Nikta Zafarjafarzadeh , Elham Feridouni , Sudabe Sobhani-Moghaddam , Javad Amini , Samaneh Mollazadeh , Reza Ataei , Hamed Ghomi , Cordian Beyer , Nima Sanadgol","doi":"10.1016/j.neurobiolaging.2025.04.002","DOIUrl":"10.1016/j.neurobiolaging.2025.04.002","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is an age-associated disorder characterized by cognitive decline, with dementia representing the final stage of a complex clinical-biological process rather than simply a more severe form of cognitive decline. Circular RNAs (circRNAs), novel non-coding RNAs, have emerged as key regulators of brain function and associated disorders. This study explores the role of circRNAs in AD by reviewing experimentally validated circRNAs in human and animal models. We identified 10 human (seven pathogenic, three protective) and six animal (three pathogenic, three protective) AD-related circRNAs. Experimental studies have confirmed that human protective circRNAs are predominantly downregulated in AD, where they function by sequestering specific miRNAs within cells, particularly miR-7, miR-142–5p, and miR-217, which have well-recognized neuroinflammatory functions. In-silico analysis revealed that circLPAR1 (pathogenic), circHUWE1 (pathogenic), and circHOMER1 (protective) interact with miRNAs that mainly control AD-related genes. Notably, circHOMER1 plays a key role in regulating multiple AD-related pathways, including autophagy, apoptosis, and PI3K-AKT and amyloid fiber formation. Furthermore, circRNA/protein interaction analysis revealed that circHUWE1 predominantly associates with RNA transport proteins, whereas circHOMER1 interacts with proteins involved in mRNA surveillance pathways. Remarkably, docking analysis demonstrated that circAβ-a (pathogenic) exhibits a strong affinity for eukaryotic translation initiation factor 4A3 protein, while circHOMER1 shows a higher binding affinity for DGCR8 microprocessor complex subunit protein. Our study presents a concise list of circRNAs as potential key targets for further investigation in AD research. Future experimental research is essential to uncover their precise mechanisms and assess their potential as biomarkers, offering promising avenues for developing interventions to alleviate cognitive decline in AD.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"151 ","pages":"Pages 54-69"},"PeriodicalIF":3.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-11DOI: 10.1016/j.neurobiolaging.2025.04.003
Lucas Nogueira de Carvalho Pelegrini , Patricia Regina Manzine , Cecilia Patricia Popolin , Sabrina Dorta , Marina Mantellatto Grigoli , Vanessa Alexandre-Silva , Renata Pedroso , Ari Alex Ramos , Henrique Pott , Marcia Regina Cominetti
The APOE gene, particularly its ε4 allele, is a significant genetic risk factor for Alzheimer’s disease (AD) and influences amyloid-β (Aβ) pathology and cognitive decline. This study explores the relationship between APOEε4 genotype, plasma levels of soluble ADAM10 (sADAM10), and cognitive performance in cognitively unimpaired (CU) older adults and those with AD dementia. It is a cross-sectional analysis that included 85 participants assessed for cognitive function, APOE genotype, and plasma sADAM10 levels. ADAM10, a key enzyme in the non-amyloidogenic pathway of Aβ precursor protein (APP) processing, has emerged as a promising biomarker due to its altered levels in AD patients. Our findings revealed significantly higher plasma sADAM10 levels in AD participants compared to CU individuals, with APOEε4 carriers exhibiting a nearly twofold increase in sADAM10 levels. A negative correlation was observed between plasma sADAM10 concentrations and cognitive performance, independent of APOEε4 status. Notably, the study highlights the potential of sADAM10 as a blood-based biomarker, emphasizing its relevance in APOEε4-mediated AD pathology. Importantly, most studies exploring ADAM10 and APOE interactions have been conducted in high-income countries, limiting the generalizability of their findings to diverse populations. This study is the first to be conducted in a Global South country, offering critical insights into underrepresented populations and underscoring the need for more inclusive research in AD. Future research should include larger cohorts and longitudinal designs to validate these findings and explore targeted interventions leveraging sADAM10 activity in the context of APOEε4-associated AD progression.
APOE基因，特别是其ε4等位基因，是阿尔茨海默病（AD）的重要遗传危险因素，并影响淀粉样蛋白-β (a β)病理和认知能力下降。本研究探讨了认知功能未受损（CU）老年人和AD痴呆患者的APOEε4基因型、血浆可溶性ADAM10 （sADAM10）水平和认知表现之间的关系。这是一项横断面分析，包括85名参与者，评估其认知功能、APOE基因型和血浆sADAM10水平。ADAM10是a β前体蛋白（APP）加工非淀粉样变途径的关键酶，由于其在AD患者中的水平改变，已成为一种有希望的生物标志物。我们的研究结果显示，与CU个体相比，AD参与者的血浆sADAM10水平明显更高，APOEε4携带者的sADAM10水平几乎增加了两倍。血浆sADAM10浓度与认知能力呈负相关，与APOEε4状态无关。值得注意的是，该研究强调了sADAM10作为一种基于血液的生物标志物的潜力，强调了它与apoeε 4介导的AD病理的相关性。重要的是，大多数探索ADAM10和APOE相互作用的研究都是在高收入国家进行的，限制了其研究结果在不同人群中的普遍性。这项研究是首次在全球南方国家进行的研究，为代表性不足的人群提供了重要见解，并强调了对阿尔茨海默病进行更具包容性研究的必要性。未来的研究应该包括更大的队列和纵向设计来验证这些发现，并探索在apoeε 4相关AD进展的背景下利用sADAM10活性的有针对性的干预措施。
{"title":"Higher soluble ADAM10 plasma levels are associated with decreased cognitive performance in older adults carrying APOEε4","authors":"Lucas Nogueira de Carvalho Pelegrini , Patricia Regina Manzine , Cecilia Patricia Popolin , Sabrina Dorta , Marina Mantellatto Grigoli , Vanessa Alexandre-Silva , Renata Pedroso , Ari Alex Ramos , Henrique Pott , Marcia Regina Cominetti","doi":"10.1016/j.neurobiolaging.2025.04.003","DOIUrl":"10.1016/j.neurobiolaging.2025.04.003","url":null,"abstract":"<div><div>The APOE gene, particularly its ε4 allele, is a significant genetic risk factor for Alzheimer’s disease (AD) and influences amyloid-β (Aβ) pathology and cognitive decline. This study explores the relationship between APOEε4 genotype, plasma levels of soluble ADAM10 (sADAM10), and cognitive performance in cognitively unimpaired (CU) older adults and those with AD dementia. It is a cross-sectional analysis that included 85 participants assessed for cognitive function, APOE genotype, and plasma sADAM10 levels. ADAM10, a key enzyme in the non-amyloidogenic pathway of Aβ precursor protein (APP) processing, has emerged as a promising biomarker due to its altered levels in AD patients. Our findings revealed significantly higher plasma sADAM10 levels in AD participants compared to CU individuals, with APOEε4 carriers exhibiting a nearly twofold increase in sADAM10 levels. A negative correlation was observed between plasma sADAM10 concentrations and cognitive performance, independent of APOEε4 status. Notably, the study highlights the potential of sADAM10 as a blood-based biomarker, emphasizing its relevance in APOEε4-mediated AD pathology. Importantly, most studies exploring ADAM10 and APOE interactions have been conducted in high-income countries, limiting the generalizability of their findings to diverse populations. This study is the first to be conducted in a Global South country, offering critical insights into underrepresented populations and underscoring the need for more inclusive research in AD. Future research should include larger cohorts and longitudinal designs to validate these findings and explore targeted interventions leveraging sADAM10 activity in the context of APOEε4-associated AD progression.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"151 ","pages":"Pages 70-75"},"PeriodicalIF":3.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Blood-brain barrier (BBB) dysfunction has been hypothesized to be a triggering factor in neurodegeneration. This study compared moderate-severe obstructive sleep apnea (OSA) patients with controls to evaluate the effects of this sleep disorder on BBB integrity, as well as explore the impact of continuous positive airway pressure (CPAP) treatment on BBB.
Methods
This study included moderate-severe OSA patients, OSA patients being treated with CPAP for at least 12 months (OSA-CPAP), and a control group with no neurological or psychiatric diseases. Participants underwent neurological examination, cognitive assessment (to exclude cognitive impairment) and lumbar puncture for cerebrospinal-fluid (CSF) biomarkers analysis [β-amyloid42 (Aβ42), total-tau, phosphorylated tau, ratio between CSF and serum albumin levels (Qalb)].
Results
38 moderate-severe OSA patients (mean age 65.50 ± 9.16), 12 patients with OSA treated with CPAP (OSA-CPAP, mean age 65.42 ± 6.45) and 25 controls (mean age 65.64 ± 8.10) were included. Moderate-severe OSA patients showed higher Qalb than controls (p = 0.026); also OSA-CPAP patients presented higher Qalb than controls (p = 0.044). Qalb did not differ comparing moderate-severe OSA and OSA-CPAP groups. OSA patients showed lower CSF Aβ42 levels compared to both controls (p < 0.001) and the OSA-CPAP patients (p < 0.001).
Conclusions
These findings confirmed CSF Aβ42 alteration and documented BBB dysfunction, as indicated by the higher Qalb, in OSA patients. The metabolic and oxidative damage caused by hypoxia could account for these phenomenona; however, the BBB impairment seems to be not reversible, as OSA-CPAP patients presented the BBB alteration although normal CSF Aβ42 levels. Further studies exploring BBB function and its clinical implication for neurodegeneration in OSA are needed.
{"title":"Persistent blood-brain barrier dysregulation in patients with obstructive sleep apnea following long-term continuous positive airway pressure treatment","authors":"Mariana Fernandes , Fabio Placidi , Francesca Izzi , Marzia Nuccetelli , Sergio Bernardini , Nicola Biagio Mercuri , Claudio Liguori","doi":"10.1016/j.neurobiolaging.2025.04.001","DOIUrl":"10.1016/j.neurobiolaging.2025.04.001","url":null,"abstract":"<div><h3>Introduction</h3><div>Blood-brain barrier (BBB) dysfunction has been hypothesized to be a triggering factor in neurodegeneration. This study compared moderate-severe obstructive sleep apnea (OSA) patients with controls to evaluate the effects of this sleep disorder on BBB integrity, as well as explore the impact of continuous positive airway pressure (CPAP) treatment on BBB.</div></div><div><h3>Methods</h3><div>This study included moderate-severe OSA patients, OSA patients being treated with CPAP for at least 12 months (OSA-CPAP), and a control group with no neurological or psychiatric diseases. Participants underwent neurological examination, cognitive assessment (to exclude cognitive impairment) and lumbar puncture for cerebrospinal-fluid (CSF) biomarkers analysis [β-amyloid42 (Aβ<sub>42</sub>), total-tau, phosphorylated tau, ratio between CSF and serum albumin levels (Qalb)].</div></div><div><h3>Results</h3><div>38 moderate-severe OSA patients (mean age 65.50 ± 9.16), 12 patients with OSA treated with CPAP (OSA-CPAP, mean age 65.42 ± 6.45) and 25 controls (mean age 65.64 ± 8.10) were included. Moderate-severe OSA patients showed higher Qalb than controls (p = 0.026); also OSA-CPAP patients presented higher Qalb than controls (p = 0.044). Qalb did not differ comparing moderate-severe OSA and OSA-CPAP groups. OSA patients showed lower CSF Aβ<sub>42</sub> levels compared to both controls (p < 0.001) and the OSA-CPAP patients (p < 0.001).</div></div><div><h3>Conclusions</h3><div>These findings confirmed CSF Aβ<sub>42</sub> alteration and documented BBB dysfunction, as indicated by the higher Qalb, in OSA patients. The metabolic and oxidative damage caused by hypoxia could account for these phenomenona; however, the BBB impairment seems to be not reversible, as OSA-CPAP patients presented the BBB alteration although normal CSF Aβ<sub>42</sub> levels. Further studies exploring BBB function and its clinical implication for neurodegeneration in OSA are needed.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"151 ","pages":"Pages 89-94"},"PeriodicalIF":3.7,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143854914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-05DOI: 10.1016/j.neurobiolaging.2025.03.013
Daniel J. McKeown , Emily Roberts , Anna J. Finley , Nicholas J. Kelley , Hannah A.D. Keage , Victor R. Schinazi , Oliver Baumann , Ahmed A. Moustafa , Douglas J. Angus
Age-related cognitive decline associations with human electroencephalography (EEG) have previously focused on periodic activity. However, EEG primarily consists of non-oscillatory aperiodic activity, characterised with an exponent and offset value. In a secondary analysis of a cohort of 111 healthy participants aged 17 – 71 years, we examined the associations of the aperiodic exponent and offset in resting EEG with a battery of cognitive tests consisting of the Colour-Word Interference Test, Wechsler Adult Intelligence Scale IV Digit Span Test, Rey Auditory Learning Test, Delis-Kaplan Executive Function System Trail Making Test, and the Verbal Fluency Test. Using Principal Component Analysis and K-Means Clustering, we identified clusters of electrodes that exhibited similar aperiodic exponent and offset activity during resting-state eyes-closed EEG. Robust linear models were then used to model how aperiodic activity interacted with age and their associations with performance during each cognitive test. Offset by age interactions were identified for the Verbal Fluency Test, where smaller offsets were associated with poorer performance in adults as early as 33 years of age. Greater aperiodic activity is increasingly related to better verbal fluency performance with age in adulthood.
{"title":"Lower aperiodic EEG activity is associated with reduced verbal fluency performance across adulthood","authors":"Daniel J. McKeown , Emily Roberts , Anna J. Finley , Nicholas J. Kelley , Hannah A.D. Keage , Victor R. Schinazi , Oliver Baumann , Ahmed A. Moustafa , Douglas J. Angus","doi":"10.1016/j.neurobiolaging.2025.03.013","DOIUrl":"10.1016/j.neurobiolaging.2025.03.013","url":null,"abstract":"<div><div>Age-related cognitive decline associations with human electroencephalography (EEG) have previously focused on periodic activity. However, EEG primarily consists of non-oscillatory aperiodic activity, characterised with an exponent and offset value. In a secondary analysis of a cohort of 111 healthy participants aged 17 – 71 years, we examined the associations of the aperiodic exponent and offset in resting EEG with a battery of cognitive tests consisting of the Colour-Word Interference Test, Wechsler Adult Intelligence Scale IV Digit Span Test, Rey Auditory Learning Test, Delis-Kaplan Executive Function System Trail Making Test, and the Verbal Fluency Test. Using Principal Component Analysis and K-Means Clustering, we identified clusters of electrodes that exhibited similar aperiodic exponent and offset activity during resting-state eyes-closed EEG. Robust linear models were then used to model how aperiodic activity interacted with age and their associations with performance during each cognitive test. Offset by age interactions were identified for the Verbal Fluency Test, where smaller offsets were associated with poorer performance in adults as early as 33 years of age. Greater aperiodic activity is increasingly related to better verbal fluency performance with age in adulthood.</div></div>","PeriodicalId":19110,"journal":{"name":"Neurobiology of Aging","volume":"151 ","pages":"Pages 29-41"},"PeriodicalIF":3.7,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143807426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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