Zahinoor Ismail, Rebeca Leon, Byron Creese, Clive Ballard, Philippe Robert, Eric E Smith
BACKGROUND: Disease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding MBI would better identify AD, we interrogated associations between MBI in MCI, and cerebrospinal fluid biomarkers [β-amyloid (Aβ), phosphorylated-tau (p-tau), and total-tau (tau)-ATN], cross-sectionally and longitudinally...
July 29, 2023: Molecular Neurodegeneration
Sen Yang, Jung Hyun Park, Hui-Chen Lu
Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of aging (NDAs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Glucose is the major brain fuel and glucose hypometabolism has been observed in brain regions vulnerable to aging and NDAs. Many neurodegenerative susceptible regions are in the topological central hub of the brain connectome, linked by densely interconnected long-range axons...
July 20, 2023: Molecular Neurodegeneration
Erica S Modeste, Lingyan Ping, Caroline M Watson, Duc M Duong, Eric B Dammer, Erik C B Johnson, Blaine R Roberts, James J Lah, Allan I Levey, Nicholas T Seyfried
BACKGROUND: Despite being twice as likely to get Alzheimer's disease (AD), African Americans have been grossly underrepresented in AD research. While emerging evidence indicates that African Americans with AD have lower cerebrospinal fluid (CSF) levels of Tau compared to Caucasians, other differences in AD CSF biomarkers have not been fully elucidated. Here, we performed unbiased proteomic profiling of CSF from African Americans and Caucasians with and without AD to identify both common and divergent AD CSF biomarkers...
July 19, 2023: Molecular Neurodegeneration
Yingbin Lin, Anlan Lin, Lili Cai, Weibin Huang, Shanzhi Yan, Yuanxiang Wei, Xinglin Ruan, Wenting Fang, Xiaoman Dai, Jinbo Cheng, Jie Zhang, Wanjin Chen, Qinyong Ye, Xiaochun Chen, Jing Zhang
BACKGROUND: Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer's disease (AD). Nuclear acetyl-CoA pools are generated partially from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). However, the underlying mechanism of histone acetylation dysregulation in AD remains poorly understood. METHODS: We detected ACSS2 expression and histone acetylation levels in the brains of AD patients and 5 × FAD mice...
July 12, 2023: Molecular Neurodegeneration
Yasuteru Inoue, Francis Shue, Guojun Bu, Takahisa Kanekiyo
Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. Severe VCID includes post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. While VCID is acknowledged as the second most common form of dementia after Alzheimer's disease (AD) accounting for 20% of dementia cases, VCID and AD frequently coexist. In VCID, cerebral small vessel disease (cSVD) often affects arterioles, capillaries, and venules, where arteriolosclerosis and cerebral amyloid angiopathy (CAA) are major pathologies...
July 11, 2023: Molecular Neurodegeneration
Sidhanth Chandra, Antonio Di Meco, Hemraj B Dodiya, Jelena Popovic, Leah K Cuddy, Ian Q Weigle, Xiaoqiong Zhang, Katherine Sadleir, Sangram S Sisodia, Robert Vassar
BACKGROUND: Previous studies show that antibiotic-mediated (abx) alteration of the gut microbiome (GMB) results in a reduction of amyloid beta (Aβ) plaques and proinflammatory microglial phenotype in male APPPS1-21 mice. However, the effect of GMB perturbation on astrocyte phenotypes and microglial-astrocyte communication in the context of amyloidosis has not been examined. METHODS: To study whether the GMB modulates astrocyte phenotype in the context of amyloidosis, APPPS1-21 male and female mice were treated with broad-spectrum abx leading to GMB perturbation...
July 6, 2023: Molecular Neurodegeneration
Yogesh Singh, Christoph Trautwein, Joan Romani, Madhuri S Salker, Peter H Neckel, Isabel Fraccaroli, Mahkameh Abeditashi, Nils Woerner, Jakob Admard, Achal Dhariwal, Morten K D Dueholm, Karl-Herbert Schäfer, Florian Lang, Daniel E Otzen, Hilal A Lashuel, Olaf Riess, Nicolas Casadei
BACKGROUND: Braak's hypothesis states that sporadic Parkinson's disease (PD) follows a specific progression of pathology from the peripheral to the central nervous system, and this progression can be monitored by detecting the accumulation of alpha-Synuclein (α-Syn) protein. Consequently, there is growing interest in understanding how the gut (commensal) microbiome can regulate α-Syn accumulation, as this could potentially lead to PD. METHODS: We used 16S rRNA and shotgun sequencing to characterise microbial diversity...
July 4, 2023: Molecular Neurodegeneration
Shan P Yu, Michael Q Jiang, Seong S Shim, Soheila Pourkhodadad, Ling Wei
Stroke and late-onset Alzheimer's disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD)...
July 3, 2023: Molecular Neurodegeneration
Vijay K Ramanan, Gregory S Day
No abstract text is available yet for this article.
June 28, 2023: Molecular Neurodegeneration
Jihoon Lee, Ki Woon Sung, Eun-Jin Bae, Dabin Yoon, Dasarang Kim, Jin Saem Lee, Da-Ha Park, Daniel Youngjae Park, Su Ran Mun, Soon Chul Kwon, Hye Yeon Kim, Joo-Ok Min, Seung-Jae Lee, Young Ho Suh, Yong Tae Kwon
BACKGROUND: There are currently no disease-modifying therapeutics for Parkinson's disease (PD). Although extensive efforts were undertaken to develop therapeutic approaches to delay the symptoms of PD, untreated α-synuclein (α-syn) aggregates cause cellular toxicity and stimulate further disease progression. PROTAC (Proteolysis-Targeting Chimera) has drawn attention as a therapeutic modality to target α-syn. However, no PROTACs have yet shown to selectively degrade α-syn aggregates mainly owing to the limited capacity of the proteasome to degrade aggregates, necessitating the development of novel approaches to fundamentally eliminate α-syn aggregates...
June 24, 2023: Molecular Neurodegeneration
Moonil Kang, Ting Fang Alvin Ang, Sherral A Devine, Richard Sherva, Shubhabrata Mukherjee, Emily H Trittschuh, Laura E Gibbons, Phoebe Scollard, Michael Lee, Seo-Eun Choi, Brandon Klinedinst, Connie Nakano, Logan C Dumitrescu, Alaina Durant, Timothy J Hohman, Michael L Cuccaro, Andrew J Saykin, Walter A Kukull, David A Bennett, Li-San Wang, Richard P Mayeux, Jonathan L Haines, Margaret A Pericak-Vance, Gerard D Schellenberg, Paul K Crane, Rhoda Au, Kathryn L Lunetta, Jesse B Mez, Lindsay A Farrer
BACKGROUND: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. METHODS: We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components...
June 22, 2023: Molecular Neurodegeneration
Lei Guo, Jiqing Cao, Jianwei Hou, Yonghe Li, Min Huang, Li Zhu, Larry Zhang, Yeji Lee, Mariana Lemos Duarte, Xianxiao Zhou, Minghui Wang, Chia-Chen Liu, Yuka Martens, Michael Chao, Alison Goate, Guojun Bu, Vahram Haroutunian, Dongming Cai, Bin Zhang
BACKGROUND: Alzheimer's disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate sex-specific molecular networks of AD. METHODS: We integrated large-scale human postmortem brain transcriptomic data of AD from two cohorts (MSBB and ROSMAP) via multiscale network analysis and identified key drivers with sexually dimorphic expression patterns and/or different responses to APOE genotypes between sexes...
June 20, 2023: Molecular Neurodegeneration
Michal Nemergut, Sérgio M Marques, Lukas Uhrik, Tereza Vanova, Marketa Nezvedova, Darshak Chandulal Gadara, Durga Jha, Jan Tulis, Veronika Novakova, Joan Planas-Iglesias, Antonin Kunka, Anthony Legrand, Hana Hribkova, Veronika Pospisilova, Jiri Sedmik, Jan Raska, Zbynek Prokop, Jiri Damborsky, Dasa Bohaciakova, Zdenek Spacil, Lenka Hernychova, David Bednar, Martin Marek
BACKGROUND: Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown. METHODS: Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations...
June 6, 2023: Molecular Neurodegeneration
Keenan A Walker, Lydia M Le Page, Niccolò Terrando, Michael R Duggan, Michael T Heneka, Brianne M Bettcher
Peripheral inflammation, defined as inflammation that occurs outside the central nervous system, is an age-related phenomenon that has been identified as a risk factor for Alzheimer's disease. While the role of chronic peripheral inflammation has been well characterized in the context of dementia and other age-related conditions, less is known about the neurologic contribution of acute inflammatory insults that take place outside the central nervous system. Herein, we define acute inflammatory insults as an immune challenge in the form of pathogen exposure (e...
June 5, 2023: Molecular Neurodegeneration
Diego Sepulveda-Falla
No abstract text is available yet for this article.
June 1, 2023: Molecular Neurodegeneration
Ariel Ionescu, Topaz Altman, Eran Perlson
Axon degeneration and Neuromuscular Junction (NMJ) disruption are key pathologies in the fatal neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Despite accumulating evidence that axons and NMJs are impacted at a very early stage of the disease, current knowledge about the mechanisms leading to their degeneration remains elusive. Cytoplasmic mislocalization and accumulation of the protein TDP-43 are considered key pathological hallmarks of ALS, as they occur in ~ 97% of ALS patients, both sporadic and familial...
May 31, 2023: Molecular Neurodegeneration
Paul J Sampognaro, Shruti Arya, Giselle M Knudsen, Emma L Gunderson, Angelica Sandoval-Perez, Molly Hodul, Kathryn Bowles, Charles S Craik, Matthew P Jacobson, Aimee W Kao
No abstract text is available yet for this article.
May 30, 2023: Molecular Neurodegeneration
Xinyan Li, Wenting Chen, Xian Huang, Wei Jing, Tongmei Zhang, Quntao Yu, Hongyan Yu, Hao Li, Qing Tian, Yumei Ding, Youming Lu
No abstract text is available yet for this article.
May 15, 2023: Molecular Neurodegeneration
Thomas Koeglsperger, Svenja-Lotta Rumpf, Patricia Schließer, Felix L Struebing, Matthias Brendel, Johannes Levin, Claudia Trenkwalder, Günter U Höglinger, Jochen Herms
BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy. Understanding the early pathological changes that precede Lewy body pathology (LBP) and cell loss in PD will likely support the identification of novel diagnostic and therapeutic strategies and help to differentiate LBP-dependent and -independent alterations...
May 12, 2023: Molecular Neurodegeneration
John Zhou, Neeraj Singh, James Galske, Jacob Hudobenko, Xiangyou Hu, Riqiang Yan
BACKGROUND: Abnormal accumulation of amyloid beta peptide (Aβ) in the brain induces a cascade of pathological changes in Alzheimer's disease (AD), and inhibiting BACE1, which is required for Aβ generation, is therefore being explored for the treatment of AD by reducing Aβ accumulation. As Bace1 knockout mice exhibit increased number of reactive astrocytes and AD brains have reactive astrocytes that surround amyloid plaques, we investigated the role of BACE1 in astrocytes and determined whether BACE1 regulates astrocytic functions...
May 4, 2023: Molecular Neurodegeneration
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