Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer's disease

Brain perfusion and normal blood brain barrier integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and control brains to characterise pathological transcriptional signatures. We found that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. EC transcriptional signatures identified mechanisms for impaired b-amyloid clearance. Evidence for immune activation was found with upregulation of interferon signalling genes in EC and in pericytes (PC). Transcriptional signatures suggested dysregulation of vascular homeostasis and angiogenesis with upregulation of pro-angiogenic signals (HIF1A) and metabolism in EC, but downregulation of homeostatic growth factor pathways (VEGF, EGF, insulin) in EC and PC and of extracellular matrix genes in fibroblasts (FB). Our genomic dissection of vascular cell risk gene enrichment suggests a potentially causal role for EC and defines transcriptional signatures associated with microvascular dysfunction in AD.

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Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease

10.1101/2020.04.04.025825 ◽

2020 ◽

Cited By ~ 5

Author(s):

Kun Leng ◽

Emmy Li ◽

Rana Eser ◽

Antonia Piergies ◽

Rene Sit ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Entorhinal Cortex ◽

Neuronal Loss ◽

Selective Vulnerability ◽

Brain Regions ◽

Neuronal Populations ◽

Expression Of Genes ◽

Single Nucleus

ABSTRACTAlzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus – brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively – from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.

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SPECIFIC PROPERTIES OF TUBULIN IN THE PREFRONTAL CORTEX IN CONTROL, SCHIZOPHRENIA AND VASCULAR DEMENTIA

"Medical & pharmaceutical journal "Pulse" ◽

10.26787/nydha-2686-6838-2020-22-11-65-71 ◽

2020 ◽

pp. 65-71

Author(s):

Burbaeva G.Sh. ◽

Androsova L.V. ◽

Vorobyeva E.A. ◽

Savushkina O.K.

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prefrontal Cortex ◽

Vascular Dementia ◽

Binding Activity ◽

Nephelometric Method ◽

Rate Of Polymerization ◽

Mental Diseases ◽

And Control ◽

The Brain

The aim of the study was to evaluate the rate of polymerization of tubulin into microtubules and determine the level of colchicine binding (colchicine-binding activity of tubulin) in the prefrontal cortex in schizophrenia, vascular dementia (VD) and control. Colchicine-binding activity of tubulin was determined by Sherlinе in tubulin-enriched extracts of proteins from the samples. Measurement of light scattering during the polymerization of the tubulin was carried out using the nephelometric method at a wavelength of 450-550 nm. There was a significant decrease in colchicine-binding activity and the rate of tubulin polymerization in the prefrontal cortex in both diseases, and in VD to a greater extent than in schizophrenia. The obtained results suggest that not only in Alzheimer's disease, but also in other mental diseases such as schizophrenia and VD, there is a decrease in the level of tubulin in the prefrontal cortex of the brain, although to a lesser extent than in Alzheimer's disease, and consequently the amount of microtubules.

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Distinct network topology in Alzheimer’s disease and behavioral variant frontotemporal dementia

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00752-w ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Adeline Su Lyn Ng ◽

Juan Wang ◽

Kwun Kei Ng ◽

Joanna Su Xian Chong ◽

Xing Qian ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontotemporal Dementia ◽

Network Topology ◽

Neuropsychiatric Symptoms ◽

Brain Network ◽

Salience Network ◽

Behavioral Variant Frontotemporal Dementia ◽

Control Networks ◽

And Control

Abstract Background Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) cause distinct atrophy and functional disruptions within two major intrinsic brain networks, namely the default network and the salience network, respectively. It remains unclear if inter-network relationships and whole-brain network topology are also altered and underpin cognitive and social–emotional functional deficits. Methods In total, 111 participants (50 AD, 14 bvFTD, and 47 age- and gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Functional connectivity was derived among 144 brain regions of interest. Graph theoretical analysis was applied to characterize network integration, segregation, and module distinctiveness (degree centrality, nodal efficiency, within-module degree, and participation coefficient) in AD, bvFTD, and healthy participants. Group differences in graph theoretical measures and empirically derived network community structures, as well as the associations between these indices and cognitive performance and neuropsychiatric symptoms, were subject to general linear models, with age, gender, education, motion, and scanner type controlled. Results Our results suggested that AD had lower integration in the default and control networks, while bvFTD exhibited disrupted integration in the salience network. Interestingly, AD and bvFTD had the highest and lowest degree of integration in the thalamus, respectively. Such divergence in topological aberration was recapitulated in network segregation and module distinctiveness loss, with AD showing poorer modular structure between the default and control networks, and bvFTD having more fragmented modules in the salience network and subcortical regions. Importantly, aberrations in network topology were related to worse attention deficits and greater severity in neuropsychiatric symptoms across syndromes. Conclusions Our findings underscore the reciprocal relationships between the default, control, and salience networks that may account for the cognitive decline and neuropsychiatric symptoms in dementia.

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Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer’s disease

Nature Genetics ◽

10.1038/s41588-021-00894-z ◽

2021 ◽

Author(s):

Samuel Morabito ◽

Emily Miyoshi ◽

Neethu Michael ◽

Saba Shahin ◽

Alessandra Cadete Martini ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Chromatin Accessibility ◽

Single Nucleus

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Associations between Brain Perfusion and Sleep Disturbance in Patients with Alzheimer's Disease

Dementia and Neurocognitive Disorders ◽

10.12779/dnd.2017.16.3.72 ◽

2017 ◽

Vol 16 (3) ◽

pp. 72

Author(s):

Jooyeon J. Im ◽

Hyeonseok S. Jeong ◽

Jong-Sik Park ◽

Seung-Hee Na ◽

Yong-An Chung ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sleep Disturbance ◽

Brain Perfusion

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Single-cell transcriptomic analysis elucidates APOE genotype specific changes across cell types in two brain regions in Alzheimer’s disease

10.21203/rs.3.rs-291648/v1 ◽

2021 ◽

Author(s):

Stella Belonwu ◽

Yaqiao Li ◽

Daniel Bunis ◽

Arjun Arkal Rao ◽

Caroline Warly Solsberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Single Cell ◽

Molecular Mechanisms ◽

Apoe Genotype ◽

Cell Types ◽

Brain Regions ◽

Single Cell Level ◽

Cell Level ◽

Single Nucleus

Abstract Alzheimer’s Disease (AD) is a complex neurodegenerative disease that gravely affects patients and imposes an immense burden on caregivers. Apolipoprotein E4 (APOE4) has been identified as the most common genetic risk factor for AD, yet the molecular mechanisms connecting APOE4 to AD are not well understood. Past transcriptomic analyses in AD have revealed APOE genotype-specific transcriptomic differences; however, these differences have not been explored at a single-cell level. Here, we leverage the first two single-nucleus RNA sequencing AD datasets from human brain samples, including nearly 55,000 cells from the prefrontal and entorhinal cortices. We observed more global transcriptomic changes in APOE4 positive AD cells and identified differences across APOE genotypes primarily in glial cell types. Our findings highlight the differential transcriptomic perturbations of APOE isoforms at a single-cell level in AD pathogenesis and have implications for precision medicine development in the diagnosis and treatment of AD.

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EAAT2 Expression in the Hippocampus, Subiculum, Entorhinal Cortex and Superior Temporal Gyrus in Alzheimer’s Disease

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.702824 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jason H. Y. Yeung ◽

Thulani H. Palpagama ◽

Oliver W. G. Wood ◽

Clinton Turner ◽

Henry J. Waldvogel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Entorhinal Cortex ◽

Excitatory Amino Acid ◽

Glutamate Uptake ◽

Expression Patterns ◽

Superior Temporal Gyrus ◽

Altered Expression ◽

And Control ◽

Transporter Expression

Alzheimer’s disease (AD) is a neuropathological disorder characterized by the presence and accumulation of amyloid-beta plaques and neurofibrillary tangles. Glutamate dysregulation and the concept of glutamatergic excitotoxicity have been frequently described in the pathogenesis of a variety of neurodegenerative disorders and are postulated to play a major role in the progression of AD. In particular, alterations in homeostatic mechanisms, such as glutamate uptake, have been implicated in AD. An association with excitatory amino acid transporter 2 (EAAT2), the main glutamate uptake transporter, dysfunction has also been described. Several animal and few human studies examined EAAT2 expression in multiple brain regions in AD but studies of the hippocampus, the most severely affected brain region, are scarce. Therefore, this study aims to assess alterations in the expression of EAAT2 qualitatively and quantitatively through DAB immunohistochemistry (IHC) and immunofluorescence within the hippocampus, subiculum, entorhinal cortex, and superior temporal gyrus (STG) regions, between human AD and control cases. Although no significant EAAT2 density changes were observed between control and AD cases, there appeared to be increased transporter expression most likely localized to fine astrocytic branches in the neuropil as seen on both DAB IHC and immunofluorescence. Therefore, individual astrocytes are not outlined by EAAT2 staining and are not easily recognizable in the CA1–3 and dentate gyrus regions of AD cases, but the altered expression patterns observed between AD and control hippocampal cases could indicate alterations in glutamate recycling and potentially disturbed glutamatergic homeostasis. In conclusion, no significant EAAT2 density changes were found between control and AD cases, but the observed spatial differences in transporter expression and their functional significance will have to be further explored.

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Surface-based analysis of cortical thickness and volume loss in Alzheimer’s disease

Proceedings of IMPRS ◽

10.18060/23524 ◽

2019 ◽

Vol 2 (1) ◽

Author(s):

Emily Iannopollo ◽

Ryan Plunkett ◽

Kara Garcia

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Magnetic Resonance ◽

Cortical Thickness ◽

Surface Matching ◽

Cortical Surface ◽

Volume Loss ◽

Cortical Volume ◽

Human Connectome Project ◽

And Control

Background and Hypothesis: Magnetic resonance imaging (MRI) has become a useful tool in monitoring the progression of Alzheimer's disease. Previous surface-based analysis has focused on changes in cortical thickness associated with the disease1. The objective of this study is to analyze MRI-derived cortical reconstructions for patterns of atrophy in terms of both cortical thickness and cortical volume. We hypothesize that Alzheimer’s Disease progression will be associated with a more significant change in volume than thickness. Experimental Design or Project Methods: MRI data was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). All subjects with baseline and two-year 3T MRI scans were included. Segmentation of MRIs into gray and white matter was performed with FreeSurfer2,3,4,5. Subjects whose scans did not segment accurately were excluded. Surfaces were then registered to a common atlas with Ciftify6, and anatomically-constrained Multimodal Surface Matching (aMSM) was used to analyze longitudinal changes in each subject7. This produced continuous surface maps showing changes in cortical surface area and thickness. These maps were multiplied to create cortical volume maps8. Permutation Analysis of Linear Models (PALM) was used to perform two-sample t-tests comparing the maps of the Alzheimer’s and control groups9. Results: Preliminary analysis of nine Alzheimer’s subjects and nine control subjects produced surface maps displaying patterns that were expected given previous research findings10,11. There was increased volume and thickness loss in Alzheimer’s subjects relative to controls, with relatively high loss in structures of the medial temporal lobe. Future analysis of a larger sample will determine whether statistically significant differences exist between the Alzheimer’s and control groups in terms of thickness loss and volume loss. Conclusion and Potential Impact: If significant results are found, surface-based analysis of cortical volume may allow for detection of atrophy at an earlier stage in disease progression than would be possible based on cortical thickness. References 1. Clarkson MJ, Cardoso MJ, Ridgway GR, Modat M, Leung KK, Rohrer JD, Fox NC, Ourselin S. A comparison of voxel and surface based cortical thickness estimation methods. NeuroImage. 2011 Aug 1; 57(3):856-65. 2. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999;9:179194. 3. Fischl B, Sereno M, Dale A. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage. 1999;9:195–207. 4. Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, van der Kouwe A, Killiany R, Kennedy D, Klaveness S, Montillo A, Makris N, Rosen B, Dale AM. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 2002;33:341-355. 5. Fischl B, Salat DH, van der Kouwe AJ, Makris N, Segonne F, Quinn BT, Dale AM. Sequence-independent segmentation of magnetic resonance images. Neuroimage 2004;23 Suppl 1:S69-84. 6. Glasser MF, Sotiropoulos SN, Wilson JA, Coalson TS, Fischl B, Andersson JL, Xu J, Jbabdi S, Webster M, Polimeni JR, Van Essen DC, Jenkinson M, WU-Minn HCP Consortium. The minimal preprocessing pipelines for the Human Connectome Project. Neuroimage. 2013 Oct 15;80:105-24. 7. Robinson EC, Garcia K, Glasser MF, Chen Z, Coalson TS, Makropoulos A, Bozek J, Wright R, Schuh A, Webster M, Hutter J, Price A, Cordero Grande L, Hughes E, Tusor N, Bayly PV, Van Essen DC, Smith SM, Edwards AD, Hajnal J, Jenkinson M, Glocker B, Rueckert D. Multimodal surface matching with higher-order smoothness constraints. Neuroimage. 2018;167:453-65. 8. Marcus DS, Harwell J, Olsen T, Hodge M, Glasser MF, Prior F, Jenkinson M, Laumann T, Curtiss SW, Van Essen DC. Informatics and data mining tools and strategies for the human connectome project. Front Neuroinform 2011;5:4. 9. Winkler AM, Ridgway GR, Webster MA, Smith SM, Nichols TE. Permutation inference for the general linear model. NeuroImage, 2014;92:381-397 10. Matsuda, H. MRI morphometry in Alzheimer’s disease. Ageing Research Reviews. 2016 Sep;30:17-24. 11. Risacher SL, Shen L, West JD, Kim S, McDonald BC, Beckett LA, Harvey DJ, Jack CR Jr, Weiner MW, Saykin AJ. Alzheimer's Disease Neuroimaging Initiative (ADNI). Longitudinal MRI atrophy biomarkers: relationship to conversion in the ADNI cohort. Neurobiol Aging. 2010 Aug;31(8):1401-18.

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