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Article ; Online: Alzheimer’s Disease Research Using Human Microglia

Lih-Fen Lue / Thomas G. Beach / Douglas G. Walker

Cells, Vol 8, Iss 8, p

2019 Volume 838

Abstract: Experimental studies of neuroinflammation in Alzheimer’s disease (AD) have mostly investigated microglia, the brain-resident macrophages. This review focused on human microglia obtained at rapid autopsies. Studies employing methods to isolate and culture ...

Abstract	Experimental studies of neuroinflammation in Alzheimer’s disease (AD) have mostly investigated microglia, the brain-resident macrophages. This review focused on human microglia obtained at rapid autopsies. Studies employing methods to isolate and culture human brain microglia in high purity for experimental studies were discussed. These methods were employed to isolate human microglia for investigation of a number of features of neuroinflammation, including activation phenotypes, neurotoxicity, responses to abnormal aggregated proteins such as amyloid beta, phagocytosis, and the effects of aging and disease on microglia cellular properties. In recent years, interest in human microglia and neuroinflammation has been renewed due to the identification of inflammation-related AD genetic risk factors, in particular the triggering receptor expressed on myeloid cells (TREM)-2. Because of the difficulties in developing effective treatments for AD, there has been a general need for greater understanding of the functions of microglia in normal and AD brains. While most experimental studies on neuroinflammation have employed rodent microglia, this review considered the role of human microglia in experimental studies. This review focused on the development of in vitro methodology for the culture of postmortem human microglia and the key findings obtained from experimental studies with these cells.
Keywords	neuroinflammation ; microglia ; cell culture ; brain ; amyloid ; neurodegeneration ; autopsy ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2019-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease

Xianjun Dong / Yunfei Bai / Zhixiang Liao / David Gritsch / Xiaoli Liu / Tao Wang / Rebeca Borges-Monroy / Alyssa Ehrlich / Geidy E. Serrano / Mel B. Feany / Thomas G. Beach / Clemens R. Scherzer

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 12

Abstract: Abstract Little is known about circular RNAs (circRNAs) in specific brain cells and human neuropsychiatric disease. Here, we systematically identify over 11,039 circRNAs expressed in vulnerable dopamine and pyramidal neurons laser-captured from 190 human ...

Abstract	Abstract Little is known about circular RNAs (circRNAs) in specific brain cells and human neuropsychiatric disease. Here, we systematically identify over 11,039 circRNAs expressed in vulnerable dopamine and pyramidal neurons laser-captured from 190 human brains and non-neuronal cells using ultra-deep, total RNA sequencing. 1526 and 3308 circRNAs are custom-tailored to the cell identity of dopamine and pyramidal neurons and enriched in synapse pathways. 29% of Parkinson’s and 12% of Alzheimer’s disease-associated genes produced validated circRNAs. circDNAJC6, which is transcribed from a juvenile-onset Parkinson’s gene, is already dysregulated during prodromal, onset stages of common Parkinson’s disease neuropathology. Globally, addiction-associated genes preferentially produce circRNAs in dopamine neurons, autism-associated genes in pyramidal neurons, and cancers in non-neuronal cells. This study shows that circular RNAs in the human brain are tailored to neuron identity and implicate circRNA-regulated synaptic specialization in neuropsychiatric diseases.
Keywords	Science ; Q
Language	English
Publishing date	2023-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Microglial Phenotyping in Neurodegenerative Disease Brains

Douglas G. Walker / Lih-Fen Lue / Thomas G. Beach / Ikuo Tooyama

Cells, Vol 8, Iss 7, p

Identification of Reactive Microglia with an Antibody to Variant of CD105/Endoglin

2019 Volume 766

Abstract: Inflammation is considered a key pathological process in neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), but there are still mechanisms not understood. In the brain, most microglia are performing essential ... ...

Abstract	Inflammation is considered a key pathological process in neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), but there are still mechanisms not understood. In the brain, most microglia are performing essential homeostatic functions, but can also respond to pathogenic stimuli by producing harmful pro-inflammatory cytokines or free radicals. Distinguishing between damaging and homeostatic microglia in human diseased brain tissues is a challenge. This report describes findings using a monoclonal antibody to CD105/Endoglin (R&D Systems MAB1097) that identifies subtypes of activated microglia. CD105/Endoglin is a co-receptor for transforming growth factor beta (TGFβ) receptor that antagonizes TGFβ signaling. CD105/Endoglin is a marker for vascular endothelial cells, but was originally identified as a marker for activated macrophages. This antibody did not identify endothelial cells in brain sections, only microglia-like cells. In this study, we examined with this antibody tissue section from middle temporal gyrus derived from human brains from normal control subjects with low-plaque pathology, high-plaque pathology, and AD cases, and also substantia nigra samples from control and PD cases, in conjunction with antibodies to markers of pathology and microglia. In low-plaque pathology cases, CD105-positive microglia were mostly absent, but noticeably increased with increasing pathology. CD105-positive cells strongly colocalized with amyloid-beta plaques, but not phosphorylated tau positive tangles. In substantia nigra, strong microglial CD105 staining was observed in microglia associated with degenerating dopaminergic neurons and neuromelanin. In PD cases with few surviving dopaminergic neurons, this staining had decreased. By Western blot, this antibody identified polypeptide bands of 70 kDa in brain samples, and samples from microglia, macrophages, and brain endothelial cells. In comparison with other tested CD105 antibodies, this antibody did not recognize the glycosylated ...
Keywords	neuroinflammation ; neuropathology ; transforming growth factor ; activation ; microglia ; immunohistochemistry ; human ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure

Xianwei Chen / Guoqiang Sun / E Tian / Mingzi Zhang / Hayk Davtyan / Thomas G. Beach / Eric M. Reiman / Mathew Blurton‐Jones / David M. Holtzman / Yanhong Shi

Advanced Science, Vol 8, Iss 18, Pp n/a-n/a (2021)

2021

Abstract: Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. Huge efforts have been made to develop anti‐AD drugs in the past decades. However, all drug development programs for disease‐modifying therapies have failed. ... ...

Abstract	Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. Huge efforts have been made to develop anti‐AD drugs in the past decades. However, all drug development programs for disease‐modifying therapies have failed. Possible reasons for the high failure rate include incomplete understanding of complex pathophysiology of AD, especially sporadic AD (sAD), and species difference between humans and animal models used in preclinical studies. In this study, sAD is modeled using human induced pluripotent stem cell (hiPSC)‐derived 3D brain organoids. Because the blood–brain barrier (BBB) leakage is a well‐known risk factor for AD, brain organoids are exposed to human serum to mimic the serum exposure consequence of BBB breakdown in AD patient brains. The serum‐exposed brain organoids are able to recapitulate AD‐like pathologies, including increased amyloid beta (Aβ) aggregates and phosphorylated microtubule‐associated tau protein (p‐Tau) level, synaptic loss, and impaired neural network. Serum exposure increases Aβ and p‐Tau levels through inducing beta‐secretase 1 (BACE) and glycogen synthase kinase‐3 alpha / beta (GSK3α/β) levels, respectively. In addition, single‐cell transcriptomic analysis of brain organoids reveals that serum exposure reduced synaptic function in both neurons and astrocytes and induced immune response in astrocytes. The human brain organoid‐based sAD model established in this study can provide a powerful platform for both mechanistic study and therapeutic development in the future.
Keywords	brain organoids ; disease modeling ; induced pluripotent stem cells ; serum exposure ; sporadic Alzheimer's disease ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Soluble P‐tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau

Niklas Mattsson‐Carlgren / Shorena Janelidze / Randall J Bateman / Ruben Smith / Erik Stomrud / Geidy E Serrano / Eric M Reiman / Sebastian Palmqvist / Jeffrey L Dage / Thomas G Beach / Oskar Hansson

EMBO Molecular Medicine, Vol 13, Iss 6, Pp n/a-n/a (2021)

2021

Abstract: Abstract Alzheimer’s disease is characterized by β‐amyloid plaques and tau tangles. Plasma levels of phospho‐tau217 (P‐tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β‐ ... ...

Abstract	Abstract Alzheimer’s disease is characterized by β‐amyloid plaques and tau tangles. Plasma levels of phospho‐tau217 (P‐tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β‐amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post‐mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P‐tau217, but P‐tau217 was not elevated in patients with non‐Alzheimer’s disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging (“BioFINDER‐2”, N = 426), where β‐amyloid and tau PET were independently associated with P‐tau217. P‐tau217 concentrations correlated with β‐amyloid PET (but not tau PET) in early disease stages and with both β‐amyloid and (more strongly) tau PET in late disease stages. Finally, P‐tau217 mediated the association between β‐amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P‐tau217 concentration is increased by both β‐amyloid plaques and tau tangles and is congruent with the hypothesis that P‐tau is involved in β‐amyloid‐dependent formation of neocortical tau tangles.
Keywords	Alzheimer’s disease ; amyloid ; phosphorylated tau ; plasma ; tau ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Differential methylation analysis in neuropathologically confirmed dementia with Lewy bodies

Communications Biology, Vol 7, Iss 1, Pp 1-

2024 Volume 10

Abstract: Abstract Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of ...

Abstract	Abstract Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Impaired hepatic amyloid-beta degradation in Alzheimer's disease.

Chera L Maarouf / Jessica E Walker / Lucia I Sue / Brittany N Dugger / Thomas G Beach / Geidy E Serrano

PLoS ONE, Vol 13, Iss 9, p e

2018 Volume 0203659

Abstract: Extensive research strongly suggests that amyloid beta (Aβ) aggregates in the brain have a central role in Alzheimer's disease (AD) pathogenesis. Pathological Aβ deposition is likely due to an altered balance between overproduction and elimination. ... ...

Abstract	Extensive research strongly suggests that amyloid beta (Aβ) aggregates in the brain have a central role in Alzheimer's disease (AD) pathogenesis. Pathological Aβ deposition is likely due to an altered balance between overproduction and elimination. Rodent studies have suggested that the liver has a major role in Aβ degradation. It is possible alterations of liver function could affect brain Aβ levels through changes in blood Aβ concentration. In this study, we hypothesized hepatic Aβ degradation to be impaired in AD subjects. To test our hypothesis, an Aβ degradation assay was developed using synthetic fluorescein-labeled Aβ40 and Aβ42 spiked into human liver homogenates. Aβ degradation rates were lower in AD-derived homogenates as compared with those from non-demented (ND) control subjects, even after accounting for such covariates as age, sex, and APOE genotype. The protein expression of potential Aβ-degrading enzymes were also examined. Neprilysin levels were not different in AD liver samples, while cathepsin D and insulin-degrading enzyme were significantly altered in AD subjects. The results support the possibility that impaired hepatic Aβ degradation could be a factor contributing to increased brain Aβ accumulation and AD.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Patterns of Expression of Purinergic Receptor P2RY12, a Putative Marker for Non-Activated Microglia, in Aged and Alzheimer’s Disease Brains

Douglas G. Walker / Tiffany M. Tang / Anarmaa Mendsaikhan / Ikuo Tooyama / Geidy E. Serrano / Lucia I. Sue / Thomas G. Beach / Lih-Fen Lue

International Journal of Molecular Sciences, Vol 21, Iss 2, p

2020 Volume 678

Abstract: Neuroinflammation is considered a key pathological process in neurodegenerative diseases of aging, including Alzheimer’s disease (AD). Many studies have defined phenotypes of reactive microglia, the brain-resident macrophages, with different antigenic ... ...

Abstract	Neuroinflammation is considered a key pathological process in neurodegenerative diseases of aging, including Alzheimer’s disease (AD). Many studies have defined phenotypes of reactive microglia, the brain-resident macrophages, with different antigenic markers to identify those potentially causing inflammatory damage. We took an alternative approach with the goal of characterizing the distribution of purinergic receptor P2RY12-positive microglia, a marker previously defined as identifying homeostatic or non-activated microglia. We examined the expression of P2RY12 by dual-color light and fluorescence immunohistochemistry using sections of middle temporal gyrus from AD, high plaque and low plaque non-demented cases in relation to amyloid beta (Aβ) plaques and phosphorylated tau, markers of pathology, and HLA-DR, IBA-1, CD68, and progranulin, microglial phenotype markers. In low plaque cases, P2RY12-positive microglia mostly had non-activated morphologies, while the morphologies of P2RY12-positive microglia in AD brains were highly variable, suggesting its expression could encompass a wider range of phenotypes than originally hypothesized. P2RY12 expression by microglia differed depending on the types of plaques or tangles they were associated with. Areas of inflammation characterized by lack of P2RY12-positive microglia around mature plaques could be observed, but many diffuse plaques showed colocalization with P2RY12-positive microglia. Based on these results, P2RY12 expression by microglia should not be considered solely a marker of resting microglia as P2RY12 immunoreactivity was identifying microglia positive for CD68, progranulin and to a limited extent HLA-DR, markers of activation.
Keywords	activation phenotypes ; microglia ; neuroinflammation ; immunohistochemistry ; temporal cortex ; alzheimer’s disease ; amyloid ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation

Karpagam Srinivasan / Brad A. Friedman / Ainhoa Etxeberria / Melanie A. Huntley / Marcel P. van der Brug / Oded Foreman / Jonathan S. Paw / Zora Modrusan / Thomas G. Beach / Geidy E. Serrano / David V. Hansen

Cell Reports, Vol 31, Iss 13, Pp 107843- (2020)

2020

Abstract: Summary: Damage-associated microglia (DAM) profiles observed in Alzheimer’s disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we ... ...

Abstract	Summary: Damage-associated microglia (DAM) profiles observed in Alzheimer’s disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile. Instead, HAM display an enhanced human aging profile, in addition to other disease-related changes such as APOE upregulation. Analyses of whole-tissue RNA-seq and single-cell/nucleus RNA-seq datasets corroborate our findings and suggest that the lack of DAM response in human microglia occurs specifically in AD tissues, not other neurodegenerative settings. These results, which can be browsed at http://research-pub.gene.com/BrainMyeloidLandscape, provide a genome-wide picture of microglial activation in human AD and highlight considerable differences between mouse models and human disease.
Keywords	Alzheimer’s disease ; microglia ; aging ; transcriptomics ; neurodegenerative diseases ; neuroinflammation ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prevalence of REM sleep behavior disorder in Sun City, Arizona

David R. Shprecher / Geidy E. Serrano / Nan Zhang / Anthony Intorcia / Kathryn J. Davis / Michael Glass / Jasmine Curry / Jessica Walker / Brett Cutler / Michael Callan / Angelica Garcia / Lucia I. Sue / Thomas G. Beach

Heliyon, Vol 6, Iss 1, Pp e03140- (2020)

2020

Abstract: Objective: To determine prevalence of REM sleep behavior disorder (RBD) [prodromal Lewy body disease] in Sun City, Arizona. Patients and methods: We attempted, by telephone and mail, a survey using the RBD single item question for probable RBD (pRBD) and ...

Abstract	Objective: To determine prevalence of REM sleep behavior disorder (RBD) [prodromal Lewy body disease] in Sun City, Arizona. Patients and methods: We attempted, by telephone and mail, a survey using the RBD single item question for probable RBD (pRBD) and the Innsbruck RBD Inventory. Individuals answering “yes” to 4/5 Inventory questions were considered to have high likelihood RBD (HL-RBD.) Results: Response rate was 484/3000 individuals contacted (16%), mean age 78; 48 (9.9%) endorsed pRBD by RBD1Q; 16 (3.3%) had HL-pRBD. Prevalence of idiopathic cases (without neurodegenerative disease) was 8.8% pRBD and 2.8% HL-RBD. Conclusion: Our estimated definite RBD prevalence of 1.7% (61.3% of HL-RBD) was similar to previous community-based studies.
Keywords	Clinical research ; Nervous system ; Neurology ; Neuroscience ; Pathology ; Parkinson disease ; Science (General) ; Q1-390 ; Social sciences (General) ; H1-99
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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