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Article: Molecular Biology.

Goate, Alison M

2019 Volume 19, Issue 3, Page(s) 217–220

Abstract: Recent advances in molecular biology techniques permit scientists to identify genetic contributions to alcoholism. Two main types of technology are commonly used to identify genes that cause or predispose a person to a disease: positional cloning ... ...

Abstract	Recent advances in molecular biology techniques permit scientists to identify genetic contributions to alcoholism. Two main types of technology are commonly used to identify genes that cause or predispose a person to a disease: positional cloning techniques and candidate gene techniques. Positional cloning techniques allow disease genes to be identified based solely on their location within the genome without prior knowledge of the gene's function. Techniques for confirming the role of candidate genes rely on sufficient prior understanding of the disease process to implicate possible disease-related genes. Scientists use cloning techniques or the application of certain enzymes to reproduce a candidate gene in sufficient quantity for study. As the human genome project progresses and the gene map becomes increasingly complete, more and more disease genes will be identified through a combination of positional cloning and the candidate gene approach.
Language	English
Publishing date	2019-12-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	427760-0
ISSN	0090-838X
ISSN	0090-838X
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Zs.B 2180: Show issues

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Article: The influence of 17q21.31 and

Harerimana, Nadia V / Goate, Alison M / Bowles, Kathryn R

Frontiers in aging neuroscience

2022 Volume 14, Page(s) 1021918

Abstract: Advances in genomic research over the last two decades have greatly enhanced our knowledge concerning the genetic landscape and pathophysiological processes involved in multiple neurodegenerative diseases. However, current insights arise almost ... ...

Abstract	Advances in genomic research over the last two decades have greatly enhanced our knowledge concerning the genetic landscape and pathophysiological processes involved in multiple neurodegenerative diseases. However, current insights arise almost exclusively from studies on individuals of European ancestry. Despite this, studies have revealed that genetic variation differentially impacts risk for, and clinical presentation of neurodegenerative disease in non-European populations, conveying the importance of ancestry in predicting disease risk and understanding the biological mechanisms contributing to neurodegeneration. We review the genetic influence of two important disease-associated loci, 17q21.31 (the "
Language	English
Publishing date	2022-10-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2022.1021918
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Book: Pathobiology of Alzheimer's disease

Goate, Alison M.

(Neuroscience perspectives)

1995

Author's details	ed. by Alison M. Goate
Series title	Neuroscience perspectives
Keywords	Alzheimer Disease ; Amyloid beta-Protein ; Neurofibrillary Tangles ; tau Proteins ; Alzheimerkrankheit ; Pathophysiologie
Subject	Pathologische Physiologie ; Physiologische Pathologie ; Physiopathologie ; Alzheimer-Krankheit ; Alzheimersche Krankheit ; Alzheimer-Demenz ; Morbus Alzheimer ; Greisenblödsinn ; Alzheimer's Disease
Language	German
Size	XIV, 256 S. : Ill., graph. Darst.
Publisher	Academic Press u.a.
Publishing place	London u.a.
Publishing country	Great Britain
Document type	Book
HBZ-ID	HT007251572
ISBN	0-12-286965-6 ; 978-0-12-286965-5
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1996 A 4060	order for loan	Magazin

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Article ; Online: Novel presenilin 1 and 2 double knock-out cell line for in vitro validation of PSEN1 and PSEN2 mutations.

Pimenova, Anna A / Goate, Alison M

Neurobiology of disease

2020 Volume 138, Page(s) 104785

Abstract: Mutations in APP (amyloid precursor protein), PSEN1 (presenilin 1) or PSEN2 (presenilin 2) are the main cause of early-onset familial forms of Alzheimer's disease (autosomal dominant AD or ADAD). These genes affect γ-secretase-dependent generation of ... ...

Abstract	Mutations in APP (amyloid precursor protein), PSEN1 (presenilin 1) or PSEN2 (presenilin 2) are the main cause of early-onset familial forms of Alzheimer's disease (autosomal dominant AD or ADAD). These genes affect γ-secretase-dependent generation of Amyloid β (Aβ) peptides, the main constituent of amyloid plaques and one of the pathological hallmarks of AD. Evaluation of patients with ADAD includes assessment of family history, clinical presentation, biomarkers, neuropathology when available and DNA sequencing data. These analyses frequently uncover novel variants of unknown significance in ADAD genes. This presents a barrier to recruitment of such individuals into clinical trials, unless a biochemical test can demonstrate that a novel mutation results in altered APP processing in a manner consistent with pathogenicity. Here we describe generation and characterization of a novel presenilin 1 and 2 double knock-out in N2A mouse neuroblastoma cells using CRISPR/Cas9, which results in complete ablation of Aβ production, decreased Pen-2 expression and Nicastrin glycosylation. Because of the absence of background Aβ secretion from endogenous γ-secretases, these cells can be used for validation of PSEN1 and PSEN2 variant effects on production of Aβ or other γ-secretase substrates and for biochemical studies of γ-secretase function using novel variants. We examined several PSEN1 and PSEN2 mutations of known and unknown pathogenicity. Known mutants increased Aβ42/Aβ40 ratio with varying effect on Aβ40, Aβ42, total Aβ levels and Pen-2 expression, which aligns with previous work on these mutants. Our data on novel PSEN1 V142F, G206V and G206D mutations suggest that these mutations underlie the reported clinical observations in ADAD patients. We believe our novel cell line will be valuable for the scientific community for reliable validation of presenilin mutations and helpful in defining their pathogenicity to improve and facilitate evaluation of ADAD patients, particularly in the context of enrollment in clinical trials.
MeSH term(s)	Alzheimer Disease/diagnosis ; Alzheimer Disease/genetics ; Amyloid Precursor Protein Secretases/genetics ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Animals ; Cell Line ; Mice ; Mutation ; Patient Selection ; Peptide Fragments/metabolism ; Plaque, Amyloid/genetics ; Presenilin-1/genetics ; Presenilin-2/genetics
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Peptide Fragments ; Presenilin-1 ; Presenilin-2 ; Psen2 protein, mouse ; presenilin 1, mouse ; Amyloid Precursor Protein Secretases (EC 3.4.-)
Language	English
Publishing date	2020-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2020.104785
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Article ; Online: Microglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer's Disease Genetics.

Podleśny-Drabiniok, Anna / Marcora, Edoardo / Goate, Alison M

Trends in neurosciences

2020 Volume 43, Issue 12, Page(s) 965–979

Abstract: Alzheimer's disease (AD) is a debilitating, chronic neurodegenerative disease. Genetic studies involving genome-wide association studies (GWAS) and meta-analysis have discovered numerous genomic loci associated with AD; however, the causal genes and ... ...

Abstract	Alzheimer's disease (AD) is a debilitating, chronic neurodegenerative disease. Genetic studies involving genome-wide association studies (GWAS) and meta-analysis have discovered numerous genomic loci associated with AD; however, the causal genes and variants remain unidentified in most loci. Integration of GWAS signals with epigenomic annotations has demonstrated that AD risk variants are enriched in myeloid-specific enhancers, implicating myeloid cells in AD etiology. AD risk variants in these regulatory elements modify disease susceptibility by regulating the expression of genes that play crucial roles in microglial phagocytosis. Several of these AD risk genes are specifically expressed in myeloid cells, whereas others are ubiquitously expressed but are regulated by AD risk variants within myeloid enhancers in a cell type-specific manner. We discuss the impact of established AD risk variants on microglial phagocytosis and debris processing via the endolysosomal system.
MeSH term(s)	Alzheimer Disease/genetics ; Genome-Wide Association Study ; Humans ; Microglia ; Neurodegenerative Diseases ; Phagocytosis
Language	English
Publishing date	2020-10-27
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	282488-7
ISSN	1878-108X ; 0378-5912 ; 0166-2236
ISSN (online)	1878-108X
ISSN	0378-5912 ; 0166-2236
DOI	10.1016/j.tins.2020.10.002
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Zs.MG 53: Show issues

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Article ; Online: Genetic architecture of Alzheimer's disease.

Neuner, Sarah M / Tcw, Julia / Goate, Alison M

Neurobiology of disease

2020 Volume 143, Page(s) 104976

Abstract: Advances in genetic and genomic technologies over the last thirty years have greatly enhanced our knowledge concerning the genetic architecture of Alzheimer's disease (AD). Several genes including APP, PSEN1, PSEN2, and APOE have been shown to exhibit ... ...

Abstract	Advances in genetic and genomic technologies over the last thirty years have greatly enhanced our knowledge concerning the genetic architecture of Alzheimer's disease (AD). Several genes including APP, PSEN1, PSEN2, and APOE have been shown to exhibit large effects on disease susceptibility, with the remaining risk loci having much smaller effects on AD risk. Notably, common genetic variants impacting AD are not randomly distributed across the genome. Instead, these variants are enriched within regulatory elements active in human myeloid cells, and to a lesser extent liver cells, implicating these cell and tissue types as critical to disease etiology. Integrative approaches are emerging as highly effective for identifying the specific target genes through which AD risk variants act and will likely yield important insights related to potential therapeutic targets in the coming years. In the future, additional consideration of sex- and ethnicity-specific contributions to risk as well as the contribution of complex gene-gene and gene-environment interactions will likely be necessary to further improve our understanding of AD genetic architecture.
MeSH term(s)	Alzheimer Disease/genetics ; Genetic Predisposition to Disease/genetics ; Humans
Language	English
Publishing date	2020-06-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2020.104976
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Article ; Online: Heterogeneous effects of genetic risk for Alzheimer's disease on the phenome.

Wu, Hei Man / Goate, Alison M / O'Reilly, Paul F

Translational psychiatry

2021 Volume 11, Issue 1, Page(s) 406

Abstract: Here we report how four major forms of Alzheimer's disease (AD) genetic risk-APOE-ε4, APOE-ε2, polygenic risk and familial risk-are associated with 273 traits in ~500,000 individuals in the UK Biobank. The traits cover blood biochemistry and cell traits, ...

Abstract	Here we report how four major forms of Alzheimer's disease (AD) genetic risk-APOE-ε4, APOE-ε2, polygenic risk and familial risk-are associated with 273 traits in ~500,000 individuals in the UK Biobank. The traits cover blood biochemistry and cell traits, metabolic and general health, psychosocial health, and cognitive function. The difference in the profile of traits associated with the different forms of AD risk is striking and may contribute to heterogenous presentation of the disease. However, we also identify traits significantly associated with multiple forms of AD genetic risk, as well as traits showing significant changes across ages in those at high risk of AD, which may point to their potential roles in AD etiology. Finally, we highlight how survivor effects, in particular those relating to shared risks of cardiovascular disease and AD, can generate associations that may mislead interpretation in epidemiological AD studies. The UK Biobank provides a unique opportunity to powerfully compare the effects of different forms of AD genetic risk on the phenome in the same cohort.
MeSH term(s)	Alzheimer Disease/genetics ; Apolipoproteins E/genetics ; Genotype ; Humans ; Multifactorial Inheritance ; Phenotype ; Risk Factors
Chemical Substances	Apolipoproteins E
Language	English
Publishing date	2021-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-021-01518-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Microglial efferocytosis: Diving into the Alzheimer's disease gene pool.

Romero-Molina, Carmen / Garretti, Francesca / Andrews, Shea J / Marcora, Edoardo / Goate, Alison M

Neuron

2022 Volume 110, Issue 21, Page(s) 3513–3533

Abstract: Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer's disease (AD) risk. In particular, AD risk alleles primarily affect the abundance or structure, and thus the activity, of ... ...

Abstract	Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer's disease (AD) risk. In particular, AD risk alleles primarily affect the abundance or structure, and thus the activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) in the etiology of AD. These genes converge on pathways (endocytosis/phagocytosis, cholesterol metabolism, and immune response) with critical roles in core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant genes identified in the latest AD genetics and genomics studies, and describe how they may contribute to AD pathogenesis. Investigating the functional impact of AD-associated variants and genes in microglia is essential for elucidating disease risk mechanisms and developing effective therapeutic approaches.
MeSH term(s)	Humans ; Microglia/metabolism ; Alzheimer Disease/metabolism ; Genome-Wide Association Study ; Gene Pool ; Phagocytosis/genetics
Language	English
Publishing date	2022-11-01
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2022.10.015
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation.

Saroja, Sivaprakasam R / Gorbachev, Kirill / Julia, Tcw / Goate, Alison M / Pereira, Ana C

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 34, Page(s) e2108870119

Abstract: Tau protein aggregates are a major driver of neurodegeneration and behavioral impairments in tauopathies, including in Alzheimer's disease (AD). Apolipoprotein E4 ( ...

Abstract	Tau protein aggregates are a major driver of neurodegeneration and behavioral impairments in tauopathies, including in Alzheimer's disease (AD). Apolipoprotein E4 (
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Animals ; Apolipoprotein E2/genetics ; Apolipoprotein E4/genetics ; Apolipoprotein E4/metabolism ; Astrocytes/metabolism ; Disease Models, Animal ; Glypicans/metabolism ; Humans ; Mice ; Mice, Transgenic ; Phosphorylation ; Tauopathies/metabolism ; Tauopathies/physiopathology ; tau Proteins/metabolism
Chemical Substances	Apolipoprotein E2 ; Apolipoprotein E4 ; Glypicans ; tau Proteins
Language	English
Publishing date	2022-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2108870119
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Article ; Online: Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease.

Tcw, Julia / Goate, Alison M

Cold Spring Harbor perspectives in medicine

2017 Volume 7, Issue 6

Abstract: Alzheimer's disease (AD) is characterized neuropathologically by neuronal cell loss, extracellular neuritic plaques composed of β-amyloid (Aβ), and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Aβ is generated by ... ...

Abstract	Alzheimer's disease (AD) is characterized neuropathologically by neuronal cell loss, extracellular neuritic plaques composed of β-amyloid (Aβ), and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Aβ is generated by proteolytic processing of the β-amyloid precursor protein (APP). Most individuals with Down syndrome (DS) have three copies of
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Brain/metabolism ; Brain/pathology ; Down Syndrome/genetics ; Down Syndrome/metabolism ; Humans ; Mutation, Missense ; Neurofibrillary Tangles ; Plaque, Amyloid ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Protein Precursor ; tau Proteins
Language	English
Publishing date	2017-06-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a024539
Database	MEDical Literature Analysis and Retrieval System OnLINE

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