The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques

SUMMARY Gene expression profiles of more than 10,000 individual microglial cells isolated from cortex and hippocampus of male and female AppNL-G-F mice over time demonstrate that progressive amyloid-b accumulation accelerates two main activated microglia states that are also present during normal aging. Activated response microglia (ARMs) are composed of specialized subgroups overexpressing MHC type II and putative tissue repair genes (Dkk2, Gpnmb, and Spp1) and are strongly enriched with Alzheimer’s disease (AD) risk genes. Microglia from female mice progress faster in this activation trajectory. Similar activated states are also found in a second AD model and in human brain. Apoe, the major genetic risk factor for AD, regulates the ARMs but not the interferon response microglia (IRMs). Thus, the ARMs response is the converging point for aging, sex, and genetic AD risk factors.

[1]  Eric Karran,et al.  The Cellular Phase of Alzheimer’s Disease , 2016, Cell.

[2]  B. Hyman,et al.  Neuropathological alterations in Alzheimer disease. , 2011, Cold Spring Harbor perspectives in medicine.

[3]  D. Holtzman,et al.  ApoE facilitates the microglial response to amyloid plaque pathology , 2018, The Journal of experimental medicine.

[4]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[5]  A. Goate,et al.  Cruchaga & Goate reply , 2015, Nature.

[6]  Cole Trapnell,et al.  The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells , 2014, Nature Biotechnology.

[7]  C. Jack,et al.  Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers , 2013, The Lancet Neurology.

[8]  Bradley T. Hyman,et al.  Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta , 2013, Neuron.

[9]  Amaia M. Arranz,et al.  PLD3 gene and processing of APP , 2017, Nature.

[10]  Charles C. White,et al.  A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease , 2018, Nature Neuroscience.

[11]  Tom Michoel,et al.  Microglial brain region-dependent diversity and selective regional sensitivities to ageing , 2015, Nature Neuroscience.

[12]  C. Mazure,et al.  Sex differences in Alzheimer's disease and other dementias , 2016, The Lancet Neurology.

[13]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Benjamin E. L. Lauffer,et al.  Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses , 2016, Nature Communications.

[15]  A. Fagan,et al.  Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  R. Tanzi,et al.  ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function , 2013, Neuron.

[17]  Åsa K. Björklund,et al.  Smart-seq2 for sensitive full-length transcriptome profiling in single cells , 2013, Nature Methods.

[18]  S. Makin,et al.  The amyloid hypothesis on trial , 2018, Nature.

[19]  R. Ransohoff.  A polarizing question: do M1 and M2 microglia exist? , 2016, Nature Neuroscience.

[20]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[21]  A. Singleton,et al.  TREM2 variants in Alzheimer's disease. , 2013, The New England journal of medicine.

[22]  S. Itohara,et al.  Single App knock-in mouse models of Alzheimer's disease , 2014, Nature Neuroscience.

[23]  T. Gale,et al.  Sex differences in Alzheimer's disease , 2018, Current opinion in psychiatry.

[24]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[25]  Nick C Fox,et al.  Clinical and biomarker changes in dominantly inherited Alzheimer's disease. , 2012, The New England journal of medicine.

[26]  L. Tran,et al.  Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease , 2013, Cell.

[27]  A. Regev,et al.  Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution , 2017, Cell reports.

[28]  A. Goate,et al.  Alzheimer’s Disease Genetics: From the Bench to the Clinic , 2014, Neuron.

[29]  Lino C. Gonzalez,et al.  TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia , 2016, Neuron.

[30]  Hannah A. Pliner,et al.  Reversed graph embedding resolves complex single-cell trajectories , 2017, Nature Methods.

[31]  B. Hyman,et al.  Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions , 1993, Neuron.

[32]  Emily Merrill,et al.  Novel methods for integration and visualization of genomics and genetics data in Alzheimer's disease , 2019, Alzheimer's & Dementia.

[33]  F. Edwards,et al.  Genetic variability in response to Aβ deposition influences Alzheimer’s risk , 2018 .

[34]  Åsa K. Björklund,et al.  Full-length RNA-seq from single cells using Smart-seq2 , 2014, Nature Protocols.

[35]  Karl Herrup,et al.  The case for rejecting the amyloid cascade hypothesis , 2015, Nature Neuroscience.

[36]  J. Hardy,et al.  Polygenic score prediction captures nearly all common genetic risk for Alzheimer's disease , 2017, Neurobiology of Aging.

[37]  Johannes E. Schindelin,et al.  Fiji: an open-source platform for biological-image analysis , 2012, Nature Methods.

[38]  for the Alzheimer’s Disease Neuroimaging Initiative,et al.  Sex differences in Alzheimer disease — the gateway to precision medicine , 2018, Nature Reviews Neurology.

[39]  Wei Shi,et al.  featureCounts: an efficient general purpose program for assigning sequence reads to genomic features , 2013, Bioinform..

[40]  J. Hardy,et al.  Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease , 2016, Current Opinion in Neurobiology.

[41]  Nick C Fox,et al.  Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease , 2017, Nature Genetics.

[42]  B. Hyman,et al.  Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid β-peptide deposition in homozygous APPV717F transgenic mice , 2000, Acta Neuropathologica.

[43]  J. Hardy,et al.  The amyloid hypothesis of Alzheimer's disease at 25 years , 2016, EMBO molecular medicine.

[44]  James A. Eddy,et al.  Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases , 2016, Scientific Data.

[45]  Kevin W. Eliceiri,et al.  ImageJ2: ImageJ for the next generation of scientific image data , 2017, BMC Bioinformatics.

[46]  H. Weiner,et al.  Microglial signatures and their role in health and disease , 2018, Nature Reviews Neuroscience.

[47]  S. M. Sumi,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1991, Neurology.

[48]  Nick C Fox,et al.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease , 2013, Nature Genetics.

[49]  Evan Z. Macosko,et al.  Single‐Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell‐State Changes , 2019, Immunity.

[50]  R. Marioni,et al.  GWAS on family history of Alzheimer’s disease , 2018, bioRxiv.

[51]  Erick R. Scott,et al.  Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease , 2013, Nature.

[52]  B. Becher,et al.  High‐Dimensional Single‐Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease , 2018, Immunity.

[53]  S. Itohara,et al.  Cognitive deficits in single App knock-in mouse models , 2016, Neurobiology of Learning and Memory.

[54]  O. Garaschuk,et al.  Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain , 2017, Cell reports.

[55]  Markus Glatzel,et al.  The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. , 2017, Immunity.

[56]  Keith A. Johnson,et al.  CD33 Alzheimer’s disease locus: Altered monocyte function and amyloid biology , 2013, Nature Neuroscience.

[57]  Benjamin A. Logsdon,et al.  The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer's disease , 2018, Scientific Data.

[58]  M. Owen,et al.  Alzheimer's disease: The amyloid hypothesis on trial , 2016, British Journal of Psychiatry.

[59]  I. Amit,et al.  A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease , 2017, Cell.

[60]  A. Regev,et al.  Preparation of Single‐Cell RNA‐Seq Libraries for Next Generation Sequencing , 2014, Current protocols in molecular biology.

[61]  J. Hardy,et al.  A Critique of the Drug Discovery and Phase 3 Clinical Programs Targeting the Amyloid Hypothesis for Alzheimer Disease , 2014, Annals of neurology.

[62]  C. Clark,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1994, Neurology.

[63]  S. Gygi,et al.  Identification of a Unique TGF-β Dependent Molecular and Functional Signature in Microglia , 2013, Nature Neuroscience.

[64]  B. Winblad,et al.  APP mouse models for Alzheimer's disease preclinical studies , 2017, The EMBO journal.

[65]  Paul Hoffman,et al.  Integrating single-cell transcriptomic data across different conditions, technologies, and species , 2018, Nature Biotechnology.

[66]  Neil Buckholtz,et al.  Accelerating Medicines Partnership: Alzheimer’s Disease (AMP-AD) Knowledge Portal Aids Alzheimer’s Drug Discovery through Open Data Sharing , 2016, Expert opinion on therapeutic targets.

[67]  Melanie A. Huntley,et al.  Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models. , 2018, Cell reports.

[68]  W. M. van der Flier,et al.  Epidemiology and risk factors of dementia , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[69]  Andrew J. Hill,et al.  Single-cell mRNA quantification and differential analysis with Census , 2017, Nature Methods.

[70]  D. Borchelt,et al.  Accelerated Amyloid Deposition in the Brains of Transgenic Mice Coexpressing Mutant Presenilin 1 and Amyloid Precursor Proteins , 1997, Neuron.

[71]  David A. Knowles,et al.  Inferring relevant cell types for complex traits using single-cell gene expression , 2017, bioRxiv.

[72]  E. Marcello,et al.  Sex-Specific Features of Microglia from Adult Mice , 2018, Cell reports.

[73]  C. Behl,et al.  Beyond Amyloid – Widening the View on Alzheimer's Disease , 2017, Journal of neurochemistry.

[74]  Michelle K. Lupton,et al.  A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease , 2018, Molecular Psychiatry.

[75]  B. Strooper,et al.  The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics , 2011, Nature Reviews Drug Discovery.