Abstract
Background Alzheimer’s disease (AD) is the primary cause of cognitive deficit in elderly humans. Late-onset AD (LOAD) is sporadic, multifactorial, non-Mendelian accounting at present for 95% of the cases in contrast to the genetic form. Risk factors for sporadic AD include Gene: Environment interactions. There is increasing evidence that lifestyle and environmental stress such as infection and chronic inflammation are underlying culprits of neurodegenerative dementia. Dementias that share or mimic pathological processes of AD include cerebrovascular diseases, Lewy body disease, TDP-43 proteinopathy. To date, very few mouse models reproduce the pathophysiological progression of mixed-vascular-AD, while the majority of studies have employed transgenic animals reproducing the familial form.
Methods We have re-engineered the Polyinosinic:polycytidylic acid (PolyI:C) sterile infection model in wildtype C57Bl6 mice to obtain chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months and 16 months), taking the hippocampus as a reference brain region, based on its vulnerability, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD and Controls (CTL), parallely in Vascular dementia (VaD) patient specimens.
Results We found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological rearrangements progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression over the course of aging, with a peak in differential expression at 9 months. We confirm that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD and VaD shows a reproducibility of some gene targets in vascular dementia specimens rather than AD ones, in which only GFAP is strongly increased at the severe stages.
Conclusions The PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation is sufficient to cause neuropathological processes resembling a mixed-VaD-AD phenotype, with progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling and the loss of neuronal functionality seen to some extent in humans.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Authors’ information Lavinia Alberi Auber, University of Fribourg and Swiss Integrative Centre of Human Health, Passage du Cardinal 13B, CH-1700 Fribourg, Switzerland. Email: lavinia.alberi{at}unifr.ch. Tel: 0041-26-3006512. Praveen Bathini, email: praveen.bathini{at}unifr.ch; Isabel Dupanloup, email: isabelle.dupanloup{at}sib.swiss, Elena Zenaro, email: elena.zenaro{at}univr.it, Eleonora Terrabuio ,email: eleonora.terrabuio{at}univr.it, Amrei Fischer, email: amrei.fischer{at}unifr.ch, Edona Ballabani, email: edona.ballabani{at}unifr.ch, Marie-Agnes Doucey, email: MarieAgnes.Doucey{at}ichnossciences.com.
Evidence of amyloid angiopathy has been added (Figure 3). Vascular markers, Klf4, Angptl4, Cyp1b1 have been investigated in the mouse hippocampus (Table 2), AD and VaD brain samples (Figure 7, Supplementary Table 8 and 9). Gene profiling of hippocampi from VaD patients has been added to test the reproducibility of the model (Figure 7).
List of Abbreviations
- ABCA7
- ATP-binding cassette sub-family A member 7
- AD
- Alzheimer’s disease
- Angptl4
- Angiopoietin like 4
- ApoE
- Apolipoprotein E
- ApoEε4
- Apolipoprotein E variant ε4
- Aβ
- Amyloid beta
- BBB
- Blood Brain Barrier
- BIN1
- Box-dependent-interacting protein 1
- CA
- Cornu Ammonis
- CAA
- Cerebral Amyloid Angiopathy
- CD2AP
- CD2 Associated Protein
- CD33
- Myeloid Cell Surface Antigen CD3
- CELF1
- CUGBP Elav-like family member 1
- c-fos
- Proto-oncogene c-Fos
- Cyp1b1
- Cytochrome P450 1B1
- Cldn5
- Claudin 5
- CLU
- Clusterin
- CNS
- Central Nervous System
- CR1
- Complement receptor type 1
- CSF
- Cerebrospinal fluid
- CTL
- Control
- Cx
- Cortex
- DABCO
- 1,4-diazabicyclo [2.2.2] octane
- DAPI
- 4′,6-diamidino-2-phenylindole
- DEGs
- Differentially Expressed Genes
- dsRNA
- Double-strand RNA
- EC
- Entorhinal cortex
- EDTA
- Ethylenediaminetetraacetic acid
- EGR2
- Early growth response protein 2
- EPHA1
- Ephrin type-A receptor 1
- FERMT2
- Fermitin family homolog 2
- GD
- Gestational Day
- GEA
- Gene enrichment analysis
- GFAP
- Glial fibrillary acidic protein
- GlpR2
- Glucagon like peptide 2 receptor
- GO
- Gene ontology
- GRIN1
- Glutamate Ionotropic Receptor NMDA Type Subunit 1
- GWAS
- Genome Wide Association Studies
- H2-Aa
- H-2 class II histocompatibility antigen, A-B alpha chain
- Iba-1
- Ionized calcium binding adaptor molecule1
- Ide
- Insulin degrading enzyme
- IL
- Interleukin
- INPP5D
- Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1
- KCNJ2
- Potassium Inwardly Rectifying Channel Subfamily J Member 2
- KEGG
- Kyoto Encyclopedia of Genes and Genomes
- Klf4
- zinc finger-containing Krüppel-like factor
- KS
- Kolmogorov-Smirnov
- c-Jun
- Transcription factor AP-1
- LCN2
- Lipocalin 2
- LPS
- Lipopolysaccharide
- MAP2
- Microtubule-associated protein 2
- MAPK
- Mitogen-activated protein kinase 1
- MCI
- Mild Cognitively Impairment
- MCP-1
- Monocyte Chemoattractant Protein-1
- MEF2C
- Myocyte-specific enhancer factor 2C
- mM
- milliMolar
- M-MLV
- Moloney Murine Leukemia Virus Reverse Transcriptase mo month
- mRNA
- Messenger RNA
- MS4A4A
- Membrane-spanning 4-domains subfamily A member 4A
- ND
- Neurodegenerative disease
- NME8
- Thioredoxin domain-containing protein 3
- NN
- Saline controls
- Notch1
- Neurogenic locus notch homolog protein 1
- PFA
- Paraformaldehyde
- PICALM
- Phosphatidylinositol-binding clathrin assembly protein
- PLCG2
- 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2
- pM
- picomolar
- PLIN4
- Perilipin 4
- PMNs
- Polymorphonuclear neutrophils
- PolyI:C
- Polyinosinic:Polycytidylic acid
- PSEN
- Presenilin
- PP
- PolyI:C injected animals
- pTau
- Phosphorylated tau
- PVA
- Polyvinyl alcohol
- rpm
- revolutions per minute
- rRNA
- ribosomal RNA
- r
- Spearman’s Rank Correlation
- SEM
- Standard Error Mean
- SLC24A4
- Sodium/potassium/calcium exchanger 4
- SORL1
- Sortilin-related receptor
- SRCAP
- Snf2-related CREBBP activator protein
- TBS
- Trizma-based salt solution
- TLRs
- Toll Like receptors
- TNFα
- Tumor necrosis factor alpha
- TREM2
- Triggering receptor expressed on myeloid cells 2
- ZCWPW1
- Zinc finger CW-type PWWP domain protein 1
- μg
- microgram
- μm
- micrometer