PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease (original) (raw)
Bibliographic
Year of Publication:
2016
Contact PI Name:
Michal Schwartz
Contact PI Affiliation:
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
Co-Authors:
Kuti Baruch, Aleksandra Deczkowska, Neta Rosenzweig, Afroditi Tsitsou-Kampeli, Alaa Mohammad Sharif, Orit Matcovitch-Natan, Alexander Kertser, Eyal David, Ido Amit
Primary Reference (PubMED ID):
Funding Source:
Advanced European Research Council
Weizmann-Tanz Collaboration for Research in Alzheimer’s Disease
Israel Science Foundation (ISF)
European Community’s Seventh Framework Programme for the Innovative Medicine Initiative
Study Goal and Principal Findings:
Systemic immune suppression may curtail the ability to mount the protective, cell-mediated immune responses that are needed for brain repair. By using mouse models of Alzheimer’s disease (AD), we show that immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway evokes an interferon (IFN)-γ–dependent systemic immune response, which is followed by the recruitment of monocyte-derived macrophages to the brain. When induced in mice with established pathology, this immunological response leads to clearance of cerebral amyloid-β (Aβ) plaques and improved cognitive performance. Repeated treatment sessions were required to maintain a long-lasting beneficial effect on disease pathology. These findings suggest that immune checkpoints may be targeted therapeutically in AD.
Bibliographic Notes:
Kuti Baruch and Michal Schwartz (Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel) are corresponding authors on this paper.
Therapeutic Agent
Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
anti-PD-1 Antibody
Therapeutic Target:
Programmed Cell Death Protein 1 (PD-1)
Therapeutic Notes:
Programmed Cell Death Protein 1 (PD-1) has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples. See Agora link for more information.
Animal Model
Model Information:
Strain/Genetic Background:
C57BL/6SJL
Experimental Design
Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest
Experiment Notes
Sample sizes were chosen with adequate statistical power on the basis of the literature and past experience, and mice were allocated to experimental groups according to age, gender and genotype. Additionally, all inclusion and exclusion criteria were pre-established according to the IACUC, though these were not stated in the paper. Mice that displayed motor deficits in swimming performance were excluded from the beginning of the experiments from further analysis.
Outcomes
Histopathology
beta Amyloid Deposits
beta Amyloid Load
Activated Astrocytes
Biochemical
CD4
CD11b
CD45
Chemokine C-C Motif Ligand 2 (CCL2) mRNA
Inflammation-Inducible Protein Intercellular Adhesion Molecule 1 (ICAM1) mRNA
Interferon (IFN) gamma mRNA
Immunochemistry
Brain-beta Amyloid Deposits
Glial Fibrillary Acidic Protein (GFAP)
Myeloid Cells
Cell Biology
CNS Infiltrating Leukocytes
Flow Cytometry
Immunology
Interferon (IFN) gamma Production
Omics
Gene Expression Profile
Whole Transcriptome Analysis