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PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease


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.

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Figure 1: PD-1 blockade promotes myeloid cell recruitment to the CNS via IFN-γ.
Figure 2: PD-1 blockade reduces AD pathology and improves memory in 5XFAD and APP/PS1 mice.

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We thank I. Slutsky (Tel Aviv University, Tel Aviv, Israel) for APP/PS1 mice, S. Schwarzbaum for proofreading the manuscript, M. Azulai for animal handling and the Krenter Institute for equipment grant support. This work was supported by Advanced European Research Council (ERC) grants (no. 232835 to M.S. and no. 309788 to I.A.), by the EU Seventh Framework Program HEALTH-2011 (grant no. 279017 to M.S.), by an Israeli Science Foundation grant (no. 1782/11 to I.A.) and by the Weizmann-Tanz collaboration for research in Alzheimer's disease (to M.S.). M.S. holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology.

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Authors and Affiliations



K.B. and M.S. conceived and designed the study. K.B., A.D., N.R., A.T.-K., A.M.S. and A.K. performed experiments and analyzed and interpreted the data. O.M.-N. and E.D., under the supervision of I.A., performed RNA-seq analysis. K.B. and A.D. prepared the data for presentation. The manuscript was written by K.B. and M.S.

Corresponding authors

Correspondence to Kuti Baruch or Michal Schwartz.

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Competing interests

K.B. and M.S. are inventors of intellectual property related to this work. This study was partly funded by ImmunoBrain Checkpoint Ltd.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2 and Supplementary Table Legends (PDF 468 kb)

Supplementary Table 1

Choroid plexus response to PD-1 blockade in 5XFAD mice (XLSX 1117 kb)

Supplementary Table 2

Gene ontology analysis of choroid plexus response to PD-1 blockade in 5XFAD mice (XLSX 9 kb)

Supplementary Table 3

RNA-seq analysis of myeloid cells sorted from the brains of 5XFAD mice following PD-1 blockade (XLSX 1088 kb)

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Baruch, K., Deczkowska, A., Rosenzweig, N. et al. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med 22, 135–137 (2016).

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