Peripheral monocyte–derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease
Ping Yan, … , Jin-Moo Lee, Abhinav Diwan
Ping Yan, … , Jin-Moo Lee, Abhinav Diwan
Published May 5, 2022
Citation Information: J Clin Invest. 2022;132(11):e152565. https://doi.org/10.1172/JCI152565.
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Research Article Neuroscience

Peripheral monocyte–derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease

Abstract

Microglia, the parenchymal tissue macrophages in the brain, surround amyloid plaques in brains of individuals with Alzheimer’s disease (AD) but are ineffective at clearing amyloid to mitigate disease progression. Recent studies in mice indicate that microglia are derived exclusively from primitive yolk sac hematopoiesis and self-renew without contribution from ontogenically distinct monocytes/macrophages of definitive adult hematopoietic origin. Using a genetic fate-mapping approach to label cells of definitive hematopoietic origin throughout life span, we discovered that circulating monocytes contribute 6% of plaque-associated macrophages in aged AD mice. Moreover, peripheral monocytes contributed to a higher fraction of macrophages in the choroid plexus, meninges, and perivascular spaces of aged AD mice versus WT control mice, indicating enrichment at potential sites for entry into the brain parenchyma. Splenectomy, which markedly reduced circulating Ly6Chi monocytes, also reduced abundance of plaque-associated macrophages of definitive hematopoietic origin, resulting in increased amyloid plaque load. Together, these results indicate that peripherally derived monocytes invade the brain parenchyma, targeting amyloid plaques to reduce plaque load.

Authors

Ping Yan, Ki-Wook Kim, Qingli Xiao, Xiucui Ma, Leah R. Czerniewski, Haiyan Liu, David R. Rawnsley, Yan Yan, Gwendalyn J. Randolph, Slava Epelman, Jin-Moo Lee, Abhinav Diwan

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Figure 3

Fate mapping demonstrates peripheral monocyte–derived cells adjacent to amyloid plaques in the brain parenchyma of APP/PS1 mice.

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Fate mapping demonstrates peripheral monocyte–derived cells adjacent to ...
(A and B) Representative cortical sections from aged WTmTmG;Flt3-Cre (n = 5) and APP/PS1mTmG;Flt3-Cre mice (n = 8) demonstrating that GFP+ cells (A) are not detected in the WT brain parenchyma and (B) are seen adjacent to X-34–stained amyloid plaques in APP/PS1 mice. White arrows point to a GFP+ cell in the perivascular space in WTmTmG;Flt3-Cre brain in A and to GFP+ cells adjacent to X34-labeled amyloid plaques in B. Scale bar: 250 μm. (C–N) Representative cortical sections from aged APP/PS1mTmG;Flt3-Cre mice demonstrating X-34–stained plaque (with DAPI-stained nuclei as shown in C, G, and K; plaque is outlined) (D, H, and L) with GFP expression, (E and F) which colocalizes with a microglial marker, Iba-1; (I and J) with CD11b, a marker for activated microglia; and (M and N) with CD68, a marker for phagocytic cells also present on microglia. Scale bar: 10 μm. Dotted lines outline amyloid plaques. (O) A GFP+ cell adjacent to amyloid plaque demonstrating colocalization with Aβ (red). Dotted lines outline amyloid plaques. Scale bar: 5 μm. (P–R) Correlation between the density of GFP+ cells expressing (P) Iba-1, (Q) CD11b, and (R) CD68 in the cortex and the amyloid plaque load detected by X-34 staining. Pearson’s coefficient of correlation, R2 is shown with P < 0.001.