Alzheimer’s disease modification mediated by bone marrow-derived macrophages via a TREM2-independent pathway in mouse model of amyloidosis

Abstract

The contributions of disease-associated microglia (DAM) and in ltrating monocyte-derived macrophages (MDM) to Alzheimer's disease (AD) are still controversial. Here, using Trem2 −/− 5xFAD DAM-de cient mice, we addressed this issue by targeting the programmed cell death ligand-1 (PD-L1) immune checkpoint, shown to modify AD via MDM recruitment. Treating Trem2 −/− 5xFAD mice resulted in cognitive improvement, rescue of synapses, and reduction of soluble-amyloid beta (Aβ) 1−42 , with no effect on insoluble Aβ 1−42 . In Trem2 +/+ 5xFAD mice, the treatment enhanced cognitive performance, led to elevation in DAM levels, and reduced insoluble Aβ 1−42 . Single-cell RNA-sequencing revealed that MDM, derived from both Trem2 −/− and Trem2 +/+ 5xFAD mouse brains, express a unique set of scavenger receptors and anti-in ammatory genes. Eliminating monocytes abrogated the bene cial effect of anti-PD-L1. The results highlight the need for MDM for neuroprotection even when microglia are fully activated, and demonstrate that their activity occurs through a TREM2-independent mechanism, with the potential to overcome TREM2 polymorphism in patients.

PD-1/PD-L Axis in Neuroinflammation: New Insights

“…In 2019, Schwartz's group showed that immune checkpoint blockade targeting the PD-1/PD-L1 pathway might have beneficial results in a tau-driven disease model resembling Alzheimer's disease (AD). The use of PD-L1 blocking antibodies resulted in increased immunomodulatory monocyte-derived macrophages within the brain parenchyma, which ultimately led to the modification of brain pathology and the restoration of cognitive performance ( 59 , 60 ).…”

Targeting the immune system towards novel therapeutic avenues to fight brain aging and neurodegeneration

“…In 2016, our research team proposed an immunotherapy that targets the programmed death (PD)‐1/PD‐L1 inhibitory immune checkpoint pathway (Baruch et al, 2016) (Figure 1c), as a means of unleashing peripheral immunity and triggering a cascade of immunological events, ultimately leading to improvement of brain function in both Aβ and tau‐driven mouse models of dementia (Baruch et al, 2016; Ben‐Yehuda et al, 2021; Rosenzweig et al, 2019; Xing et al, 2021). Targeting the PD‐1/PD‐L1 pathway initiates an immune response in the periphery that drives the recruitment of specific immune cell populations towards the brain, including T regulatory cells and macrophage scavenger receptor 1 (MSR1)‐expressing bone marrow‐derived macrophages that allow the removal of aggregated misfolded proteins (Frenkel et al, 2013), rescuing synapses, protecting neurons, and arresting cognitive loss (Dvir‐Szternfeld et al, 2021; Ben‐Yehuda et al, 2021; Rosenzweig et al, 2019) (Figure 1c). Such an approach is supported by the demonstration that interferon‐γ signalling mediates the mobilization of inflammation‐resolving immune cells into the brain (Baruch et al, 2016) through activation of the choroid plexus epithelium (Kunis et al, 2013; Shechter et al, 2013).…”

“…The cellular origin of DAM and their function have been recently studied by several independent teams. A work from our group, using a bone marrow chimeric mouse model (Dvir-Szternfeld et al, 2021), and a study that used a fate-mapping reporter mice (Reed-Geaghan et al, 2020), unequivocally demonstrated that bone marrow-derived macrophages do not contribute to the DAM cell pool. Yet, facilitating the recruitment of monocyte-derived macrophages into the brain has been shown to be of utmost importance in fighting AD (Ben-Yehuda et al, 2021;el Khoury et al, 2007;Rosenzweig et al, 2019).…”

“…A work from our group, using a bone marrow chimeric mouse model (Dvir-Szternfeld et al, 2021), and a study that used a fate-mapping reporter mice (Reed-Geaghan et al, 2020), unequivocally demonstrated that bone marrow-derived macrophages do not contribute to the DAM cell pool. Yet, facilitating the recruitment of monocyte-derived macrophages into the brain has been shown to be of utmost importance in fighting AD (Ben-Yehuda et al, 2021;el Khoury et al, 2007;Rosenzweig et al, 2019). It was further shown that the beneficial effect of monocyte-derived macrophages does not require TREM2, suggesting that modulation of peripheral immunity could potentially overcome TREM2 polymorphism in AD individuals (Dvir-Szternfeld et al, 2021).…”

“…Yet, facilitating the recruitment of monocyte-derived macrophages into the brain has been shown to be of utmost importance in fighting AD (Ben-Yehuda et al, 2021;el Khoury et al, 2007;Rosenzweig et al, 2019). It was further shown that the beneficial effect of monocyte-derived macrophages does not require TREM2, suggesting that modulation of peripheral immunity could potentially overcome TREM2 polymorphism in AD individuals (Dvir-Szternfeld et al, 2021). Interestingly, TREM2 deficiency led to an increase in Aβ load and neuronal loss, as a result of microglia dysfunction to surround Aβ plaques and become apoptotic (Wang et al, 2015).…”