Radiation-induced overexpression of transthyretin inhibits retinol-mediated hippocampal neurogenesis

Kang, JiHoon; Kim, Wanyeon; Seo, Hyunduk; Kim, EunGi; Son, Bong Soo; Lee, Sung-Min; Park, Gaeul; Jo, Sunmi; Moon, Changjong; Youn, HyeSook; Youn, BuHyun

doi:10.1038/s41598-018-26762-1

Cited by 31 publications

(24 citation statements)

References 62 publications

(57 reference statements)

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“…However, as has been previously reported by others, microtubule-associated protein 2 (MAP2) was significantly decreased in both brain regions (i.e., cortex, hippocampus) in GFP-BM CON mice (Fig. 5 K, N–O) [ 75 – 77 ]. Consistent with previous findings in the hippocampus, a significant reduction in MAP2 expression was not seen in GFP-BM REPOP mice, indicating a reversal in irradiation-induced changes following monocyte engraftment.…”

Section: Resultssupporting

confidence: 77%

Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Hohsfield

Najafi

Ghorbanian

et al. 2020

J Neuroinflammation

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Background Microglia, the primary resident myeloid cells of the brain, play critical roles in immune defense by maintaining tissue homeostasis and responding to injury or disease. However, microglial activation and dysfunction has been implicated in a number of central nervous system (CNS) disorders, thus developing tools to manipulate and replace these myeloid cells in the CNS is of therapeutic interest. Methods Using whole body irradiation, bone marrow transplant, and colony-stimulating factor 1 receptor inhibition, we achieve long-term and brain-wide (~ 80%) engraftment and colonization of peripheral bone marrow-derived myeloid cells (i.e., monocytes) in the brain parenchyma and evaluated the long-term effects of their colonization in the CNS. Results Here, we identify a monocyte signature that includes an upregulation in Ccr1, Ms4a6b, Ms4a6c, Ms4a7, Apobec1, Lyz2, Mrc1, Tmem221, Tlr8, Lilrb4a, Msr1, Nnt, and Wdfy1 and a downregulation of Siglech, Slc2a5, and Ccl21a/b. We demonstrate that irradiation and long-term (~ 6 months) engraftment of the CNS by monocytes induces brain region-dependent alterations in transcription profiles, astrocytes, neuronal structures, including synaptic components, and cognition. Although our results show that microglial replacement with peripherally derived myeloid cells is feasible and that irradiation-induced changes can be reversed by the replacement of microglia with monocytes in the hippocampus, we also observe that brain-wide engraftment of peripheral myeloid cells (relying on irradiation) can result in cognitive and synaptic deficits. Conclusions These findings provide insight into better understanding the role and complexity of myeloid cells in the brain, including their regulation of other CNS cells and functional outcomes.

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Section: Resultssupporting

confidence: 77%

Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Hohsfield

Najafi

Ghorbanian

et al. 2020

J Neuroinflammation

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“…cortex, hippocampus) in GFP-BM CON mice (Fig. 5K, N-O) (67)(68)(69). Consistent with previous ndings in the hippocampus, a signi cant reduction in MAP2 expression was not seen in GFP-BM REPOP mice, indicating a reversal in irradiation-induced changes following monocyte engraftment.…”

Section: The Differential and Brain Region-dependent Effects Of Longtsupporting

confidence: 90%

Effects of long-term and brain-wide colonization of peripheral bone-marrow derived myeloid cells in the CNS

Hohsfield

Najafi

Ghorbanian

et al. 2020

Preprint

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Background Microglia, the primary resident myeloid cells of brain, play critical roles in immune defense by maintaining tissue homeostasis and responding to injury or disease. However, microglial activation and dysfunction has been implicated in a number of central nervous system (CNS) disorders, thus developing tools to manipulate and replace these myeloid cells in CNS is of therapeutic interest. Methods Using whole body irradiation, bone marrow transplant, and colony-stimulating factor 1 receptor inhibition, we achieve long-term and brain-wide (~ 80%) engraftment and colonization of peripheral bone marrow-derived myeloid cells (i.e. monocytes) in the brain parenchyma and evaluated the long-term effects of their colonization in the CNS. Results Here, we identify a monocyte signature that includes an upregulation in Ccr1, Ms4a6b, Ms4a6c, Ms4a7, Apobec1, Lyz2, Mrc1, Tmem221, Tlr8, Lilrb4a, Msr1, Nnt, and Wdfy1, and a downregulation of Siglech, Slc2a5, and Ccl21a/b. We demonstrate that irradiation and long-term (~ 6 months) engraftment of the CNS by monocytes induces brain-region dependent alterations in transcription profiles, astrocytes, neuronal structures, including synaptic components, and cognition. Although our results show that microglial replacement with peripheral derived myeloid cells is feasible and that irradiation-induced changes can be reversed by the replacement of microglia with monocytes in the hippocampus, we also observe that brain-wide engraftment of peripheral myeloid cells (relying on irradiation) can result in cognitive and synaptic deficits. Conclusions These findings provide insight into better understanding the role and complexity of myeloid cells in the brain, including their regulation of other CNS cells and functional outcomes.

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“…These include retinol dehydrogenase 5 ( Rdh5 ), cellular retinoic acid binding protein 2 ( Crabp2 ), aldehyde dehydrogenase family 1, subfamily A2 [( Aldh1a2 ; also known as retinaldehyde dehydrogenase 2 ( Raldh2 )] (see Table 1 and Supplementary Data 3 for complete list). Interestingly, another upregulated transcript encodes transthyretin (TTR), a protein that is involved with transport of retinol in the plasma and which plays an important role in neuroprotection 38 as well as memory consolidation and neurogenesis in the hippocampus 39,40 . Furthermore, TTR has also been shown to upregulate hippocampal expression of insulin-like growth factor receptor I (IGF-IR) and its nuclear translocation 41 .…”

Section: Resultsmentioning

confidence: 99%

Wilm’s tumor 1 promotes memory flexibility

et al. 2019

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Under physiological conditions, strength and persistence of memory must be regulated in order to produce behavioral flexibility. In fact, impairments in memory flexibility are associated with pathologies such as post-traumatic stress disorder or autism; however, the underlying mechanisms that enable memory flexibility are still poorly understood. Here, we identify transcriptional repressor Wilm’s Tumor 1 (WT1) as a critical synaptic plasticity regulator that decreases memory strength, promoting memory flexibility. WT1 is activated in the hippocampus following induction of long-term potentiation (LTP) or learning. WT1 knockdown enhances CA1 neuronal excitability, LTP and long-term memory whereas its overexpression weakens memory retention. Moreover, forebrain WT1-deficient mice show deficits in both reversal, sequential learning tasks and contextual fear extinction, exhibiting impaired memory flexibility. We conclude that WT1 limits memory strength or promotes memory weakening, thus enabling memory flexibility, a process that is critical for learning from new experiences.

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Radiation-induced overexpression of transthyretin inhibits retinol-mediated hippocampal neurogenesis

Cited by 31 publications

References 62 publications

Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Effects of long-term and brain-wide colonization of peripheral bone-marrow derived myeloid cells in the CNS

Wilm’s tumor 1 promotes memory flexibility

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