Physiological clearance of Aβ by spleen and splenectomy aggravates Alzheimer‐type pathogenesis

Yu, Zhongyuan; Chen, Dong-Wan; Tan, Cheng‐Rong; Zeng, Guihua; He, Chen‐Yang; Wang, Jun; Bu, Xian‐Le; Wang, Yanjiang

doi:10.1111/acel.13533

Cited by 26 publications

(20 citation statements)

References 54 publications

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“…A recent study found that hyperactivation of monocytes and macrophages in MCI patients contributes to the AD progression 44 . Monocytes in spleen could clear circulating Aβ and splenectomy might accelerate the development of AD 45 . Under the long-term high plasma levels of Aβ 1−42 stimulation, typical monocytes recruit to various damaged sites of the body rapidly, and the proportions of monocytes in spleen were increased.…”

Section: Discussionmentioning

confidence: 99%

The effects of high plasma levels of Aβ 1-42 on mononuclear macrophage in mouse models of Alzheimer’s disease

Liu

Zhu

et al. 2022

Preprint

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Microglia plays a crucial role in the pathogenesis of Alzheimer’s disease (AD). Plasma Aβ1−42 levels significantly increased 15 years before the onset of dominantly inherited AD. The effects of high plasma levels of Aβ1−42 on mononuclear macrophage, the peripheral counterparts of microglia, remains unclear. Herein, we used a parabiosis model to investigate the effects of plasma Aβ1−42 on peripheral mononuclear macrophage and the possible mechanism. We found the proportions of pro-inflammatory macrophages in peritoneal cavity, myeloid derived suppressor cells (MDSCs) in spleen, granulocyte-monocyte progenitors (GMP) in bone marrow, and the plasma levels of interleukin-6 (IL-6) were significantly decreased after 4 months sustaining stimulation with high plasma levels of Aβ1−42. The proportions of pro-inflammatory macrophages, MDSCs, GMPs, the plasma levels of IL-6 and TNF-α, as well as the numbers of bone marrow-derived macrophages (BMDMs) in mice brain were increased after 8 months sustaining stimulation with high plasma levels of Aβ1−42. In addition, the proportions of monocytes in spleen and the proliferation of bone marrow cells (BMCs) were increased, however, the phagocytic function of macrophages had no obviously alteration after high plasma levels of Aβ1−42 sustaining stimulation. These results demonstrated that high plasma levels of Aβ1−42 had a biphasic regulating effects on the amounts of pro-inflammatory macrophages, MDSCs, and bone marrow myeloid progenitor cells, as well as the secretory function of macrophage. Herein, we suggest that the alterations of the amounts and proliferations of myeloid progenitor cells in bone marrow may be involved in the regulation of peripheral mononuclear macrophages and MDSCs, intervening the effects of plasma Aβ1−42 on monocytes/macrophages might offer a new therapeutic approach to AD.

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Section: Discussionmentioning

confidence: 99%

The effects of high plasma levels of Aβ 1-42 on mononuclear macrophage in mouse models of Alzheimer’s disease

Liu

Zhu

et al. 2022

Preprint

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“…Y maze test with spontaneous alternation performance was conducted according to our previous study (Yu et al, 2021). The Y maze was consisted of three identical arms connected in the center with 120‐degree angle.…”

Section: Methodsmentioning

confidence: 99%

“…MWM test was conducted according to protocols validated by previous publications (Chen et al, 2021; Ho et al, 2021; Yu et al, 2021). In brief, the water maze was consisted of a circular pool (100 cm in diameter) and a platform (9 cm in diameter) submerged 1.0 cm under the warm water.…”

Section: Methodsmentioning

confidence: 99%

Inhibiting α1‐adrenergic receptor signaling pathway ameliorates AD‐type pathologies and behavioral deficits in APPswe/PS1 mouse model

Wang

et al. 2022

Journal of Neurochemistry

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The role of α1 adrenergic receptors (α1‐ARs) signaling pathway in the pathogenesis of Alzheimer's disease (AD) has rarely been investigated. Clarifying the pathophysiological functions of α1‐ARs in the AD brain is helpful for better understanding the pathogenesis and screening novel therapeutic targets of AD. This study included 2 arms of in vivo investigations: 1) 6‐month‐old female APPswe/PS1 mice were intravenously treated with AAV‐PHP.eB‐shRNA (α1‐ARs)‐GFP or AAV‐PHP.eB‐GFP for 3 months. 2) 3‐month‐old female APPswe/PS1 mice were daily treated with 0.5 mg/kg terazosin or an equal volume of saline for 6 months. SH‐SY5Y cell lines bearing human amyloid precursor protein were treated with terazosin or saline for investigating possible mechanisms. α1‐ARs knockdown mice exhibited improved behavioral performances in comparison with control mice. α1‐ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Aβ species, compact and total Aβ plaques, than control mice. α1‐ARs inhibitor terazosin substantially reduced Aβ deposition, attenuated downstream pathologies including tau hyperphosphorylation, glial activation, neuronal loss, synaptic dysfunction et al., and rescued behavioral deficits in APPswe/PS1 mice. In vitro investigation demonstrated that α1‐ARs inhibition down‐regulated BACE1 expression, and promoted ser9 phosphorylation of GSK‐3β, thus reducing Aβ production. This study indicates that inhibition of α1‐ARs signaling pathway might represent a promising therapeutic strategy for AD.

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“…In addition, the spleen monocytes/macrophages are reported to be involved in clearing amyloid beta. 52 Still, the physiological mechanisms underlying the association between the peripheral organs and AD remain unknown. In the ontology network of the spleen dataset, we noted "carbon metabolism" (node-147) and "neutrophil degranulation" (node-151).…”

Section: Biological Functions Of Protein Communities Whose Conformati...mentioning

confidence: 99%

Using In Vivo Intact Structure for System-wide Quantitative Analysis of Changes in Proteins

Yates

Son

Kim

et al. 2023

Preprint

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Mass spectrometry-based methods can provide a global expression profile and structural readout of proteins in complex systems. Preserving the in vivo conformation of proteins in their innate state is challenging during proteomic experiments. Here, we introduce an approach using perfusion of reagents to create a whole animal in vivo protein footprinting method that adds dimethyl labels to exposed lysine residues on intact proteins to maintain information on protein conformations. When this approach was used to measure dynamic structural changes during Alzheimer’s disease (AD) progression in a mouse model, we detected 433 proteins that underwent structural changes attributed to AD, independent of aging, across 7 tissues. We identified structural changes of co-expressed proteins and linked the communities of these proteins to their biological functions. Our findings show that structural alterations of proteins precede changes in expression, thereby showing the value of in vivo protein conformation measurement. Our method represents a new strategy for untangling mechanisms of proteostasis dysfunction caused by protein misfolding. In vivo whole-animal footprinting should have broad applicability for discovering conformational changes in systemic diseases and therapeutic interventions.

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Physiological clearance of Aβ by spleen and splenectomy aggravates Alzheimer‐type pathogenesis

Cited by 26 publications

References 54 publications

The effects of high plasma levels of Aβ 1-42 on mononuclear macrophage in mouse models of Alzheimer’s disease

The effects of high plasma levels of Aβ 1-42 on mononuclear macrophage in mouse models of Alzheimer’s disease

Inhibiting α1‐adrenergic receptor signaling pathway ameliorates AD‐type pathologies and behavioral deficits in APPswe/PS1 mouse model

Using In Vivo Intact Structure for System-wide Quantitative Analysis of Changes in Proteins

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