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Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer’s disease mouse model

ABSTRACT: Deposition of amyloid beta (Aβ) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer’s disease (AD). In recent years, impairment of autophagy has been found to be another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aβ pathology and glial cell-mediated neuroinflammation. Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aβ and decreased AD-associated neuroinflammation during disease progression. Mechanistically, single nuclei sequencing revealed AD-associated microglia to be the main target of spermidine. This microglia population was characterized by increased AXL levels and expression of genes implicated in cell migration and phagocytosis. Our data highlight that the autophagy activator spermidine holds the potential to enhance Aβ degradation and to counteract glia-mediated neuroinflammation in AD pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE206202 | GEO | 2022/07/04

REPOSITORIES: GEO

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Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer’s disease mouse model

Project description:Deposition of amyloid beta (Aβ) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer’s disease (AD). In recent years, impairment of autophagy has been found to be another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aβ pathology and glial cell-mediated neuroinflammation. Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aβ and decreased AD-associated neuroinflammation. A subsequent proteome analysis of isolated microglia confirmed the anti-inflammatory and revealed cytoskeletal effects of spermidine in APPPS1 mice. Our data highlight that the autophagy activator spermidine holds the potential to enhance Aβ degradation and to counteract microglia-mediated neuroinflammation in AD pathology.

2022-07-04 | PXD034638 | Pride

Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease

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Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology

Project description:Polygenic risk scores have identified that genetic variants without genome-wide significance still add to the genetic risk of developing Alzheimer’s disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways, is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1L166P and Thy-TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1 and FCER1G) and 11 AD GWAS genes below the genome-wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.

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Project description:Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting memory and cognition. The disease is accompanied by an abnormal deposition of ß-amyloid plaques in the brain that contributes to neurodegeneration and is known to induce glial inflammation. Studies in the APP/PS1 mouse model of ß-amyloid-induced neuropathology have suggested a role for inflammasome activation in ß-amyloid-induced neuroinflammation and neuropathology. Here, we evaluated the in vivo role of microglia-selective and full body inflammasome signalling in several mouse models of ß-amyloid-induced AD neuropathology. Unexpectedly, microglia-specific deletion of the inflammasome regulator A20 and inflammasome effector protease caspase-1 in the AppNL-G-F and APP/PS1 models failed to identify a prominent role for microglial inflammasome signalling in ß-amyloid-induced neuropathology. Moreover, global inflammasome inactivation through respectively full body deletion of caspases 1 and 11 in AppNL-G-F mice and Nlrp3 deletion in APP/PS1 mice, also failed to modulate amyloid pathology and disease progression. In agreement, single-cell RNA sequencing did not reveal an important role for Nlrp3 signalling in driving microglial activation and the transition into disease-associated states, both during homeostasis and upon amyloid pathology. Collectively, these results question a generalizable role for inflammasome activation in pre-clinical amyloid-only models of neuroinflammation.

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