Accumulation of systematic TPM1 mediates inflammation and neuronal remodeling by phosphorylating PKA and regulating the FABP5/NF-κB signaling pathway in the retina of aged mice

Rong Li, Yuxiang Liang, Bin Lin (Corresponding Author)

Research output: Journal article publicationJournal articleAcademic researchpeer-review

Abstract

The molecular mechanisms underlying functional decline during normal brain aging are poorly understood. Here, we identified the actin-associated protein tropomyosin 1 (TPM1) as a new systemic pro-aging factor associated with function deficits in normal aging retinas. Heterochronic parabiosis and blood plasma treatment confirmed that systemic factors regulated age-related inflammatory responses and the ectopic dendritic sprouting of rod bipolar (RBC) and horizontal (HC) cells in the aging retina. Proteomic analysis revealed that TPM1 was a potential systemic molecule underlying structural and functional deficits in the aging retina. Recombinant TPM1 protein administration accelerated the activation of glial cells, the dendritic sprouting of RBCs and HCs and functional decline in the retina of young mice, whereas anti-TPM1 neutralizing antibody treatment ameliorated age-related structural and function changes in the retina of aged mice. Old mouse plasma (OMP) induced glial cell activation and the dendritic outgrowth of RBCs and HCs in young mice, and yet TMP1-depleted OMP failed to reproduce the similar effect in young mice. These results confirmed that TPM1 was a systemic pro-aging factor. Moreover, we demonstrated that systematic TPM1 was an immune-related molecule, which elicited endogenous TPM1 expression and inflammation by phosphorylating PKA and regulating FABP5/NF-κB signaling pathway in normal aging retinas. Interestingly, we observed TPM1 upregulation and the ectopic dendritic sprouting of RBCs and HCs in young mouse models of Alzheimer's disease, indicating a potential role of TPM1 in age-related neurodegenerative diseases. Our data indicate that TPM1 could be targeted for combating the aging process.
Original languageEnglish
Pages (from-to)1-23
Number of pages23
JournalAging Cell
DOIs
Publication statusPublished - 11 Feb 2022

Keywords

  • aging
  • dendritic sprouting
  • inflammation
  • parabiosis
  • retina
  • tropomyosin 1

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