Journal Article

DZNE-2022-01330

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer's disease mouse model.

Freitag, K. (First author)DZNE* ; Sterczyk, N. ; Wendlinger, S. ; Obermayer, B. ; Schulz, J.Extern* ; Farztdinov, V. ; Mülleder, M. ; Ralser, M. ; Houtman, J.Extern* ; Fleck, L. ; Braeuning, C. ; Sansevrino, R.DZNE* ; Hoffmann, C.DZNE* ; Milovanovic, D.DZNE* ; Sigrist, S. J.DZNE* ; Conrad, T. ; Beule, D. ; Heppner, F. L. (Last author)DZNE* ; Jendrach, M.

2022
BioMed Central London

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Please use a persistent id in citations: doi:10.1186/s12974-022-02534-7

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 identified as 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. 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. A subsequent proteome analysis of isolated microglia confirmed the anti-inflammatory and cytoskeletal effects of spermidine in APPPS1 mice. In primary microglia and astrocytes, spermidine-induced autophagy subsequently affected TLR3- and TLR4-mediated inflammatory processes, phagocytosis of Aβ and motility. Interestingly, spermidine regulated the neuroinflammatory response of microglia beyond transcriptional control by interfering with the assembly of the inflammasome.Our data highlight that the autophagy activator spermidine holds the potential to enhance Aβ degradation and to counteract glia-mediated neuroinflammation in AD pathology.

Keyword(s): Alzheimer Disease: drug therapy (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Amyloid beta-Peptides: drug effects (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Animals (MeSH) ; Disease Models, Animal (MeSH) ; Mice (MeSH) ; Neuroinflammatory Diseases: drug therapy (MeSH) ; Spermidine: pharmacology (MeSH) ; Spermidine: therapeutic use (MeSH) ; Alzheimer’s disease ; Astrocytes ; Autophagy ; Dietary supplement ; Liquid chromatography tandem mass spectrometry ; Microglia ; Neuroinflammation ; Phagocytosis ; Single nuclei sequencing ; Spermidine ; Amyloid beta-Peptides ; Spermidine

Note: CC BY

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Contributing Institute(s):

1. Neuroimmunology (AG Heppner)
2. Molecular Neuroscience (AG Milovanovic)
3. Aging of Synapse Structure and Function (AG Sigrist)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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