Metabolites released from apoptotic cells in central nervous system orchestrates the pathological process of...

Apoptosis, a programmed cell death process activated in Alzheimer disease (AD), is not limited to neurons but extends to all cell types within the central nervous system (CNS). However, how apoptotic cells mediate their impact on surrounding cells and contribute to the pathological progression of AD remains largely unclear. Here, we report that in 5×FAD mice, cells surrounding amyloid-β (Aβ) plaques undergo apoptosis, which occurs concurrently with elevated macroautophagy/autophagy. The autophagic flux, nevertheless, is impaired in AD, as evidenced by the simultaneous accumulation of MAP1LC3/LC3 and SQSTM1/p62. As a result, although there is an increased formation of autophagosomes, misfolded proteins fail to undergo proper degradation in the subsequent process. By profiling the "metabolomic secretome" of primary neurons and glial cells under different apoptotic stimuli, we identified spermidine as a conserved apoptotic metabolite messenger in the CNS. Spermidine is actively released from apoptotic neurons or glia cells and functions in a paracrine manner to induce autophagy activation in neighboring cells. Such an effect of enhancing autophagic flux promotes both the cargo encapsulation within autophagosomes and degradation in autolysosomes in nearby cells. Conversely, the blockade of spermidine release impairs autophagic flux, thereby exacerbating cognitive impairment and pathological progression in AD. These findings reveal a link between cell apoptosis and autophagy in AD, suggesting that spermidine supplementation could serve as a promising therapeutic strategy.Abbreviations: Aβ: β-amyloid; ACM: apoptotic conditioned medium; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; CNS: central nervous system; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; ELISA: enzyme linked immunosorbent assay; GFAP: glial fibrillary acidic protein; GSDMD: gasdermin D; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; PANX1: pannexin 1; PBS: phosphate-buffered saline; SQSTM1/p62: sequestosome 1; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; RT-PCR: reverse transcription quantitative real-time polymerase chain reaction; SMOX: spermidine oxidase; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling; UV: ultraviolet; WT: wild-type.