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Primary Cilia-Autophagy Axis in Hippocampal Neurons Is Essential to Maintain Cognitive Fitness

ABSTRACT: A central hallmark of brain aging is the alteration of neuronal functions in the hippocampus, leading to a progressive decline in learning and memory. Multiple reports have shown the importance of blood-borne factors in inter-tissue communication for the maintenance of cognitive fitness and proper regulation of neuronal homeostasis throughout life. Among these blood-borne factors, we identified Osteocalcin (OCN), a bone-derived hormone. OCN induces autophagy machinery in hippocampal neurons which is essential for activity-dependent synaptic plasticity. However, the way in which blood-borne factors like OCN communicate with neurons, including their regulatory mechanisms, remains largely elusive. Here, we show the importance of a core primary cilium (PC)-proteins/autophagy machinery axis in hippocampal neurons that mediate the effects of the pro-youthful blood factor OCN on neuronal homeostasis and cognitive fitness. We found that OCN’s receptor, GPR158, is present at the PC of hippocampal neurons and mediates the regulation of autophagy machinery by OCN. During aging, PC-core proteins are reduced in hippocampal neurons and associated with neuronal PC morphological abnormalities. Restoring their levels is sufficient to improve neuronal autophagy and cognitive impairments in aged mice. Mechanistically, we found that OCN promotes neuronal autophagy in the hippocampus by the induction of PC-dependent cAMP response element-binding protein (CREB) signaling pathway. Altogether, this study proposes a novel paradigm for blood factor-neuron communication dependent on a neuronal PC/autophagy axis by identifying a novel regulatory pathway fostering cognitive fitness and providing the foundation for autophagy-based therapeutic strategies to treat age-related cognitive dysfunction.

INSTRUMENT(S): maXis

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Layer Of Hippocampus, Brain

SUBMITTER: Franck Oury

LAB HEAD: Franck Oury

PROVIDER: PXD056975 | Pride | 2024-11-07

REPOSITORIES: Pride

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			Action	DRS
	PPN_DA_FrOU_DaRO_230922_H_n0_report_pg_matrix.xlsm	Xls
	Proteomics_dataset_Nat_Aging.xlsx	Xlsx
	transfer_8364647_files_6d6bd084.zip	Other

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Project description:<p><em>Gastrodia elata</em> Blume (GE) has been widely used to treat various central and peripheral nerve diseases, and P-Hydroxybenzaldehyde (PHBA) is one of the indicative components of GE brain protection. Since the previous study of our group found that PHBA has a good effect on protecting mitochondria against cerebral ischemia-reperfusion injury in rats (I/R). We will further explore how PHBA regulates the metabolic mechanism in blood after cerebral I/R to find an effective therapeutic target to prevent and treat IS. Firstly, using the rat model of cerebral ischemia-reperfusion injury induced by middle cerebral artery occlusion/Reperfusion (MCAO/R). The therapeutic effect of PHBA on brain I/R was evaluated by neurological function score, triphenyl tetrazolium chloride (TTC), Hematoxylin and eosin (HE), and Nissl staining. Secondly, a non-targeted metabonomic based on HPLC-QTOF-MS/MS was established to identify differential metabolites. Finally, we analyzed a targeted metabolic spectrum and verified the potential therapeutic targets. The results showed that the neurological function score, cerebral infarction area, hippocampal morphology, and the number of neurons in the PHBA group were significantly improved compared with the model group. Metabonomic analysis showed that 13 different metabolites were identified between the model and PHBA group, which may be involved in the 'tricarboxylic acid cycle', 'glutathione metabolism', 'mutual transformation of pentose and glucuronates', and so on. Among them, the most significant differential metabolite, dGMP, decreased significantly after PHBA treatment. We used WB to verify the expression of membrane-associated guanosine kinase PSD-95 and The subunit of glutamate AMPA receptor GluA1, which significantly increased after PHBA treatment. In addition, we also found that PHBA increased the expression of the light chain-3 protein (LC3) and autophagy effector protein 1 (Beline1) in WB while decreasing the expression of sequestosome-1 (p62), indicating that autophagy activity was promoted. Similarly, in TUNEL staining and detection of apoptosis-related proteins, it was found that MCAO/R up-regulated the expression of Bax and Cleaved-caspase-3 while down-regulated the expression of Bcl-2, and increased the apoptosis of hippocampal neurons, but PHBA could improve this situation. In summary, these results suggest that cerebral I/R causes postsynaptic dysfunction by disrupting the interaction between PSD-95 and AMPARs, and the inhibition of the autophagy system eventually leads to the apoptosis of hippocampal neurons.</p>

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Primary Cilia-Autophagy Axis in Hippocampal Neurons Is Essential to Maintain Cognitive Fitness

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