Astrocyte-derived PTN alleviates deficits in hippocampal neurogenesis and cognition in models of multiple sclerosis.

in Stem cell reports by Yanna Song, Haoyang Li, Yuhan Li, Huiming Xu, Faisal Hayat Nazir, Wei Jiang, Lu Zheng, Changyong Tang

TLDR

  • The study found that astrocyte-derived pleiotrophin (PTN) plays a crucial role in hippocampal neurogenesis and cognition in demyelinated mice, and that overexpression of PTN reverses neurogenic and cognitive impairments caused by demyelination.

Abstract

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease that results in motor, sensory, cognitive, and affective deficits. Hippocampal demyelination, a common occurrence in MS, is linked to impaired cognitive function and mood. Despite this, the precise mechanisms underlying cognitive impairments in MS remain elusive. Pleiotrophin (PTN), secreted by neural stem cells and astrocytes, plays a crucial role in regulating cognition. This study investigates the role of astrocyte-derived PTN. We found that genetic deletion of astrocyte-derived PTN hinders hippocampal neurogenesis. Additionally, conditional ablation of PTN in astrocytes exacerbates neurogenic deficits in the demyelinated hippocampus. Importantly, overexpression of PTN in astrocytes reverses neurogenic and cognitive impairments caused by demyelination, underscoring PTN's protective role in MS. PTN cooperates with protein tyrosine phosphatase receptor type Z1 (PTPRZ1) or anaplastic lymphoma kinase (ALK) receptors to activate the AKT signaling pathway, thereby enhancing hippocampal neurogenesis and cognition in demyelinated mice. These findings illuminate novel effects of astrocyte-derived PTN on hippocampal neurogenesis and cognition.

Overview

  • The study investigates the role of astrocyte-derived pleiotrophin (PTN) in cognitive impairments in multiple sclerosis (MS).
  • The study aims to explore the mechanisms underlying cognitive impairments in MS and the potential therapeutic applications of PTN.
  • The study uses a mouse model of demyelinated hippocampus to examine the effects of PTN on hippocampal neurogenesis and cognition.

Comparative Analysis & Findings

  • The study found that genetic deletion of astrocyte-derived PTN hinders hippocampal neurogenesis, while conditional ablation of PTN in astrocytes exacerbates neurogenic deficits in the demyelinated hippocampus.
  • Overexpression of PTN in astrocytes reverses neurogenic and cognitive impairments caused by demyelination, highlighting PTN's protective role in MS.
  • PTN cooperates with protein tyrosine phosphatase receptor type Z1 (PTPRZ1) or anaplastic lymphoma kinase (ALK) receptors to activate the AKT signaling pathway, enhancing hippocampal neurogenesis and cognition in demyelinated mice.

Implications and Future Directions

  • The study suggests that targeting PTN and its downstream signaling pathways may be a promising therapeutic approach for cognitive impairment in MS.
  • Further studies are needed to explore the potential therapeutic applications of PTN in MS and to better understand the complex interactions between PTN, PTPRZ1, and ALK receptors in the hippocampus.
  • The study highlights the importance of understanding the role of astrocytes and their secreted factors, such as PTN, in modulating hippocampal neurogenesis and cognition, which may lead to novel therapeutic targets for neurological disorders.
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