Reduced expression of APLP2 in spinal GABAergic inhibitory neurons contributed to nerve injury-induced microglial activation and pain sensitization

The amyloid precursor protein (APP) is critical for the pathogenesis of Alzheimer's disease (AD). The AD patients usually have lower pain sensitivity in addition to cognitive impairments. However, considerably less is known as yet about the role of APP and its two mammalian homologues, amyloid...

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Published in:Neuropharmacology 2023-02, Vol.224, p.109334-109334, Article 109334
Main Authors: Li, Yu-Zhe, Zhu, Yue-Bin, Ge, An-Na, Gao, Min, Wang, Kang-Li, Zeng, Xiang-Ru, Li, Jing, Li, Yuan, Xu, Jia-Yu, Bai, Hu-Hu, Wu, Shu-Jin
Format: Article
Language:English
Subjects:
Allodynia
Alzheimer Disease - metabolism
Amyloid beta-Protein Precursor - metabolism
Amyloid precursor-like protein 2
Animals
GABAergic Neurons - metabolism
Hyperalgesia
Male
Mice
Mice, Inbred C57BL
Microglia
Microglia - metabolism
Pain Threshold - physiology
Peripheral Nerve Injuries - metabolism
Peripheral nerve injury
Spinal Cord - metabolism
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Summary:The amyloid precursor protein (APP) is critical for the pathogenesis of Alzheimer's disease (AD). The AD patients usually have lower pain sensitivity in addition to cognitive impairments. However, considerably less is known as yet about the role of APP and its two mammalian homologues, amyloid precursor-like protein 1 and 2 (APLP1, APLP2), in spinal processing of nociceptive information. Here we found that all APP family members were present in spinal cord dorsal horn of adult male C57BL/6J mice. Peripheral nerve injury specifically reduced the expression of spinal APLP2 that correlated with neuropathic mechanical allodynia. The loss of APLP2 was confined to inhibitory GABAergic interneurons. Targeted knockdown of APLP2 in GABAergic interneurons of GAD2-Cre mice evoked pain hypersensitivity by means of microglia activation. Our data showed that GABAergic terminals expressed APLP2, a putative cell adhesion protein that interacted with microglia-specific integrin molecule CD11b. Knocking down APLP2 in GAD2-positive neurons to disrupt the trans-cellular interaction led to microglia-dependent pain sensitization. Our data thus revealed an important role of APLP2 for GABAergic interneurons to control microglial activity and pain sensitivity. •Nerve injury reduced the APLP2 expression in spinal cord GABAergic interneurons.•Targeted knockdown of APLP2 in GABAergic neurons evoked pain hypersensitivity.•APLP2 in GABAergic neurons controlled microglia activity.•Inhibition of microglia alleviated pain sensitization induced by APLP2 knockdown.•Reinstatement of APLP2 expression in GABAergic neurons alleviated neuropathic pain.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2022.109334