Sarm1, or sterile alpha and TIR motif-containing 1, is the fifth TLR (Toll-like receptor) adaptor. It has diverse functions in the immune and nervous systems and is a key mediator of Wallerian degeneration (WD). Sarm1 contains an intrinsic NADase enzymatic activity that is essential for its pro-degenerative functions, making it a crucial factor in axonal degeneration pathways [3,4,5].

In spinal cord injury (SCI) mouse models, conditional knockout (CKO) of Sarm1 in the central nervous system (CNS) using Nestin-Cre and GFAP-Cre transgenic mice crossed with Sarm1flox/flox mice showed that deletion of Sarm1 in neurons and astrocytes promoted neuronal regeneration at the intermediate phase and reduced neuroinflammation at the early phase after SCI, through down-regulation of NF-κB signaling, potentially due to up-regulation of HSP70. FK866, an inhibitor of Sarm1, also reduced neuroinflammation and promoted neuronal regeneration after SCI, indicating Sarm1-mediated pro-degenerative pathway and neuroinflammation promotes the pathological progress of SCI [1]. In APP/PS1 AD model mice, CKO of Sarm1 in the CNS delayed cognitive decline, reduced Aβ deposition and inflammatory infiltration, and inhibited neurodegeneration, likely through down-regulation of TNF-α signaling [2]. In a mouse paclitaxel model of chemotherapy-induced peripheral neuropathy (CIPN), Sarm1 knockout mice prevented loss of axonal function in a gene-dosage-dependent manner, and irreversible SARM1 inhibitors protected axon structure and function [3].

In conclusion, Sarm1 is a significant factor in axonal degeneration and neuroinflammation. Studies using Sarm1 KO/CKO mouse models have revealed its roles in diseases such as SCI, Alzheimer's disease, and CIPN. These models have provided insights into how Sarm1 contributes to pathological processes, highlighting its potential as a therapeutic target for neurodegenerative disorders [1,2,3].

References:

1. Liu, Huitao, Zhang, Jingjing, Xu, Xingxing, Huang, Zhihui, Teng, Honglin. 2021. SARM1 promotes neuroinflammation and inhibits neural regeneration after spinal cord injury through NF-κB signaling. In Theranostics, 11, 4187-4206. doi:10.7150/thno.49054. https://pubmed.ncbi.nlm.nih.gov/33754056/

2. Miao, Xuemeng, Wu, Qian, Du, Siyu, Wang, Ying, Huang, Zhihui. 2024. SARM1 Promotes Neurodegeneration and Memory Impairment in Mouse Models of Alzheimer's Disease. In Aging and disease, 15, 390-407. doi:10.14336/AD.2023.0516-1. https://pubmed.ncbi.nlm.nih.gov/37307837/

3. Bosanac, Todd, Hughes, Robert O, Engber, Thomas, Bentley, Jonathan, Krauss, Raul. . Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy. In Brain : a journal of neurology, 144, 3226-3238. doi:10.1093/brain/awab184. https://pubmed.ncbi.nlm.nih.gov/33964142/

4. Figley, Matthew D, Gu, Weixi, Nanson, Jeffrey D, DiAntonio, Aaron, Ve, Thomas. 2021. SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. In Neuron, 109, 1118-1136.e11. doi:10.1016/j.neuron.2021.02.009. https://pubmed.ncbi.nlm.nih.gov/33657413/

5. Shi, Yun, Kerry, Philip S, Nanson, Jeffrey D, Hughes, Robert O, Ve, Thomas. 2022. Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules. In Molecular cell, 82, 1643-1659.e10. doi:10.1016/j.molcel.2022.03.007. https://pubmed.ncbi.nlm.nih.gov/35334231/