Sarm1, short for 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, making it respond to metabolic changes like an increased NMN/NAD+ ratio, which then triggers axon destruction [4]. It is also involved in the NF-κB signaling pathway [1].

Conditional knockout (CKO) mouse models have been instrumental in revealing Sarm1's functions. In spinal cord injury (SCI) models, Sarm1Nestin-CKO and Sarm1GFAP-CKO mice showed that conditional deletion of Sarm1 in neurons and astrocytes promoted neuronal regeneration at the intermediate phase after SCI and reduced neuroinflammation at the early phase through down-regulation of NF-κB signaling, which might be due to up-regulation of HSP70. This led to improved behavioral performance post-SCI [1]. In Alzheimer's disease (AD) model mice, SARM1Nestin-CKO mice had delayed cognitive decline, reduced Aβ deposition, and less inflammatory infiltration, suggesting Sarm1 promotes neurodegeneration and memory impairment in AD [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 [3].

In conclusion, Sarm1 is crucial in axon degeneration, neuroinflammation, and neurodegenerative diseases. Studies using CKO and KO mouse models have revealed its role in SCI, AD, and CIPN, highlighting its potential as a therapeutic target in these disease areas. Understanding Sarm1's functions through these models helps in developing novel strategies for treating neurodegenerative disorders.

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/