| First Author | Tohumeken S | Year | 2023 |
| Journal | Neurobiol Dis | Volume | 177 |
| Pages | 105987 | PubMed ID | 36603748 |
| Mgi Jnum | J:333422 | Mgi Id | MGI:7430595 |
| Doi | 10.1016/j.nbd.2023.105987 | Citation | Tohumeken S, et al. (2023) Neuronal deletion of nSMase2 reduces the production of Abeta and directly protects neurons. Neurobiol Dis 177:105987 |
| abstractText | Extracellular vesicles (EVs) have been proposed to regulate the deposition of Abeta. Multiple publications have shown that APP, amyloid processing enzymes and Abeta peptides are associated with EVs. However, very little Abeta is associated with EVs compared with the total amount Abeta present in human plasma, CSF, or supernatants from cultured neurons. The involvement of EVs has largely been inferred by pharmacological inhibition or whole body deletion of the sphingomyelin hydrolase neutral sphingomyelinase-2 (nSMase2) that is a key regulator for the biogenesis of at-least one population of EVs. Here we used a Cre-Lox system to selectively delete nSMase2 from pyramidal neurons in APP/PS1 mice (APP/PS1-SMPD3-Nex1) and found a approximately 70% reduction in Abeta deposition at 6 months of age and approximately 35% reduction at 12 months of age in both cortex and hippocampus. Brain ceramides were increased in APP/PS1 compared with Wt mice, but were similar to Wt in APP/PS1-SMPD3-Nex1 mice suggesting that elevated brain ceramides in this model involves neuronally expressed nSMase2. Reduced levels of PSD95 and deficits of long-term potentiation in APP/PS1 mice were normalized in APP/PS1-SMPD3-Nex1 mice. In contrast, elevated levels of IL-1beta, IL-8 and TNFalpha in APP/PS1 mice were not normalized in APP/PS1-SMPD3-Nex1 mice compared with APP/PS1 mice. Mechanistic studies showed that the size of liquid ordered membrane microdomains was increased in APP/PS1 mice, as were the amounts of APP and BACE1 localized to these microdomains. Pharmacological inhibition of nSMase2 activity with PDDC reduced the size of the liquid ordered membrane microdomains, reduced the localization of APP with BACE1 and reduced the production of Abeta(1)(-)(40) and Abeta(1)(-)(42). Although inhibition of nSMase2 reduced the release and increased the size of EVs, very little Abeta was associated with EVs in all conditions tested. We also found that nSMase2 directly protected neurons from the toxic effects of oligomerized Abeta and preserved neural network connectivity despite considerable Abeta deposition. These data demonstrate that nSMase2 plays a role in the production of Abeta by stabilizing the interaction of APP with BACE1 in liquid ordered membrane microdomains, and directly protects neurons from the toxic effects of Abeta. The effects of inhibiting nSMase2 on EV biogenesis may be independent from effects on Abeta production and neuronal protection. |
