AUTHOR=Bedoya-Guzmán Ferley A. , Pacheco-Herrero Mar , Salomon-Cruz Ivan Daniel , Barrera-Sandoval Angela Maria , Gutierrez Vargas Johanna Andrea , Villamil-Ortiz Javier Gustavo , Villegas Lanau Carlos Andres , Arias-Londoño Julián David , Area-Gomez Estela , Cardona Gomez Gloria Patricia 

TITLE=BACE1 and SCD1 are associated with neurodegeneration

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 15 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2023.1194203

DOI=10.3389/fnagi.2023.1194203

ISSN=1663-4365

ABSTRACT=Proteolytic processing of amyloid protein precursor by β‐site secretase enzyme (BACE1) is dependent on the cellular lipid composition and is affected by endomembrane trafficking in dementia and Alzheimer´s disease (AD). Stearoyl-CoA desaturase 1 (SCD1) is responsible the synthesis of fatty acid monounsaturation (MUFAs), whose accumulation is strongly associated with cognitive dysfunction. In this study, we analyzed the relationship between BACE1 and SCD1 in vivo, in vitro neurodegenerative models and their association in familial AD (FAD), sporadic AD (SAD), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Our findings showed that BACE1 and SCD1 immunoreactivities were increased and colocalized in astrocytes of the hippocampus in a rat model of global cerebral ischemia (2-VO).  A synergistic effect of double BACE1/SCD1 silencing on the recovery of motor and cognitive functions was obtained. This neuroprotective regulation involved the segregation of phospholipids (PLs) associated with polyunsaturated fatty acids in the hippocampus, cerebrospinal fluid, and serum. The double silencing on sham and ischemic groups was stronger in the serum, inducing an inverse ratio between total phosphatydilcholine (PC) and lysophosphatidylcholine (LPC), represented mainly by the reduction of PC 38:4 and PC36:4 and an increase in LPC 16:0 and LPC 18:0. Furthermore, PC 38:4 and PC:36:4 levels augmented in pathological condition in in vitro AD models. BACE1 and SCD1 increase were confirmed in the hippocampus of FAD, SAD and CADASIL. Therefore, the findings suggest a novel convergence of BACE-1 and SCD1 in neurodegeneration, related to pro-inflammatory phospholipids.