Stearoyl-CoA Desaturase inhibition reverses immune, synaptic and cognitive impairments in an Alzheimer’s disease mouse model

Abstract

The defining features of Alzheimer’s disease (AD) include alterations in protein aggregation, immunity, lipid metabolism, synapses, and learning and memory. Of these, lipid abnormalities are the least understood. Here, we investigate the role of Stearoyl-CoA desaturase (SCD), a crucial regulator of fatty acid desaturation, in AD pathogenesis. We show that inhibiting brain SCD activity for 1-month in the 3xTg mouse model of AD alters core AD-related transcriptomic pathways in the hippocampus, and that it concomitantly restores essential components of hippocampal function, including dendritic spines and structure, immediate-early gene expression, and learning and memory itself. Moreover, SCD inhibition dampens activation of microglia, key mediators of spine loss during AD and the main immune cells of the brain. These data reveal that brain fatty acid metabolism links AD genes to downstream immune, synaptic, and functional impairments, identifying SCD as a potential target for AD treatment.

A Review of the Pathogenesis and Chinese Medicine Intervention of Alzheimer's Disease

“…Studies have shown that fatty acids can affect gene expression and metabolic responses not only by altering intracellular and extracellular signaling pathways but also by altering intracellular and extracellular signaling pathways in many different cells and tissue types [77]. The recent study found Stearoyl-CoA desaturase (SCD) which is a key regulator of fatty acid desaturation, inhibition of its activity in the 3xTg mouse model of AD brain alters core transcriptomic pathways associated with AD in the hippocampus [78]. With the improvement of quality of life and lifestyle changes, high sugar and high-fat diets (HFDs) have become an important part of the contemporary diet.…”

Free ferrous ions sustain activity of mammalian stearoyl-CoA desaturase-1

“…Preclinical studies of SCD1 inhibitors have shown benefits for the treatment of cancers (Yahagi et al 2005; Scaglia and Igal 2008; Scaglia, Chisholm, and Igal 2009; Ackerman and Simon 2014; Theodoropoulos et al 2016; Savino et al 2020; Oatman et al 2021). SCD1 is also a validated target for reversing the pathology in neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases (Vincent et al 2018; Fanning et al 2019; Nuber et al 2021; Hamilton et al 2022).…”

Radiosynthesis and Preliminary Evaluation of [11C]SSI-4 for the Positron Emission Tomography Imaging of Stearoyl CoA Desaturase 1

“…Human SCD1 is ubiquitously expressed in lipogenic tissues, with high levels in lacrimal glands, brown fat, liver, and brain. , SCD1 is a major regulator of the whole-body energy homeostasis and overexpression of SCD1 is implicated in metabolic perturbations found in several disorders such as diabetes, obesity, metabolic syndrome, Alzheimer’s disease, Parkinson’s disease, skin disorders, and cancer, suggesting that SCD1 can serve as a plausible diagnostic and therapeutic target. − ,− An analysis of gene expression profiles reveals the presence of overexpression of SCD1 in several cancers. ,− This increase in SCD1 expression is positively correlated with cancer aggressiveness and poor patient prognosis in liver, thyroid, prostate, pancreatic, kidney, skin, and breast cancer. Inhibiting SCD1 as a therapy has been reported in several preclinical studies for various tumors including glioblastoma, breast, lung, thyroid, prostate, liver, ovarian, gastric, bladder, and clear cell renal cell carcinomas and early clinical trials for acne and obesity. ,− …”

“…38 Despite its short half-life (t 1/2 = 20.4 min), carbon-11 ( 11 C) is one of the most widely used PET radionuclides because of its favorable physical and biological characteristics and established C-11 PET radiochemistry. 39 The replacement of one stable 12 C atom in a drug candidate with positron emitting 11 C will not alter its chemical and/or biological profile, shortening the time of drug development from the bench to the bedside. In this study, we designed and C-11 labeled SSI-4 at the urea carbonyl via [ 11 S1).…”