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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.

SUBMITTER: Hamilton LK 

PROVIDER: S-EPMC9021296 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Hamilton Laura K LK   Moquin-Beaudry Gaël G   Mangahas Chenicka L CL   Pratesi Federico F   Aubin Myriam M   Aumont Anne A   Joppé Sandra E SE   Légiot Alexandre A   Vachon Annick A   Plourde Mélanie M   Mounier Catherine C   Tétreault Martine M   Fernandes Karl J L KJL  

Nature communications 20220420 1

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  ...[more]

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