Central inhibition of stearoyl-CoA desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer’s disease mouse model
Abstract Evidence from genetic and epidemiological studies point to lipid metabolism defects in both the brain and periphery being at the core of Alzheimer’s disease (AD) pathogenesis. Previously, we reported that central inhibition of the rate-limiting enzyme in monounsaturated fatty acid synthesis...
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| Format: | Article |
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Nature Portfolio
2024-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-58272-8 |
| _version_ | 1797219871274041344 |
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| author | Laura K. Hamilton Paule E. H. M’Bra Sophia Mailloux Manon Galoppin Anne Aumont Karl J. L. Fernandes |
| author_facet | Laura K. Hamilton Paule E. H. M’Bra Sophia Mailloux Manon Galoppin Anne Aumont Karl J. L. Fernandes |
| author_sort | Laura K. Hamilton |
| collection | DOAJ |
| description | Abstract Evidence from genetic and epidemiological studies point to lipid metabolism defects in both the brain and periphery being at the core of Alzheimer’s disease (AD) pathogenesis. Previously, we reported that central inhibition of the rate-limiting enzyme in monounsaturated fatty acid synthesis, stearoyl-CoA desaturase (SCD), improves brain structure and function in the 3xTg mouse model of AD (3xTg-AD). Here, we tested whether these beneficial central effects involve recovery of peripheral metabolic defects, such as fat accumulation and glucose and insulin handling. As early as 3 months of age, 3xTg-AD mice exhibited peripheral phenotypes including increased body weight and visceral and subcutaneous white adipose tissue as well as diabetic-like peripheral gluco-regulatory abnormalities. We found that intracerebral infusion of an SCD inhibitor that normalizes brain fatty acid desaturation, synapse loss and learning and memory deficits in middle-aged memory-impaired 3xTg-AD mice did not affect these peripheral phenotypes. This suggests that the beneficial effects of central SCD inhibition on cognitive function are not mediated by recovery of peripheral metabolic abnormalities. Given the widespread side-effects of systemically administered SCD inhibitors, these data suggest that selective inhibition of SCD in the brain may represent a clinically safer and more effective strategy for AD. |
| first_indexed | 2024-04-24T12:40:32Z |
| format | Article |
| id | doaj.art-727f5ff5e5f646b18dbc82d5031be3e6 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T12:40:32Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-727f5ff5e5f646b18dbc82d5031be3e62024-04-07T11:14:56ZengNature PortfolioScientific Reports2045-23222024-04-0114111310.1038/s41598-024-58272-8Central inhibition of stearoyl-CoA desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer’s disease mouse modelLaura K. Hamilton0Paule E. H. M’Bra1Sophia Mailloux2Manon Galoppin3Anne Aumont4Karl J. L. Fernandes5Research Center of the University of Montreal Hospital (CRCHUM)Research Center on Aging, CIUSSS de l’Estrie-CHUSResearch Center of the University of Montreal Hospital (CRCHUM)Research Center of the University of Montreal Hospital (CRCHUM)Research Center on Aging, CIUSSS de l’Estrie-CHUSResearch Center of the University of Montreal Hospital (CRCHUM)Abstract Evidence from genetic and epidemiological studies point to lipid metabolism defects in both the brain and periphery being at the core of Alzheimer’s disease (AD) pathogenesis. Previously, we reported that central inhibition of the rate-limiting enzyme in monounsaturated fatty acid synthesis, stearoyl-CoA desaturase (SCD), improves brain structure and function in the 3xTg mouse model of AD (3xTg-AD). Here, we tested whether these beneficial central effects involve recovery of peripheral metabolic defects, such as fat accumulation and glucose and insulin handling. As early as 3 months of age, 3xTg-AD mice exhibited peripheral phenotypes including increased body weight and visceral and subcutaneous white adipose tissue as well as diabetic-like peripheral gluco-regulatory abnormalities. We found that intracerebral infusion of an SCD inhibitor that normalizes brain fatty acid desaturation, synapse loss and learning and memory deficits in middle-aged memory-impaired 3xTg-AD mice did not affect these peripheral phenotypes. This suggests that the beneficial effects of central SCD inhibition on cognitive function are not mediated by recovery of peripheral metabolic abnormalities. Given the widespread side-effects of systemically administered SCD inhibitors, these data suggest that selective inhibition of SCD in the brain may represent a clinically safer and more effective strategy for AD.https://doi.org/10.1038/s41598-024-58272-8 |
| spellingShingle | Laura K. Hamilton Paule E. H. M’Bra Sophia Mailloux Manon Galoppin Anne Aumont Karl J. L. Fernandes Central inhibition of stearoyl-CoA desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer’s disease mouse model Scientific Reports |
| title | Central inhibition of stearoyl-CoA desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer’s disease mouse model |
| title_full | Central inhibition of stearoyl-CoA desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer’s disease mouse model |
| title_fullStr | Central inhibition of stearoyl-CoA desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer’s disease mouse model |
| title_full_unstemmed | Central inhibition of stearoyl-CoA desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer’s disease mouse model |
| title_short | Central inhibition of stearoyl-CoA desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer’s disease mouse model |
| title_sort | central inhibition of stearoyl coa desaturase has minimal effects on the peripheral metabolic symptoms of the 3xtg alzheimer s disease mouse model |
| url | https://doi.org/10.1038/s41598-024-58272-8 |
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