Evidence of disturbed insulin signaling in animal models of Alzheimer’s disease

Alves, Silas Franco dos Reis; Servilha-Menezes, Gabriel; Rossi, Luciana; Silva, Rui Milton Patrício da; García-Cairasco, Norberto

doi:10.1016/j.neubiorev.2023.105326

Cited by 5 publications

(2 citation statements)

References 232 publications

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“…For instance, obesity has been previously associated with age-related neurodegenerative processes, such as mild cognitive impairment and Alzheimer's disease (AD) [1][2][3][4]. Insulin receptors are present in several neural cell types, including glia and neurons [5], suggesting that AD might be related to insulin resistance [6,7]. Obesity-induced insulin resistance could fuel some of the culprits of age-related neurodegeneration, such as mitochondrial dysfunction, amyloid-beta deposit, protein aggregation, and neuroinflammation, to name a few.…”

Section: Introductionmentioning

confidence: 99%

High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage

Berdún,

Obis,

Mota-Martorell

et al. 2024

Antioxidants

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Obesity is a risk factor for highly prevalent age-related neurodegenerative diseases, the pathogenesis of whichinvolves mitochondrial dysfunction and protein oxidative damage. Lipoxidation, driven by high levels of peroxidizable unsaturated fatty acids and low antioxidant protection of the brain, stands out as a significant risk factor. To gain information on the relationship between obesity and brain molecular damage, in a porcine model of obesity we evaluated (1) the level of mitochondrial respiratory chain complexes, as the main source of free radical generation, by Western blot; (2) the fatty acid profile by gas chromatography; and (3) the oxidative modification of proteins by mass spectrometry. The results demonstrate a selectively higher amount of the lipoxidation-derived biomarker malondialdehyde-lysine (MDAL) (34% increase) in the frontal cortex, and positive correlations between MDAL and LDL levels and body weight. No changes were observed in brain fatty acid profile by the high-fat diet, and the increased lipid peroxidative modification was associated with increased levels of mitochondrial complex I (NDUFS3 and NDUFA9 subunits) and complex II (flavoprotein). Interestingly, introducing n3 fatty acids and a probiotic in the high-fat diet prevented the observed changes, suggesting that dietary components can modulate protein oxidative modification at the cerebral level and opening new possibilities in neurodegenerative diseases’ prevention.

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Section: Introductionmentioning

confidence: 99%

High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage

Berdún,

Obis,

Mota-Martorell

et al. 2024

Antioxidants

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“…A key mediator of an organism's metabolic state is insulin signaling, which reflects the nutritional status of an organism. Insulin signaling induces a systemic response that regulates anabolic and catabolic pathways and influences learning and memory in various species [43][44][45][46][47]. More specifically, within the mushroom body (MB), a key site for associative learning and memory in insects [48,49], the insulin receptor significantly influences memory formation in Drosophila [15,42,50,51].…”

Section: Introductionsmentioning

confidence: 99%

Critical roles of ERK and Akt signaling in metabolically dependent memory formation inDrosophilalarvae

Franz,

Widmann

2024

Preprint

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In the fruit flyDrosophila, memory formation is intricately linked to metabolic state. Our previous findings showed that the preferential support of memory under increased energy levels is mediated by the insulin receptor in the mushroom body (MB), a key memory center in the insect brain. This study analyzed the role of the insulin receptor’s downstream pathways, Ras-Raf-MEK-ERK and PI3K/Akt, in metabolically dependent memory formation. We evaluated their impact on memory processes by employing RNA interference-mediated downregulation of key components, extracellular signal-regulated kinase (ERK) and protein kinase B (Akt), in the MB ofDrosophilalarvae. To enhance energy levels, larvae were fed sugar for 60 minutes prior to aversive olfactory conditioning. Our findings revealed that genetically downregulating ERK and Akt in the MB significantly impaired metabolically dependent memory formation, without affecting naive sensory perception or olfactory learning. Immunohistochemical analysis confirmed the presence of active forms of ERK and Akt in the MB, underscoring their roles in modulating memory processes under elevated energy levels. The pivotal roles of these kinases suggest a broader implication of insulin signaling in memory formation under different metabolic conditions, and illuminate the connections between metabolic regulation and memory dynamics in the MB.

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A high fat diet potentiates neonatal iron overload-induced memory impairments in rats

do Nascimento,

de Freitas,

dos Passos

et al. 2024

Eur J Nutr

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Evidence of disturbed insulin signaling in animal models of Alzheimer’s disease

Cited by 5 publications

References 232 publications

High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage

High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage

Critical roles of ERK and Akt signaling in metabolically dependent memory formation inDrosophilalarvae

A high fat diet potentiates neonatal iron overload-induced memory impairments in rats

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