Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two global epidemics that share several metabolic defects, such as insulin resistance, altered glucose metabolism, and mitochondrial defects. Importantly, strong evidence demonstrates that type 2 diabetes significantly increases the risk of cognitive decline and dementia, particularly AD. Neurodegeneration associated with T2D represents a serious complication of the disease, and there is strong evidence demonstrating a link between T2D, cognitive impairment, and dementia, specifically vascular dementia and AD. A recent meta-analysis revealed that patients with T2D have a 50% increased risk of developing AD compared to age-matched non-diabetics. AD is considered the leading cause of dementia and accounts for 60-70% of all dementia cases due to the aging population,
There is a close association between altered glucose metabolism, mitochondrial dysfunction and IR in neurodegeneration associated with type 2 diabetes and AD. Indeed, insulin signaling regulates neuronal glucose uptake through glucose transporter 4 (GLUT4) as well as mitochondrial function. Reduced levels of the mitochondrial chaperones heat shock proteins (HSPs) 60 and 10 in the type 2 diabetic hypothalamus have also been previously shown to cause mitochondrial failure and neuronal IR. Furthermore, increased levels of oxidative stress can directly cause structural and functional modifications in proteins, lipids, and nucleic acids. Mitochondrial dysfunction causes overproduction of ROS and oxidative damage. Furthermore, the increase in oxidative stress associated with T2D is responsible for an increase in iron (Fe 2+ )-mediated cell death through phospholipid peroxidation, this process being called ferroptosis. The Fenton reaction increases the levels of hydroxyl radicals (•OH), which are responsible for an increase in lipid peroxidation, particularly affecting unsaturated fatty acids.
Increased neuronal oxidative stress has been shown to activate the apoptotic cascade by triggering the release of cytochrome c and promoting the accumulation of Aβ in synaptic mitochondria contributing to cognitive decline. Taken together, the T2D-associated alterations discussed above may promote an energy crisis and increased oxidative stress/damage, increasing the risk of cognitive decline and development of AD. Mitophagy in neuronal cells, especially at synapses, is crucial to prevent synaptic damage and loss. The accumulation of damaged mitochondria at synapses is responsible for increased levels of oxidative stress and inadequate energy production, resulting in decreased neurotransmission and eventually cognitive impairment.
Mitochondrial function is essential to maintain neuronal integrity, because neurons have a high energy demand. Neurodegenerative diseases, such as Alzheimer's disease (AD), are exacerbated by mitochondrial dysfunction. Mitochondrial autophagy (mitophagy) attenuates neurodegenerative diseases by eradicating dysfunctional mitochondria. In neurodegenerative disorders, there is a disruption of the mitophagy process. High levels of iron also interfere with the mitophagy process and the mtDNA released after mitophagy is pro-inflammatory and triggers the cGAS-STING pathway that aids AD pathology. In the AD brain, glucose hypometabolism is mainly attributed to decreased energy metabolism caused by oxidative phosphorylation, implying that mitochondrial dysfunction is likely to play an important role in the development of AD.
Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two global epidemics that share several metabolic defects, such as insulin resistance, altered glucose metabolism, and mitochondrial defects. Importantly, strong evidence demonstrates that type 2 diabetes significantly increases the risk of cognitive decline and dementia, particularly AD. Neurodegeneration associated with T2D represents a serious complication of the disease, and there is strong evidence demonstrating a link between T2D, cognitive impairment, and dementia, specifically vascular dementia and AD. A recent meta-analysis revealed that patients with T2D have a 50% increased risk of developing AD compared to age-matched non-diabetics. AD is considered the leading cause of dementia and accounts for 60-70% of all dementia cases due to the aging population,
There is a close association between altered glucose metabolism, mitochondrial dysfunction and IR in neurodegeneration associated with type 2 diabetes and AD. Indeed, insulin signaling regulates neuronal glucose uptake through glucose transporter 4 (GLUT4) as well as mitochondrial function. Reduced levels of the mitochondrial chaperones heat shock proteins (HSPs) 60 and 10 in the type 2 diabetic hypothalamus have also been previously shown to cause mitochondrial failure and neuronal IR. Furthermore, increased levels of oxidative stress can directly cause structural and functional modifications in proteins, lipids, and nucleic acids. Mitochondrial dysfunction causes overproduction of ROS and oxidative damage. Furthermore, the increase in oxidative stress associated with T2D is responsible for an increase in iron (Fe 2+ )-mediated cell death through phospholipid peroxidation, this process being called ferroptosis. The Fenton reaction increases the levels of hydroxyl radicals (•OH), which are responsible for an increase in lipid peroxidation, particularly affecting unsaturated fatty acids.
Increased neuronal oxidative stress has been shown to activate the apoptotic cascade by triggering the release of cytochrome c and promoting the accumulation of Aβ in synaptic mitochondria contributing to cognitive decline. Taken together, the T2D-associated alterations discussed above may promote an energy crisis and increased oxidative stress/damage, increasing the risk of cognitive decline and development of AD. Mitophagy in neuronal cells, especially at synapses, is crucial to prevent synaptic damage and loss. The accumulation of damaged mitochondria at synapses is responsible for increased levels of oxidative stress and inadequate energy production, resulting in decreased neurotransmission and eventually cognitive impairment.
https://www.sciencedirect.com/science/article/pii/S0959438823000193 (2023)
Mitochondrial function is essential to maintain neuronal integrity, because neurons have a high energy demand. Neurodegenerative diseases, such as Alzheimer's disease (AD), are exacerbated by mitochondrial dysfunction. Mitochondrial autophagy (mitophagy) attenuates neurodegenerative diseases by eradicating dysfunctional mitochondria. In neurodegenerative disorders, there is a disruption of the mitophagy process. High levels of iron also interfere with the mitophagy process and the mtDNA released after mitophagy is pro-inflammatory and triggers the cGAS-STING pathway that aids AD pathology. In the AD brain, glucose hypometabolism is mainly attributed to decreased energy metabolism caused by oxidative phosphorylation, implying that mitochondrial dysfunction is likely to play an important role in the development of AD.
https://www.sciencedirect.com/science/article/abs/pii/S1359644623000636 (2023)