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Alzheimer’s Gene Linked to Diabetes

Researchers found that the Alzheimer’s gene ApoE4 could be linked to type 3 diabetes.

The Apolipoprotein E (APOE) gene is one of the strongest genetic risk factors for Alzheimer’s disease. Diabetes and impaired insulin signaling in the brain are linked to the development of Alzheimer’s disease. This study shows how apoE4 and insulin resistance can contribute to the development of Alzheimer’s disease.

Since impaired insulin signaling in the central nervous system has been linked to the pathogenesis of Alzheimer’s disease, the researchers hypothesized that insulin signaling in the brain could be affected by apoE isoforms. Researchers examined molecules in the brain of apoE3 and apoE4-TR mice at 3, 12, and 22 months of age, which represent young, middle and old ages. They found key insulin-related signaling molecules that include p-Akt and p-GSK3β were significantly decreased in both the cortex and hippocampus of apoE4-TR mice at 22 months of age. There were no significant differences in the 3 and 12 months of age groups. The researchers then examined levels of phosphorylated-Insulin Receptor (p-IR), which is the upstream molecule of p-Akt. There was a decreased ratio of p-IR to total IR detected in the cortex of apoE4-TR mice at 22 months of age compared with apoE3-TR mice, which indicates that basal insulin signaling is impaired in apoE4-TR mice in an age-dependent manner. The levels of p-Akt and p-GSK3β were critical sites to peripheral insulin signaling in apoE4-TR and apoE4-TR mice at 22 months of age; this means the basal peripheral insulin signaling remained intact in aged apoE4-TR mice.

The researchers also investigated whether peripheral insulin resistance impairs cerebral insulin signaling in an apoE isoform-dependent manner using a high fat diet induced insulin resistance mouse model. ApoE3 and apoE4-TR 8 month-old mice were fed with a high fat diet (60% fat) or a normal fat diet (5.8% fat) for 4 months. The results were the fasting glucose levels of the high-fat diet fed mice were significantly higher than the normal fat diet mice. The apoE4-TR high fat diet fed mice had a significant decrease in the activation of downstream insulin signaling compared with the high-fat fed apoE3-TR mice at 12 months of age. These results show that the high-fat diet induced peripheral insulin resistance and apoE4 work together to reduce cerebral insulin signaling.

Next the researchers investigated whether apoE4 affects insulin sensitivity in the brain. Insulin was given to the left hippocampus of aged apoE-TR mice or high-fat diet fed apoE-TR mice by micro dialysis and insulin signaling was evaluated in both ipsilateral and contralateral sides of insulin delivery. The results were that the increase of insulin-induced signaling in the hippocampus was significantly lower in the apoE4-TR mice than the apoE3-TR mice in both the aged condition and high-fat diet treatment. This result suggests that aged apoE4-TR mice develop cerebral insulin resistance, which can be accelerated by high-fat diet-induced peripheral insulin resistance conditions.

ApoE isoforms were tested to see the response of insulin in neurons. ApoE primary neurons were treated with apoE3 or apoE4, followed by insulin stimulation. The apoE4 treatment led to reduced insulin signaling in primary neurons, which suggests that apoE4 suppresses the action of insulin in neurons.

To explore how apoE4 impairs insulin signaling, the researchers investigated whether apoE4 could disrupt insulin and insulin resistance interaction by binding to either insulin or insulin receptors. A solid-phase binding assay using recombinant insulin or insulin receptors was incubated with immobilized apoE3 or apoE4 and they did not detect any specific binding between apoE3 and insulin. They found that both apoE3 and apoE4 specifically bound to insulin receptors with apoE4 having a higher affinity than apoE4.

To investigate the intracellular trafficking and distribution of IR after incubation with apoE and/or insulin, IR-GFP-expressing cells were labeled as a marker of early endosome and recycling endosome. In absence of insulin, nearly 20% of IR-GFP co-localized with transferrin. This suggests that slower recycling of apoE4 might trap IR in the endosomal compartment and impair its ability to bind insulin and trigger IR signaling at the cell surface.

Overall, the study found that apoE impairs signaling in an age-dependent manner and can be further accelerated by peripheral insulin resistance conditions. ApoE4 can also be responsible for several pathogenic effects of apoE4, including trapping functional receptors in non-productive compartments.

These findings show how the mechanisms are responsible for apoE isoform affect cerebral insulin signaling and how insulin-based prevention and therapy can be used for Alzheimer’s disease. So by understanding how apoE4 is a strong risk factor for cognitive decline, we can start to try to improve the way we treat Alzheimer’s disease by possibly treating with insulin.

Practice Pearls:

  • ApoE4 impairs cerebral insulin signaling in an age-dependent manner.
  • Both peripheral insulin resistance and apoE4 impair insulin signaling together.
  • Diabetes and impaired brain insulin are associated with development of Alzheimer’s disease.

Reference:

Zhao N, Liu C, Van Inglegom AJ, et al. Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes. Neuron. 2017 96(1); 115-129.e5.

 

Jessica Quach, Doctor of Pharmacy Candidate 2018, GA-PCOM School of Pharmacy