Disease Mechanism: A Biochemical View of How Alzheimer’s Disease and Type 2 Diabetes are Linked

Type 2 diabetes is caused by insulin resistance and lack of active insulin. Aβ oligomers have been associated with disrupted insulin signaling in the brain (Duarte et al., 2012). Impairment of the insulin signaling pathway has been linked to cognitive defects in Alzheimer’s patients (de la Monte, 2009). Aβ oligomers bind to the membrane surface, which removes the insulin receptors (IRs) at the synapses. This removal leads to stimulation of pro-apoptotic pathways activated by c-Jun N-terminal kinase (JNK) pathway. This activation phosphorylates insulin substrate-1 (IRS1) at Serine residue 636 (pIRS1-Ser636), which makes IRS1 inactive and suppresses insulin.

To counter this, the insulin signaling pathway down regulates oligomeric binding sites. Normal insulin function results in the binding of insulin to its receptor, which activates IRS1 by phosphorylating at Tyrosine residue 465 (pIRS1-Tyr465)(Kaminari et al.). This phosphorylation activates cell survival Akt/PKB kinase (Akt), which promotes insulin’s neurotrophic effects. In this state, Akt phosphorylates/ inactivates Glycogen Synthase Kinase-3β (GSK-3β), which is an enzyme associated with the hyper-phosphorylation of the Tau protein.

Figure 1. Kaminari et al. proposed mechanism for MMP-9’s neuroprotective function in inhibiting amyloid β mediated impairment of the insulin survival pathway (Kaminari et al.).

Insulin receptors located in the hippocampus are said to be responsible for insulin-induced enhancement of cognitive function in healthy humans (Biessels, G. & Reagan, L., 2015). This receptor is a heterotetrameric protein made up of two extracellular α‑subunits which are attributed to the insulin-binding domain, and two transmembrane β‑subunits (Biessels, G. & Reagan, L., 2015).

Figure 2. Insulin receptor signaling in the hippocampus of a healthy human (Biessels, G. & Reagan, L., 2015).

Healthy insulin receptor signaling starts with insulin crossing the highly selective blood-brain barrier (BBB), and binding to insulin receptors throughout the central nervous system (CNS), including the hippocampus. This activation modulates the phosphorylation state of IRS-1and autophosphorylation of the insulin receptor β-subunits follows. The phosphoinositide 3‑kinase (PI3K)–Akt pathway and the MAPK/ERK kinase (MEK)–extracellular signal-regulated kinase (ERK) pathway are stimulated, which contributes to insulin’s neurotrophic effects (Biessels, G. & Reagan, L., 2015).

In a study released in 2016, Luo et al. found that insulin affected the solubility and toxicity of amyloid-β and its aggregates. Aggregated insulin did not have a strong effect on amyloid-β aggregation. However, monomeric insulin immediately induced conformational transitions in monomeric amyloid-β. Their results showed that interactions between insulin and amyloid-β increased solubility of monomeric amyloid-β (Luo et al., 2016). Their findings also suggest that reduced insulin receptor binding might be caused by formation of  amyloid-β/insulin complexes that do not match the receptor binding site. Their observation lead them to suggest that Alzheimer’s disease may also contribute to the type 2 diabetes progression. Similar findings were recorded in 2014 by Liu et al. in their paper “Amyloid Beta-Derived Diffusible Ligands (ADDLs) Induce Abnormal Expression of Insulin Receptors in Rat Hippocampal Neurons” in which ADDLs induced conformational changes in insulin receptors, which made them unable to bind to insulin.

This leads us to now wonder about the possible treatments for Alzheimer’s disease patients who suffer from type 2 diabetes. A discussion on treatment options can be found on the page “Proposed Treatments for Alzheimer’s Disease Linked to Type 2 Diabetes”.

4 Replies to “Disease Mechanism: A Biochemical View of How Alzheimer’s Disease and Type 2 Diabetes are Linked

  1. Hi Aisha, a great and exhaustive summary of this really interesting disease interaction and well done website. You mentioned in your summary that “Their results showed that interactions between insulin and amyloid-β increased solubility of monomeric amyloid-β (Luo et al., 2016).” If I’m understanding correctly, this would indicate that insulin does not make the β-amyloid aggregates already present more soluble? If that’s the correct interpretation, then, perhaps, do you think intranasal insulin would be an effective prophylactic treatment? Or, at the very least, a treatment that could slow the progression of the disease? I didn’t know that neurons transported larger molecules like insulin, so that’s super interesting.

    1. Hello Matt,
      Thank you very much for your critique.
      Your interpretation is correct. Most of the literature I came across specified that insulin had increased the solubility of monomeric amyloid-β. Intranasal delivery of insulin has been shown to slow the progression of the disease, and in some cases recover some lost cognitive abilities. The insulin molecules are able to travel adjacent to the nerves for widespread distribution throughout the CNS.

  2. Hi Aisha, really interesting literature review. One thing I was wondering about is that you say that AB oligomers bind to the membrane which removes IR from the synapse. Do you know how this occurs mechanistically? Do the AB oligomers bind to a receptor (or ever IR) itself an induce a downstream signaling pathway that leads to the internalization of the IR receptor? Or is the effect due to signal that affects transcription and translation of the IR receptor? Or something else entirely! Thanks!

  3. Hi Aisha. You mentioned that insulin affected the solubility and toxicity of amyloid-β and its aggregates, but only in the monomeric form, not the aggregated form. I am wondering what causes insulin to aggregate and whether this is specific to type II diabetes or if any individual may develop insulin aggregates. It’s interesting that Luo et al. suggested that Alzheimer’s disease may also contribute to the type II diabetes progression, since in class, we talked about how type II diabetes may lead to Alzheimer’s, but we did not talk about the reverse relationship. Great theme page!

Leave a Reply

Your email address will not be published. Required fields are marked *