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”.