**5. Aβ and insulin resistance**

**Aβ depresses insulin signaling** Insulin resistance is recognized as a contributing factor in development of AD to the point that AD has been referred to as "type 3 diabetes" [4, 5]. This coincides with Aβ being a pathological hallmark of AD as Aβ contributes to insulin resistance [297]. Aβ oligomers are known impair insulin signaling in neurons [332] by competing with insulin for receptor binding sites [297] and studies have linked Aβ oligomers to decreased insulin receptor numbers [332].

Development of insulin resistance provides neurons with a dangerous dilemma as neurons rely on insulin signaling for Aβ clearance and inhibition of amyloidogenic processing. Insulin increases Aβ trafficking from the trans golgi-network leading to secretion [333]. Secretion of Aβ may be important in preventing neurodegeneration as intraneural Aβ accumulations have been found in brain regions prone to early AD in patients with mild cognitive impairment [334] and studies done with transgenic mice indicate that intracellular Aβ accumulation is an early event of the neuropathological phenotype [335-337]. Insulin signalling protects against Aβ toxicity [298] and inhibits GSK-3β activity [204] which, in addition to hyperphosphorylat‐ ing tau, promotes amyloidogenic APP cleavage [160, 338].

Insulin signaling pathways in the brain are complex and depend on a delicate balance of cell activity to function properly. Accumulation of Aβ perturbs this balance resulting in insulin resistance and formation of a vicious cycle as insulin signaling is no longer able to clear and regulate Aβ. As Aβ oligomers increase, insulin resistance worsens. This cycle is perpetuated by competition between insulin and Aβ as substrates for IDE.

**Insulin, Aβ and insulin degrading enzyme** IDE is responsible for insulin degradation but has also been shown to degrade Aβ peptides [339-341], a process known to be decreased in AD brains [318]. Studies have shown that increased insulin signaling can increase levels of IDE [44] which can be abolished by pharmacological inhibition of PI3K. Aβ can decrease PI3K activity, [342] and thus is able to prevent its own degradation. In cases of hyperinsulinemia, excess insulin blocks IDE binding sites which further diminishes Aβ degradation [115].

In summary, Aβ contributes to insulin resistance [297, 332] by occupying binding sites on insulin receptors [297] and is associated with decreased insulin receptor numbers in neurons [332]. Decreases in insulin signaling result in increased Aβ processing as well as activation of GSK-3β which promotes Aβ processing [160, 338]. Insulin signaling impairment also leads to decreased IDE, which is needed to degrade Aβ [339-341, 343]. IDE deficiencies are exacerbated in hyperinsulinemic conditions as IDE binding sites are overloaded with excess insulin and made unavailable for Aβ [115]. Lack of insulin signaling and IDE availability allows for continued accumulation of Aβ, further depression of insulin signaling systems, increased neuronal vulnerability and further neurodegeneration.

**Figure 3.** T2DM can lead to the induction of insulin resistance in the brain. (2) Reduction of insulin signaling in the brain increases the activities of GSK-3β and β secretases which (3) increase levels of toxic Aβ oligomers. Furthermore, (4) insulin resistance lowers the expression of Aβ-degrading IDE. (5) Reduced IDE then leads to increased Aβ and (6) accumulation of Aβ oligomers. T2DM also causes (7) hyperinsulinemia which exacerbates IDE deficiencies because (8) excess insulin occupies IDE binding sites rendering them unavailable for Aβ. The increased amyloidogenic processing that occurs in insulin resistance combined with decreased Aβ clearance by IDE results in a deleterious positive-feed‐ back cycle as (9) Aβ oligomers contribute to insulin resistance in the brain. As Aβ levels continue to rise, insulin resist‐ ance worsens leading to further production of the toxic peptide.
