**6. Conclusion**

γ secretase to produce Aβ [301]. γ-secretase is a complex composed of at least 4 components: PS1 or PS2, nicastrin, anterior pharynx defective-1 (APH-1) and presenilin enhancer-2 (PEN-2) [327, 328]. βCTF cleavage by γ secretase produces either Aβ40 or Aβ42 peptides [301]. Aβ42 is the more hydrophic and amyloidogenic of the 2 species and makes up about 10% of Aβ produced [329]. An increased Aβ42/Aβ40 ratio has consistently been shown in fAD patients

**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

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‐

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

**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

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

insulin blocks IDE binding sites which further diminishes Aβ degradation [115].

suggesting that Aβ42 is critical to AD pathogensis [330, 331].

ing tau, promotes amyloidogenic APP cleavage [160, 338].

by competition between insulin and Aβ as substrates for IDE.

**5. Aβ and insulin resistance**

424 Understanding Alzheimer's Disease

insulin receptor numbers [332].

By 2050 it's estimated that over 100 million people worldwide will have AD [344] causing a substantial financial burden for health care systems. In that same time span, the annual cost of treating AD is predicated to exceed \$1 trillion in the United States alone [345]. These crippling social and economical effects place increased priority for advancement of AD research.

AD and T2DM also share commonality in the form of insulin resistance. Lack of insulin neurotrophic support in the brain leaves neurons defenseless against oxidative stress, Aβ toxicity and apoptosis. Aβ is especially dangerous to neurons because it further depresses insulin signaling and can alter levels of protective enzymes involved in its degradation such as IDE. AD is a disease that not only causes death in weakened cells but also further depresses

Alzheimer's Disease and Diabetes http://dx.doi.org/10.5772/54913 427

Because AD affects multiple structures and pathways, it is likely that successful treatment will involve a comprehensive battery of therapeutics rather than a single therapy. T2DM plays a major role in vascular abnormalities and insulin resistance which parallel AD pathologies. As a result, further exploration of the relationship between T2DM and AD may be a promising direction of future research. Moreover, preventative measures against T2DM such as proper diet and dedication to an active lifestyle may take center stage as a means of curbing the AD

2 Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB,

[1] Ott, A, et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neu‐

[3] Frolich, L, et al. A disturbance in the neuronal insulin receptor signal transduction in

[4] Rivera, E. J, et al. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in

[5] Steen, E, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? J Alzheimers Dis, (2005). ,

[2] Ritchie, K, & Lovestone, S. The dementias. Lancet, (2002). , 1759-1766.

sporadic Alzheimer's disease. Ann N Y Acad Sci, (1999). , 290-293.

acetylcholine. J Alzheimers Dis, (2005). , 247-268.

, Zaid Aboud1,2 and Gordon W. Glazner1,2

protective mechanisms making recovery unattainable.

1 St. Boniface Hospital Research Centre, Winnipeg, MB, Canada

epidemic.

Canada

**References**

63-80.

**Author details**

Brent D. Aulston1,2, Gary L. Odero1

rology, (1999). , 1937-1942.

**Figure 4.** Vascular hypothesis of AD. The vascular complications have been casually linked to the progression of AD. Vascular dysfunction resulting from type 2 diabetes results in a state of cerebral hypoperfusion, leading to significant energy depletion in the brain. Neurodegeneration results in cognitive impairments and ultimately AD.

While AD remains a disease of more questions than answers, a wide array of evidence suggests a close relationship between AD and T2DM. T2DM has been characterized as having both macrovascular and microvascular complications that result in CVD. It is the vasculature that provides the tangible pathological link between T2DM and AD. Significant data has been collected in favor of the vascular hypothesis of AD, which is founded on the idea that preexisting CVD sets into motion pathological cascades that ultimately result in AD.

AD and T2DM also share commonality in the form of insulin resistance. Lack of insulin neurotrophic support in the brain leaves neurons defenseless against oxidative stress, Aβ toxicity and apoptosis. Aβ is especially dangerous to neurons because it further depresses insulin signaling and can alter levels of protective enzymes involved in its degradation such as IDE. AD is a disease that not only causes death in weakened cells but also further depresses protective mechanisms making recovery unattainable.

Because AD affects multiple structures and pathways, it is likely that successful treatment will involve a comprehensive battery of therapeutics rather than a single therapy. T2DM plays a major role in vascular abnormalities and insulin resistance which parallel AD pathologies. As a result, further exploration of the relationship between T2DM and AD may be a promising direction of future research. Moreover, preventative measures against T2DM such as proper diet and dedication to an active lifestyle may take center stage as a means of curbing the AD epidemic.
