**8.2 Potential mechanisms of amylin-Aβ-induced toxicity in neurons and pancreatic β cells**

Several studies have showed that amyloid aggregates have been found to be associated with disruption of several cellular functions, including mitochondrial activity [83, 84], oxidative stress [85], receptor mediated functions [86, 87], disruption of Ca2+ homeostasis [88], and membrane depolarization and disorder [89]. Possibly there is a toxic interaction between Aβ and tau that together with insulin resistance participate in the progression of AD. Similarly, the accumulation of amylin in the brain and its ability to induce neurotoxicity and form "cross-seeding" aggregates with Aβ provide a role for this pancreatic amyloidogenic protein in neurodegeneration [89].

**221**

amyloid deposits in the brain.

*resistances, and finally cell death.*

**9. Conclusions**

**Figure 5.**

to prevent neurodegeneration [90, 95, 96].

more studies about this issue are needed.

*Diabetes Mellitus and Amyloid Beta Protein Pathology in Dementia*

On the other hand, it is likely that there is also a synergistic interaction between

Both in the animal models and in the clinical trials of AD, those drugs related to production of insulin have been observed or have focused on improving the mechanisms of insulin and improving the condition of patients with cognitive impairment [93]. Analogues of amylin, for example, pramlintide, have been used as adjunctive therapy with insulin for diabetes [94] and are also being evaluated for their ability

The advantages of studying therapies for T2D in diseases that occur with an insane process are evident. However, no one has questioned whether targeted therapies for dementias could be useful in the treatment of T2D. Immunotherapy targeting Aβ has been shown to improve blood glucose by increasing sensitivity to insulin [97, 98]. Thus, we believe that amyloid deposits as therapeutic targets could be key in the treatment of dementias and alterations in glucose metabolism. But

the accumulation of amylin in the pancreas and the insulin secretion decrease, which will lead to abnormalities in glucose metabolism, promoting the development of neurodegenerative diseases (**Figure 5**). It is suggested that amylin mediates neurotoxicity by crossing the blood-brain barrier and binding to its receptors [90–92]. This leads to the hyperamulinemia of insulin resistance and to the accumulation of

*Association between AD and T2D. Both AD and T2D present cellular loss and abnormal deposition of Aβ, tau, and amylin. These aggregates have the ability to promote the accumulation of amyloid by cross-seeding in neurons and pancreatic cells. The aggregation of amyloid deposits is favored by the presence of aggregates of tau and amylin, which in turn leads to oxidative stress, mitochondrial dysfunction, inflammation, insulin* 

*DOI: http://dx.doi.org/10.5772/intechopen.84473*

*Diabetes Mellitus and Amyloid Beta Protein Pathology in Dementia DOI: http://dx.doi.org/10.5772/intechopen.84473*

**Figure 5.**

*Amyloid Diseases*

ity of the PHF [72].

upon the fragment of the minimal filament (92–95 amino acids culminating in Glu391). The process of proteolysis in the asp-421 of tau favors in the beginning its polymerization, and the truncation in glu391 favors the stability and insolubil-

The incidence of both AD and T2D is increasing at an alarming rate at present and has become a major public health concern in many industrialized countries [73]. Many epidemiological studies have shown that diabetic individuals have a significantly higher risk of developing AD [74]. Recently, it has become increasingly recognized that there is an overlap between the pathology of AD and vascular dementia and cerebrovascular dysfunction plays a role not only in vascular dementia but also in AD [75]. Nevertheless, clinical observations suggest that the association is independent of vascular factors [76], which raises the possibility that diabetic conditions such as insulin resistance and hyperglycemia may affect the fundamental pathogenesis of AD. Many neuronal functions are affected by changes in the insulin signaling pathway; therefore diabetes mellitus may have an important

Another possible mechanism that has been involved is the **amyloid deposition** in islets composed primarily of islet amyloid polypeptide (IAPP or amylin) that is a common feature in T2D. IAPP amyloid deposition has been correlated with disease severity, reduced β-cell mass, the development of hyperglycemia, and islet inflammation. Similarly, Aβ plays a central role in synaptic dysfunction and in the cognitive deficiencies associated with AD pathogenesis [78]. Evidences from clinical and animal studies associate the pancreatic amyloid, amylin in mediating neuronal loss in AD, suggesting its role as a potential link between AD and T2D pathogenesis [79–81]. The presence of amyloid deposits in pancreas and brain has been demonstrated in patients with T2D, which can serve as seed to increase the aggregation of these deposits. This suggests that pancreatic IAPP can potentiate amyloid beta misfolding in patients with AD [81]. Previously, de la Monte and colleges, 2008, reported that IAPP enters the brain, augments Aβ misfolding, and associates with Aβ plaques, and plasma levels correlate with AD diagnosis [82]. Interestingly, amylin has been identified in human cerebrospinal fluid and brains of diabetic patients with vascular dementia or AD and nondiabetic patients with AD. Furthermore, co-localization of amylin and Aβ deposits was also observed in postmortem human brains [81]. Likewise, amylin deposits were observed in the temporal lobe gray matter in diabetic patients [79]. Therefore, the co-existence of Aβ and amylin in the brain suggests the potential ability of amylin to infiltrate the brain and induce

**8.2 Potential mechanisms of amylin-Aβ-induced toxicity in neurons and** 

Several studies have showed that amyloid aggregates have been found to be associated with disruption of several cellular functions, including mitochondrial activity [83, 84], oxidative stress [85], receptor mediated functions [86, 87], disruption of Ca2+ homeostasis [88], and membrane depolarization and disorder [89]. Possibly there is a toxic interaction between Aβ and tau that together with insulin resistance participate in the progression of AD. Similarly, the accumulation of amylin in the brain and its ability to induce neurotoxicity and form "cross-seeding" aggregates with Aβ provide a role for this pancreatic amyloidogenic protein in

**8.1 Amyloid formation is the pathological hallmark of T2D and AD**

role in the progression of AD ([77]; see **Figure 2**).

amyloid deposition in the brain [81].

**pancreatic β cells**

neurodegeneration [89].

**220**

*Association between AD and T2D. Both AD and T2D present cellular loss and abnormal deposition of Aβ, tau, and amylin. These aggregates have the ability to promote the accumulation of amyloid by cross-seeding in neurons and pancreatic cells. The aggregation of amyloid deposits is favored by the presence of aggregates of tau and amylin, which in turn leads to oxidative stress, mitochondrial dysfunction, inflammation, insulin resistances, and finally cell death.*

On the other hand, it is likely that there is also a synergistic interaction between the accumulation of amylin in the pancreas and the insulin secretion decrease, which will lead to abnormalities in glucose metabolism, promoting the development of neurodegenerative diseases (**Figure 5**). It is suggested that amylin mediates neurotoxicity by crossing the blood-brain barrier and binding to its receptors [90–92]. This leads to the hyperamulinemia of insulin resistance and to the accumulation of amyloid deposits in the brain.

Both in the animal models and in the clinical trials of AD, those drugs related to production of insulin have been observed or have focused on improving the mechanisms of insulin and improving the condition of patients with cognitive impairment [93]. Analogues of amylin, for example, pramlintide, have been used as adjunctive therapy with insulin for diabetes [94] and are also being evaluated for their ability to prevent neurodegeneration [90, 95, 96].

### **9. Conclusions**

The advantages of studying therapies for T2D in diseases that occur with an insane process are evident. However, no one has questioned whether targeted therapies for dementias could be useful in the treatment of T2D. Immunotherapy targeting Aβ has been shown to improve blood glucose by increasing sensitivity to insulin [97, 98]. Thus, we believe that amyloid deposits as therapeutic targets could be key in the treatment of dementias and alterations in glucose metabolism. But more studies about this issue are needed.
