**8. Diabetes mellitus and amylin and amyloid-β protein pathologies in Alzheimer's disease**

AD is one of the most prevalent dementias in older people and is characterized by the progressive loss of memory and deterioration of cognitive functions such as judgment and behavior [66]. AD develops through mutations in the chromosomes (presenilin 2), chromosome 14 (presenilin 1) and chromosome 21 (PPA) [67]. Only 5% of patients with AD associate to this genetic factor. It has an early appearance in people around 45 years old; however, the most common form of appearance of this neurodegenerative disease is "sporadic" where there are no mutations and it develops in people around 65 years [68]. There is still doubt regarding the genesis of sporadic AD; risk factors that can lead to the development of AD have been described. One of these risk factors is aging and poor eating habits where it involves ingesting large quantities of fat and sugar. Therefore, obesity is a risk factor for diabetes mellitus type 2.

**219**

*(SP8, Leica).*

**Figure 4.**

*Diabetes Mellitus and Amyloid Beta Protein Pathology in Dementia*

Histopathologically, the brains of these patients present in great abundance neuritic plaques (NP) and neurofibrillary tangles. (NFT) [69, 70]. Neuritic plaques are constituted by extracellular deposits of the fibrillar beta-amyloid peptide, and associated to these, dystrophic neurites (DN), neuritic plaques bordered by astroglial cells and associated with the amyloid peptide, the tight microglial cells can be observed (**Figure 4**). Together, they unleash the inflammatory cell process observed in a brain with AD [71]. NFT are constituted by highly soluble filaments (paired helical filaments, PHF) inside the neuronal soma. The PHF are constituted by tau protein; in normal conditions, tau protein favors the stability to the microtubules and the organelles and vesicles along the axon. The genesis of PHF has been associated with posttranslational mechanisms of tau protein as in hyperphosphorylation and truncation. Recent studies have suggested that the tau protein plays a dual role in protection and toxicity upon the neurodegenerative process and neuronal death. The phosphorylation of the tau protein could be involved in processes of neuronal protection to degeneration

*Characteristic lesions of a brain with Alzheimer's disease. (A) Neuritic plaque. Dystrophic neuritis (green and blue channels) are observed in the periphery of the Aβ deposit (red channel). (B) Neurofibrillary tangles recognized by antibodies directed against phosphorylated tau protein, in the vicinity there is a neurofibrillary tangle evidenced only in the red channel, the dystrophic neuritis in the periphery show different degrees of co-localization. (C) Neuritic plaque evidenced in the red channel, the nuclei are observed in blue color. The microglial cells are closely associated with the Aβ deposit (green channel). (D) Neuritic plaque in the periphery glial cells (blue channel) are observed. And in the channel see observed neuritic dystrophic positive tau protein. Double immunostaining with antibodies directed against the phosphorylated tau protein (A, B), IBA1 (C), and GFAP (D), counterstained with triazine red dye A-D and ToPro (C). Images taken with confocal microscope* 

*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*

*Amyloid Diseases*

**Figure 3.**

of GSK3β-pSer9 (**Figure 3**).

**Alzheimer's disease**

diabetes mellitus type 2.

with PD [62]. The negative regulation of GSK3β is extremely important in the neurodegenerative disorders such as PD [63] and even more in the function of α-syn, having as consequences cognitive deficits [64, 65] which include learning and memory alterations as well as executive functions. If this negative regulation of GSK3β does not happen due to the lack of insulin, then there will be a tau phosphorylation increase which will favor the accumulation of α-syn amyloid. These aggregates of α-syn have a positive feedback over the accumulation of phosphorylated tau and facilitate the formation of Aβ deposits. The accumulation of aβ and α-syn (amyloid) activates GSK3β, even though α-syn does so by inhibiting the formation

*GSK3β activation regulated by synergistic action of α-synuclein (α-syn), phosphorylated tau (pTau), and β-amyloid (Aβ). In the presence of insulin, a GSK3β inhibition occurs that has as a result, the improvement of long-term memory in the hippocampus. When there are alterations in the recognition of the insulin or there is simply no production, no GSK3β inhibitions occur which promoted the augmentation of α-sy, pTau, and Aβ aggregates which at the same time act synergistically, augmenting GSK3β activity. Therefore, cognitive deficits that include alterations in the learning and memory processes as well as executive functions are favored.*

It is possible that patients with DM-PD deteriorate rapidly due to the favoring of the accumulation of Aβ due to the lack of insulin, since this could generate more oxidative stress and thereby damage dopaminergic neurons. However, more studies are needed regarding the interaction between Aβ and α-syn in the demential

process of PD caused by the failure in recognition of insulin such as in DM2.

**8. Diabetes mellitus and amylin and amyloid-β protein pathologies in** 

AD is one of the most prevalent dementias in older people and is characterized by the progressive loss of memory and deterioration of cognitive functions such as judgment and behavior [66]. AD develops through mutations in the chromosomes (presenilin 2), chromosome 14 (presenilin 1) and chromosome 21 (PPA) [67]. Only 5% of patients with AD associate to this genetic factor. It has an early appearance in people around 45 years old; however, the most common form of appearance of this neurodegenerative disease is "sporadic" where there are no mutations and it develops in people around 65 years [68]. There is still doubt regarding the genesis of sporadic AD; risk factors that can lead to the development of AD have been described. One of these risk factors is aging and poor eating habits where it involves ingesting large quantities of fat and sugar. Therefore, obesity is a risk factor for

**218**

Histopathologically, the brains of these patients present in great abundance neuritic plaques (NP) and neurofibrillary tangles. (NFT) [69, 70]. Neuritic plaques are constituted by extracellular deposits of the fibrillar beta-amyloid peptide, and associated to these, dystrophic neurites (DN), neuritic plaques bordered by astroglial cells and associated with the amyloid peptide, the tight microglial cells can be observed (**Figure 4**). Together, they unleash the inflammatory cell process observed in a brain with AD [71]. NFT are constituted by highly soluble filaments (paired helical filaments, PHF) inside the neuronal soma. The PHF are constituted by tau protein; in normal conditions, tau protein favors the stability to the microtubules and the organelles and vesicles along the axon. The genesis of PHF has been associated with posttranslational mechanisms of tau protein as in hyperphosphorylation and truncation. Recent studies have suggested that the tau protein plays a dual role in protection and toxicity upon the neurodegenerative process and neuronal death. The phosphorylation of the tau protein could be involved in processes of neuronal protection to degeneration

#### **Figure 4.**

*Characteristic lesions of a brain with Alzheimer's disease. (A) Neuritic plaque. Dystrophic neuritis (green and blue channels) are observed in the periphery of the Aβ deposit (red channel). (B) Neurofibrillary tangles recognized by antibodies directed against phosphorylated tau protein, in the vicinity there is a neurofibrillary tangle evidenced only in the red channel, the dystrophic neuritis in the periphery show different degrees of co-localization. (C) Neuritic plaque evidenced in the red channel, the nuclei are observed in blue color. The microglial cells are closely associated with the Aβ deposit (green channel). (D) Neuritic plaque in the periphery glial cells (blue channel) are observed. And in the channel see observed neuritic dystrophic positive tau protein. Double immunostaining with antibodies directed against the phosphorylated tau protein (A, B), IBA1 (C), and GFAP (D), counterstained with triazine red dye A-D and ToPro (C). Images taken with confocal microscope (SP8, Leica).*

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 insolubility of the PHF [72].
