**7. Diabetes mellitus and amyloid-β protein pathology in Parkinson's disease**

Clinically, Parkinson's disease is defined as a progressive disorder characterized by resting tremor, rigidity, and bradykinesia; however, there may be other manifestations less constant such as postural instability, propulsive gait, dysphagia, autonomic disorders, sebaceous sweating, salivation, and deteriorating superior functions that can lead up to dementia. This disease was described in 1817 by James Parkinson, who described the deficiency of dopamine in the brain of his patients in late 1950 and also described the treatment of this disease with L-dopa in the 1960s. Parkinson's disease is the second most frequent neurodegenerative disorder. It is a motor disease related with the disorder of the basal ganglia specifically via nigrostriatal which is formed by the axons of the dopaminergic neurons of the substance compact nigra which innervate the corpus striatum. This structure is considered the main target of dopaminergic innervation due to the high density of axons it receives and its large size. The main symptoms of Parkinson's disease are caused by the degeneration of dopaminergic neurons via nigrostriatal [47, 48]. A pathological hallmark of Parkinson's disease is the Lewy bodies (LB), eosinophilic inclusions of α-synuclein (α-syn) located in the neuronal soma especially in nigra substance [49]. Besides the (LB) there can be deposits of the protein tau (MNF) and of β-amyloid (plaques).

There is existing evidence that α-syn, tau and Aβ act in a synergistic way in the pathology of AD and PD [50, 51] accelerating the aggregation of each [52]. The presence of tau and Aβ was found in patients with PD, and the cognitive function was lower than healthy patients' [53]. It has also been demonstrated that when these three proteins are found in high concentrations, as in PD, it generates changes in CFS tau levels [54], and if these patients are obese as well, they present insulin resistance [55, 56] even though they do not suffer from DM. These patients have deficits of cognitive functions. It is possible that the resistance to insulin accelerates the demential process in patients with PD, and it can lead to more serious motor symptoms.

As described before, insulin/IGF-1 activates the route PI3K/AKT/GSK3β, which, besides being involved in the glucose metabolism and the ingestion of food, also plays an important role in the learning and memory process associated with longterm potential (LTP) in the hippocampus [57]. Apparently, insulin stabilizes the production of dopamine and decreases the alterations in movement in a PD model [58–61]. When insulin acts over IR in a suitable way, the result is neuronal survival; however, the lack of insulin provokes that the GSK3β will not be inactivated (when it is phosphorylated in Ser9 by AKT), which leads to the favoring of the formation of MNF, LB, and amyloid plaques (see **Figure 2**). These pathological structures are found frequently coexisting in the hippocampus and cerebral cortex in patients

#### **Figure 3.**

*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.*

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 of GSK3β-pSer9 (**Figure 3**).

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.
