Mixed pathologies in pancreatic β cells from subjects with neurodegenerative diseases and their interaction with prion protein

Abstract

Protein misfolding diseases refer to a variety of disorders that develop as a consequence of the misfolding of proteins in various organs. The etiologies of Parkinson’s and Alzheimer’s disease remain unclear, but it seems that type two diabetes and other prediabetic states could contribute to the appearance of the sporadic forms of these diseases. In addition to amylin deposition, other amyloidogenic proteins implicated in the pathophysiology of neurodegenerative diseases could have important roles in the pathogenesis of this disease. As we have previously demonstrated the presence of α-synuclein deposits in the pancreas of patients with synucleinopathies, as well as tau and Aβ deposits in the pancreatic tissue of Alzheimer’s disease patients, we studied the immunoreactivity of amylin, tau and α-synuclein in the pancreas of 138 subjects with neurodegenerative diseases or type two diabetes and assessed whether the pancreatic β-cells of these subjects present cooccurrence of misfolded proteins. Furthermore, we also assessed the pancreatic expression of prion protein (PrP) in these subjects and its interaction, both in the pancreas and brain, with α-synuclein, tau, Aβ and amylin. Our study shows, for the first time, that along with amylin, pancreatic α-synuclein, Aβ, PrP and tau may contribute together to the complex pathophysiology of type two diabetes and in the appearance of insulin resistance in Alzheimer’s and Parkinson’s disease. Furthermore, we show that the same mixed pathologies that are observed in the brains of patients with neurodegenerative diseases are also present outside the nervous system. Finally, we provide the first histological evidence of an interaction between PrP and Aβ, α-synuclein, amylin or tau in the pancreas and locus coeruleus. These findings will shed more light on the common pathological pathways shared by neurodegenerative diseases and type two diabetes, benefiting the exploration of common therapeutic strategies to prevent or treat these devastating amyloid diseases.

Genetic Depletion of Amylin/Calcitonin Receptors Improves Memory and Learning in Transgenic Alzheimer’s Disease Mouse Models.

“…Amylin (IAPP) is being increasingly viewed as a "second amyloid" with its identi cation in AD brains and particularly those AD patients with a history of diabetes mellitus (24,25). However, we did not observe any overt systemic effects of AMY/CTR reduction in either HetCTR or HetCTR + 5xFAD compound Tg mice; body weight and blood glucose levels did not change in either of the two strains of aged mice.…”

Molecular Mechanisms of Amylin Turnover, Misfolding and Toxicity in the Pancreas

“…Along this notion, several epidemiological studies have insinuated crosstalk between brain and islet amyloid proteins, as well as a common ethological link between T2DM and neurodegenerative diseases, such as AD and PD [ 144 , 145 , 146 , 147 ]. Additionally, it is becoming increasingly clear that both hIAPP and Aβ share similar aggregation and toxic features, thus indicating common pathogenic mechanisms (reviewed in Reference [ 148 ]).…”

“…Recently, Martinez-Valbuena and colleagues, using 138 subjects with neurodegenerative diseases or T2D, demonstrated increased immunoreactivity of IAPP, α-Syn, tau and prion protein in pancreatic cells of these subjects, as compared to controls. This indicates the possible contributory roles of these proteins toward the complex pathophysiology of T2DM and in the development of insulin resistance in AD and PD [ 145 ]. Although the detailed mechanism is not clear, cross-seeding between IAPP and Aβ/α-Syn has been proposed as the link [ 137 ].…”

“…From these reconstituted and in vivo studies, it became clear that the presence of hIAPP can stimulate α-Syn and Aβ-aggregation and possibly amyloid plaque formation in the brain. This observation may explain why T2DM patients are susceptible to developing PD and AD [ 144 , 145 , 146 , 147 ]. Interestingly, a recent study identified α-Syn as a component of islet amyloid extracted from human IAPP transgenic mice and T2D individuals [ 150 ].…”

“…It has been reported that α-Syn strains are determined by species of misfolded seeds, intracellular environments and protein–protein interactions [ 151 , 152 ]. Accordingly, the study by Martinez-Valbuena et al (2021) demonstrated the presence of different forms of α-Syn in pancreatic β-cells of subjects with neurodegenerative diseases or T2D [ 145 ], indicating the existence of a complex network of cross-reactivity between islet and brain amyloid proteins. Mechanistically, it has been proposed that the initial formation of misfolded α-Syn occurs in the gut and then spreads to the brain via peripheral autonomic nerves, thus affecting several other organs, including the heart and intestine [ 153 ].…”