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.
Highlights
Protein misfolding diseases (PMDs) comprise a broad spectrum of conditions, including Alzheimer’s (AD) and Parkinson’s disease (PD), dialysis-related amyloidosis and type two diabetes mellitus (T2DM) [45, 61]
In addition to amylin misfolding and deposition, a sizeable body of evidence has shown that other amyloidogenic proteins may have important roles in the pathogenesis of this chronic disease [10, 63, 69, 70]
In this study, we conducted a semiquantitative analysis to assess the immunoreactivity of four amyloidogenic proteins expressed in the pancreas: amylin, α-synuclein, tau and prion protein (PrP)
Summary
Protein misfolding diseases (PMDs) comprise a broad spectrum of conditions, including Alzheimer’s (AD) and Parkinson’s disease (PD), dialysis-related amyloidosis and type two diabetes mellitus (T2DM) [45, 61]. Martinez‐Valbuena et al acta neuropathol commun (2021) 9:64 polypeptide (IAPP)) in T2DM [12] Each of these disorders exhibits characteristic protein inclusions, in neurodegenerative diseases several lines of evidence have shown that the cooccurrence of other misfolded proteins related to either other neurodegenerative or nondegenerative (vascular or metabolic) conditions is a frequent event in the brains of these patients [15, 33, 34, 53, 56]. As our group previously demonstrated the presence of phosphorylated forms of α-synuclein in the pancreatic tissue of patients with synucleinopathies [39], as well as deposition of phosphorylated, truncated and oligomeric forms of tau and of Aβ in the pancreatic tissue of AD patients [40], we studied whether pancreatic β-cells of subjects with neurodegenerative diseases present cooccurrence of other misfolded proteins, as observed in the brain. We assessed the pancreatic expression of PrP in subjects with AD, PD, DLB or T2DM and its interaction, both in the pancreas and brain, with α-synuclein, tau, Aβ and amylin
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