Abstract
A link between diabetes mellitus (DM) related islet amyloid polypeptide (IAPP) and Alzheimer’s disease (AD) related amyloid-β (Aβ) has been suggested in epidemiological and clinical studies. In 2017, proof for existing interaction between type 2 DM and AD on a molecular level was provided based on research carried out in experimental animal models. We assessed aging-related neurodegenerative lesions, i.e., misfolded proteins, associated with dementia such as hyperphosphorylated τ (HPτ), Aβ, α-synuclein (αS), and phosphorylated transactive DNA binding protein 43 (pTDP43) seen in the brain and IAPP seen in the pancreas in subjects with and without DM applying immunohistochemical techniques. HPτ in the brain and IAPP in the pancreas were observed in most subjects. The prevalence and the extent of all misfolded proteins increased with age but this increase was not influenced by DM. Interestingly the extent of misfolded proteins in the brain was higher in non-diabetics when compared with diabetics in demented. A significant correlation was observed between HPτ, Aβ, αS, and pTDP43, whereas IAPP showed no association with HPτ, Aβ, and αS. In subjects with DM, the extent of pTDP43 in brain correlated with the extent of IAPP in pancreas. Thus, there is no evidence of a link between AD-related pathology and DM in humans, whereas an association was found between pTDP43 and IAPP in DM. TDP43 is ubiquitously expressed in all organs but whether TDP43 is phosphorylated in other organs in DM or whether the phosphorylation of TDP43 is influenced by glucose metabolism is yet unknown.
Highlights
With aging misfolded proteins, i.e., hyperphosphorylated τ (HPτ), amyloid- (A), phosphorylated␣-synuclein (␣S), and phosphorylated transactive DNA-binding protein 43 are frequently observed in the human brain tissue [1]
We found that the incidence and the extent of HPτ, A, phosphorylated transactive DNA-binding protein 43 (pTDP43), ␣S, and islet amyloid polypeptide (IAPP) increased with age, independent of diabetes mellitus (DM)
A strong correlation was observed between HPτ, A, ␣S, and pTDP43 that is in line with the cross-seeding hypothesis, whereas lack of correlation between HPτ, A, ␣S, and IAPP argues against this molecular mechanism in development of these lesions
Summary
␣-synuclein (␣S), and phosphorylated transactive DNA-binding protein 43 (pTDP43) are frequently observed in the human brain tissue [1]. In excess, these proteins are associated with various age related neurodegenerative diseases. M. Leino et al / TDP43 and IAPP in Aged Subjects with DM these proteins is regionally predictable; a reliable assessment of the extent of the pathologies can be carried out [2, 6, 7]. Leino et al / TDP43 and IAPP in Aged Subjects with DM these proteins is regionally predictable; a reliable assessment of the extent of the pathologies can be carried out [2, 6, 7] All these proteins can be seen simultaneously in one and the same subject, i.e., mixed pathologies [8, 9]
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