Administration of the recombinant analog of the pancreatic amyloid amylin, Pramlintide, has shown therapeutic benefits in aging and Alzheimer's disease (AD) models, both on cognition and amyloid-β (Aβ) pathology.
Our findings uncover a previously unknown function for the IAPP/Aβ cross-amyloid interaction and suggest that conversion of Aβ or IAPP into lysosome-targeted and easily degradable hetero-oligomers by heteroassociation with IAPP mimics could become a promising approach to specifically prevent amyloid-mediated inflammation in AD, T2D, or both diseases.
In humans, β-amyloid and islet amyloid polypeptide (IAPP, also known as amylin) aggregations are linked to Alzheimer's disease and type-2 diabetes, respectively.
The presence of both tau and Aβ inclusions in pancreatic β cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD.ANN NEUROL 2019;86:539-551.
However, when the concentration was high (10.24 μM), amylin lost the effects against the Aβ-induced cellular AD pathology and, together with Aβ, worsened tauopathy in neurons.
Such mechanisms include islet amyloid polypeptide (or amylin) deposition, co-localized with beta-amyloid and found in more abundance in the AD temporal cortex, blood-brain barrier breakdown and dysfunction, potentially related to pericyte degeneration, and disturbance of brain lymphatics, both in the glial lymphatic system and the newly discovered discrete central nervous system lymph vessels.
Additionally, amylin aggregates have been found in blood vessels and/or brain of patients with Alzheimer's disease, alone or co-deposited with β-amyloid.
Stratification by BMI classification, median fat mass, median HOMA-IR, median insulin, and median amylin were all metabolic or anthropometric factors which significantly interacted with sRAGE profiles within AD subjects.
Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer's disease (AD) biomarkers in the blood of AD mouse models and AD patients.
Herein, we examine the inhibitory effects of genistein on the aggregation of amyloid-β (Aβ, associated with Alzheimer's disease) and human islet amylin (hIAPP, associated with type 2 diabetes) and Aβ- and hIAPP-induced neurotoxicity using a combination of experimental and computational approaches.
Additionally, several critical gaps in the literature are discussed, such as our limited understanding of the amylin system during aging and in disease states, as well as complexities of amylin receptor signaling and of changing pathophysiology during AD progression that might underlie the seemingly conflicting or contradictory results in the amylin/AD literature.
Furthermore, both AD and T2D are amyloidogenic diseases, with abnormal aggregation of amyloid-β peptide (Aβ) and islet amyloid polypeptide (IAPP) respectively contributing to cellular death and disease pathogenesis.
SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7-9.3, p = 0.141; SNAP: HR = 3.1, 95% CI = 1.1-9.6; p = 0.046), but only SNAP was significantly different from the LL group.
Alzheimer's Disease (AD) and Type 2 diabetes mellitus (T2DM) are two incurable diseases both hallmarked by an abnormal deposition of the amyloidogenic peptides Aβ and Islet Amyloid Polypeptide (IAPP) in affected tissues.
Type 2 diabetes mellitus and Alzheimer's disease are characterized by the accumulation of fibrillar amyloid deposits consisting mainly of islet amyloid polypeptide (IAPP) and amyloid-β (Aβ), respectively.
With T2D being the risk factor for AD and the ability of IAPP to cross the blood-brain barrier, the coaggregation of Aβ and IAPP has been explored to understand the cross-talk between the two diseases.