Abstract
Type 2 diabetes (T2D) and Alzheimer’s disease (AD) are growing in prevalence worldwide. The development of T2D increases the risk of AD disease, while AD patients can show glucose imbalance due to an increased insulin resistance. T2D and AD share similar pathological features and underlying mechanisms, including the deposition of amyloidogenic peptides in pancreatic islets (i.e., islet amyloid polypeptide; IAPP) and brain (β-Amyloid; Aβ). Both IAPP and Aβ can undergo misfolding and aggregation and accumulate in the extracellular space of their respective tissues of origin. As a main response to protein misfolding, there is evidence of the role of heat shock proteins (HSPs) in moderating T2D and AD. HSPs play a pivotal role in cell homeostasis by providing cytoprotection during acute and chronic metabolic stresses. In T2D and AD, intracellular HSP (iHSP) levels are reduced, potentially due to the ability of the cell to export HSPs to the extracellular space (eHSP). The increase in eHSPs can contribute to oxidative damage and is associated with various pro-inflammatory pathways in T2D and AD. Here, we review the role of HSP in moderating T2D and AD, as well as propose that these chaperone proteins are an important link in the relationship between T2D and AD.
Highlights
Alzheimer’s disease (AD) and type 2 diabetes (T2D) are two of the most widespread age-related chronic diseases, and the prevalence of both is steadily increasing [1,2]
Co-oligomerized islet amyloid polypeptide (IAPP)–Aβ complexes exert enhanced toxicity to cells in the pancreatic islets than either IAPP or Aβ alone [52]. Considering both the critical role for heat shock proteins (HSPs) in protein folding and that they are expressed in response to misfolded or aggregated proteins, it stands to reason that these molecular chaperones have important roles as a response to aggregated Aβ/Tau in AD or IAPP in T2D
Neuroprotective effects of HSP60 have been demonstrated in a human neuroblastoma cell line, where the overexpression of HSP60 inhibited an Aβ-induced reduction of Cytochrome C Oxidase (COX) IV activity in the mitochondria, subsequently reducing apoptosis [117,120]
Summary
Alzheimer’s disease (AD) and type 2 diabetes (T2D) are two of the most widespread age-related chronic diseases, and the prevalence of both is steadily increasing [1,2]. Amyloidogenic peptides are associated with the development of T2D and AD through the formation of islet amyloid polypeptide (IAPP) and β-amyloid (Aβ), respectively [8,9,10] These two amyloidogenic peptides have similar methods of exerting toxicity involving membrane pore formation, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, and apoptosis [11,12]. Once co-localized, Aβ and IAPP may undergo a process called cross-seeding, where the aggregation and seeding of amyloidogenic peptides attract and aggregate with more similar and/or different types of amyloidogenic peptides [15,16] In this case, co-localized Aβ and IAPP may promote the formation of combined Aβ-IAPP oligomeric hetero-complexes [17,18,19]. We describe the potential roles for HSPs in AD and T2D pathogenesis
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