Type 2 diabetes (T2DM), Alzheimer's disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer's disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD.

Human pancreatic islet amyloid polypeptide (hiApp) and beta amyloid (Aβ) can accumulate in Type 2 diabetes (T2D) and Alzheimer's disease (AD) brains and evidence suggests that interaction between the two amyloidogenic proteins can lead to the formation of heterocomplex aggregates. However, the structure and consequences of the formation of these complexes remains to be determined. The main objective of this study was to characterise the different types and morphology of Aβ-hiApp heterocomplexes and determine if formation of such complexes exacerbate neurotoxicity. We demonstrate that hiApp promotes Aβ oligomerization and formation of small oligomer and large aggregate heterocomplexes. Co-oligomerized Aβ42-hIAPP mixtures displayed distinct amorphous structures and a 3-fold increase in neuronal cell death as compared to Aβ and hIAPP alone. However, in contrast to hIAPP, non-amyloidogenic rat amylin (rIAPP) reduced oligomer Aβ-mediated neuronal cell death. rIAPP exhibited reductions in Aβ induced neuronal cell death that was independent of its ability to interact with Aβ and form heterocomplexes; suggesting mediation by other pathways. Our findings reveal distinct effects of IAPP peptides in modulating Aβ aggregation and toxicity and provide new insight into the potential pathogenic effects of Aβ-IAPP hetero-oligomerization and development of IAPP based therapies for AD and T2D. Epidemiological and clinical evidence suggests a strong association between Type 2 diabetes (T2D) and Alzheimer's disease (AD), with T2D patients having a significantly higher risk of developing AD compared to non-diabetic individuals 1-3. Both AD and T2D share common pathogenic markers including inflammation, oxidative stress, metabolic dysfunction and accumulation of the amyloidogenic proteins including beta amyloid (Aβ) and pancreatic islet amyloid polypeptide (IAPP or amylin) 4,5. Aβ is the main component of senile plaques in the AD brain 6. Similar to Aβ, human IAPP (hIAPP) containing deposits are observed in the T2D pancreas 7. The accumulation of aggregated Aβ or hIAPP in the brain and pancreas has been shown to be associated with cell dysfunction and death 8,9. Aβ is produced via the N-terminal proteolytic cleavage of amyloid precursor protein (APP) by BACE1 and at the C-terminus by γ-secretase, with the final Aβ length varying from 39 to 43 amino acids 10. Aβ42 is the central component of senile plaques observed in the AD brain and is considered the main neurotoxic form 11,12. hIAPP is cleaved from the pre-pro form of IAPP and subsequently converted into a 37-amino acid structure by pancreatic β-cell secretory granules 7. Mature hIAPP modulates insulin-sensitive glucose uptake and

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.

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