Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?

Rowles, Joanne; Keane, Kevin N.; Heck, Thiago Gomes; Cruzat, Vinícius Fernandes; Verdile, Giuseppe; Newsholme, Philip

doi:10.3390/ijms21218204

Cited by 12 publications

(6 citation statements)

References 166 publications

(230 reference statements)

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“…Intracellular HSPs (iHSPs) are critical in prevention of cell stress 51 and it has been shown that, in T2D, iHSP levels are reduced, possibly because the cell has reduced ability to export them extracellularly through the secretory process 51 . Increased extracellular HSPs can promote oxidative damage and are linked to pro-inflammatory pathways in T2D 52 . HSPD1 (HSP60), that increased at 2-h only in controls, has been associated with renal tubular dysfunction in diabetes through modulation of oxidative stress in accord with the functions of other HSPs 53 .…”

Section: Discussionmentioning

confidence: 99%

Impact of severe hypoglycemia on the heat shock and related protein response

Atkin

Moin

Nandakumar

et al. 2021

Sci Rep

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Heat shock proteins contribute to diabetes-induced complications and are affected by glycemic control. Our hypothesis was that hypoglycemia-induced heat shock and related protein changes would be amplified in type 2 diabetes (T2D). This prospective, case–control study enrolled 23 T2D patients and 23 control subjects who underwent hyperinsulinemic-induced hypoglycemia (≤ 2.0 mmol/L (36 mg/dl)) with blood sampling at baseline, at hypoglycemia and after a 24-h post-hypoglycemia follow-up period. Proteomic analysis of heat shock-related and pro-inflammatory proteins was performed. At baseline, MAPKAPK5 (p = 0.02) and UBE2G2 (p = 0.003) were elevated and STUB1 decreased (p = 0.007) in T2D. At hypoglycemia: PPP3CA (p < 0.03) was increased and EPHA2 (p = 0.01) reduced in T2D; by contrast, three proteins were reduced in controls [HSPA1A (p = 0.007), HSPB1 (p < 0.02), SMAD3 (p = 0.005)] while only MAPKAPK5 was elevated (p = 0.02). In the post-hypoglycemia follow-up period, most proteins normalized to baseline by 24-h; however, STIP1 (p = 0.003), UBE2N (p = 0.004) and UBE2L3 (p < 0.04) were decreased in controls at 24-h. No protein differed from baseline at 24-h in T2D. Pro-inflammatory interleukin-6 increased at 4-h post-hypoglycemia in controls and T2D (p < 0.05 and p < 0.003, respectively) and correlated with HSPA1A; anti-inflammatory IL-10 decreased 2-h post-hypoglycemia in T2D only. Other pro-inflammatory proteins, IL-1α, IFN-γ and TNF-α, were unchanged. Heat shock and related proteins differed at baseline between T2D and controls, with an exaggerated response of heat shock and related proteins to hypoglycemia that returned to baseline, though with changes at 24-h in controls alone. An increase in pro-inflammatory IL-6, with a decrease in anti-inflammatory IL-10, suggests that the HSP system is overactivated due to underlying inflammation in T2D.Trial registration: ClinicalTrials.gov NCT03102801.

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Section: Discussionmentioning

confidence: 99%

Impact of severe hypoglycemia on the heat shock and related protein response

Atkin

Moin

Nandakumar

et al. 2021

Sci Rep

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“…Moreover, HSP90 cooperates with the E3 ubiquitin ligase CHIP to target tau for proteasomal degradation [ 108 ]. Furthermore, HSP90 inhibits Aβ toxicity by binding misfolded Aβ peptides and preventing further aggregation using an ATP-independent pathway or by changing the conformation of Aβ to a state that is less prone to aggregation via an ATP-dependent pathway [ 109 ]. However, HSP90 levels are reduced in AD, especially in the hippocampus, entorhinal cortex, and cingulate gyrus, which are the most affected in AD [ 108 ].…”

Section: Alzheimer’s Diseasementioning

confidence: 99%

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

Argueti-Ostrovsky

Alfahel

Kahn

et al. 2021

Cells

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Multiple neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are being suggested to have common cellular and molecular pathological mechanisms, characterized mainly by protein misfolding and aggregation. These large inclusions, most likely, represent an end stage of a molecular cascade; however, the soluble misfolded proteins, which take part in earlier steps of this cascade, are the more toxic players. These pathological proteins, which characterize each specific disease, lead to the selective vulnerability of different neurons, likely resulting from a combination of different intracellular mechanisms, including mitochondrial dysfunction, ER stress, proteasome inhibition, excitotoxicity, oxidative damage, defects in nucleocytoplasmic transport, defective axonal transport and neuroinflammation. Damage within these neurons is enhanced by damage from the nonneuronal cells, via inflammatory processes that accelerate the progression of these diseases. In this review, while acknowledging the hallmark proteins which characterize the most common NDDs; we place specific focus on the common overlapping mechanisms leading to disease pathology despite these different molecular players and discuss how this convergence may occur, with the ultimate hope that therapies effective in one disease may successfully translate to another.

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“…A decrease in synaptic plasticity in AD individuals is one of the more noticeable ailments since it represents cognitive decline. Also, as a result of a decrease in synaptic plasticity, neuroinflammation activates and promotes tau accumulation [38]. Increased levels of FKBP51 in conjunction with age and stress are seen to rise in individuals with AD [19].…”

Section: Hsp90-la1011 Complexmentioning

confidence: 99%

“…Observations revealed that sleep deprivation led to a rise in core body temperature, suggesting a connection between sleep deprivation and Aβ production in AD [39]. Inflammatory environments in individuals with AD create a domino effect in the Hsps' response to antagonistic environments; inflammation downregulates Hsp production since the cell is incapable of managing the stress, increasing Aβ aggregates [38]. In disease conditions, Hsp90 has been shown to play a key role in aggregated protein processing and homeostasis.…”

Section: Temperature On Hsp90 Activitymentioning

confidence: 99%

Updates on Aβ Processing by Hsp90, BRICHOS, and Newly Reported Distinctive Chaperones

Iqbal,

Lewis,

Padhye

et al. 2023

Biomolecules

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Alzheimer’s disease (AD) is an extremely devastating neurodegenerative disease, and there is no cure for it. AD is specified as the misfolding and aggregation of amyloid-β protein (Aβ) and abnormalities in hyperphosphorylated tau protein. Current approaches to treat Alzheimer’s disease have had some success in slowing down the disease’s progression. However, attempts to find a cure have been largely unsuccessful, most likely due to the complexity associated with AD pathogenesis. Hence, a shift in focus to better understand the molecular mechanism of Aβ processing and to consider alternative options such as chaperone proteins seems promising. Chaperone proteins act as molecular caretakers to facilitate cellular homeostasis under standard conditions. Chaperone proteins like heat shock proteins (Hsps) serve a pivotal role in correctly folding amyloid peptides, inhibiting mitochondrial dysfunction, and peptide aggregation. For instance, Hsp90 plays a significant role in maintaining cellular homeostasis through its protein folding mechanisms. In this review, we analyze the most recent studies from 2020 to 2023 and provide updates on Aβ regulation by Hsp90, BRICHOS domain chaperone, and distinctive newly reported chaperones.

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Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?

Cited by 12 publications

References 166 publications

Impact of severe hypoglycemia on the heat shock and related protein response

Impact of severe hypoglycemia on the heat shock and related protein response

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

Updates on Aβ Processing by Hsp90, BRICHOS, and Newly Reported Distinctive Chaperones

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