The effect of glucagon-like peptide-1 (GLP-1) receptor agonists on cell
      viability, ADAM10 maturation and the proteolysis of ADAM10 substrates in
      SH-SY5Y cells
Creators: name: Holmes, Sophie
Publisher: name: Lancaster University
Year: 2018
Subjects: APP
Alzheimer’s disease
ADAM-10
Exendin-4
Thapsigargin
NLGN-1
PrP

description: Arguably the causative agent of Alzheimer's disease (AD), amyloid
      beta (Aβ)- peptides, are generated by sequential proteolysis of the
      amyloid precursor protein (APP) by β- and γ-secretase activities.
      Alternatively, APP can be processed nonamyloidogenically by an α-secretase
      activity that cleaves within the Aβ-domain, precluding the formation of
      intact Aβ-peptides and liberating a neuroprotective fragment, sAPPα. This
      latter proteolytic event is catalysed by a disintegrin and
      metalloproteinase (ADAM) 10.
      
      Recent research has suggested that glucagon-like peptide-1 (GLP-1)
      analogues; Lixisenatide, Dulaglutide, Liraglutide, and Exenatide
      (Exendin-4), currently used to treat diabetes, may also be beneficial in
      the treatment of neurodegenerative conditions such as AD, as they have
      been shown to exert neuroprotective properties. Research has also
      suggested that one of these compounds, exendin-4, can enhance the amount
      of membrane-associated ADAM10.
      
      The current study, therefore, aims to determine firstly; whether GLP-1
      analogues can protect neuroblastoma, SH-SY5Y cells, against chemical
      stressors of relevance to AD and, secondly, whether these compounds alter
      ADAM10 maturation/activity and the proteolysis of the enzyme's
      substrates, APP, prion protein (PrP) and neuroligin1 (NLGN-1). Cells
      treated with hydrogen peroxide (as an oxidative stressor), cobalt chloride
      (as a hypoxic mimic), methylglyoxal (MG) or thapsigargin (TG) (as
      Endoplasmic Reticulum stressors) were co-treated with or without GLP-1
      analogues and cell viability was subsequently monitored along with the
      expression and proteolysis of ADAM10 and its substrates. The results of
      the study showed that the GLP-1 analogue, liraglutide, had no major effect
      in terms of protecting SH-SY5Y cells against any of the afore-mentioned
      chemical stressors. However, a second compound, exendin-4, was protective
      against TG-induced cytotoxicity. Thapsigargin impaired the proteolytic
      maturation of ADAM10 suggesting a decrease in the activity of the enzyme
      but exendin-4 was unable to reverse this effect. Nonetheless, exendin-4
      was able to partly reverse the inhibitory effect of TG on the expression
      of endogenous APP, and shedding of over-expressed NLGN1, and sAPPα in
      cells over-expressing APP695. Interestingly, TG caused an increase in
      expression of APP695, and an intracellular accumulation of PrP and,
      subsequently, did not alter the cell surface ADAM-mediated shedding of
      this protein.
      
      Collectively, these data indicate that liraglutide was ineffective in the
      protection of SH-SY5Y cells against the chemical stressors employed.
      However, exendin-4, is mildly protective against thapsigargin-mediated
      oxidative stress and is able to partly restore the TG-induced decrease in
      expression of endogenous APP, and shedding of APP695 and NLGN1. Unusually
      though, this latter effect was not associated with restored proteolytic
      maturation of ADAM10.