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Two AD-related markers, A-production and tau phosphorylation induced by IR, may be the upstream mechanisms of AD-related mitochondrial damage.159161 In addition, mitochondrial damage may be a contributing factor to the progression of diabetes to AD, as exposure to A Increases the vulnerability of brain mitochondria in diabetic rats.162 ER stress plays a complex role in the control of neuronal survival, amyloid cascade, neurodegeneration, and synaptic function in AD.163 In vitro, the abovementioned ER stress/JNK/IRS1 pathway was involved in A 1-42 oligomer-induced tau hyperphosphorylation, which may indicate that IR promotes the role of ER stress in AD.164 de la Monte et al suggested that in AD, a triangulated Mal-signaling network initiated by the brains insulin/IGF resistance is transmitted through the ceramides and ER stress homeostasis disorder, which in turn promotes IR.165 Studies have established that inflammation contributes to the pathogenesis of AD