Role of insulin pathway in AD and PD progression
=> STK11, INSR
NeuroMMSig AD T2DM SNPs subgraph:
Comorbidity association of Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) by genetic variants of clusterin (CLU) and serine/threonine kinase 11 (STK11) genes: In the normal state (green color edges), insulin protein binds to its receptor insulin receptor and this binding event activates INSR through phosphorylation. The activated INSR binds to insulin-like growth factor 1 (IGF1) and activates insulin receptor substrate 1 (IRS1). Activated IRS1 activates the phosphoinositol signaling system which activates protein kinase B (AKT) signaling and controls glycogenesis. Activated INSR binding to IGF1 also activates Src homology 2 domain containing protein (SHC) and thereby activates the MAPK signaling pathway. In the disease state (red color edges), CLU promotes neuron apoptosis. Amyloid beta peptides bind to INSR, effectively preventing activation of INSR by insulin. As a consequence, through inactivation of the phosphoinositol signaling system, AKT signaling and mitogen-activated protein kinase (MAPK) signaling pathways, binding of APP peptides suppresses the insulin signaling pathway. The CLU single nucleotide polymorphisms (SNPs) are associated with an increased production of amyloid beta peptides and the CLU variants increase the risk of T2DM by primarily inducing the insulin resistance and secondly by decreasing the production of insulin. In the case of insulin resistance, the amount of INS is increased due to its accumulation in the blood. Normally under the condition of energy stress, STK11 activates adenosine monophosphate-activated protein kinase (AMPK) by phosphorylation and AMPK activation decreases Mechanistic target of rapamycin serine/threonine kinase (mTOR) signaling activity, thereby helping degradation of β-amyloid. In T2DM, the SNP rs8111699, which maps to the enhancer region of the STK11 gene, is influencing insulin sensitivity. The other SNP (rs741765) is located in the insulator region, which may block the interaction between the enhancer and promoter of the gene, resulting in downregulation of the STK11 gene. Deficiency and dysfunction of STK11 inhibits the AMPK phosphorylation, thereby reducing the activity of AMPK, which hyper-activates mTOR signaling in AD. Moreover, in T2DM, hyperactivation of mTOR signaling inhibits IRS1 via activation of S6K1 and the IRS1 inhibition leads to insulin resistance (linking the STK11 causal graph to the CLU graph), which leads to increase in INS and glucose in blood. The black colored arrows (up and down) indicate over- or underexpression of the nodes in diseased state; while dotted arrows are inferring the possible effect of genetic variants.
Cartoon of the candidate mechanism: