Cerebral insulin, insulin signaling pathway, and brain angiogenesis

Abstract

Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

MiR-199a-5p regulates sirtuin1 and PI3K in the rat hippocampus with intrauterine growth restriction

“…Thus, our results were consistent with those of previous experiments. Previous studies have demonstrated that the PI3K/Akt signalling pathway and TNF-α played vital roles in neural development 41 , 42 . Some studies also have shown that miR-199a-5p can regulate PI3K and TNF-α.…”

Integrating insulin-like growth factor 1 and sex hormones into neuroprotection: Implications for diabetes

“…Similar to IGF1, insulin is involved in modifying BBB permeability in the brain[ 55 ] with T2D patients showing greater permeability of the BBB[ 67 ]. Insulin also acts on the PI3K and MAPK signaling cascades to enhance neuronal survival, plasticity, and subsequent cognitive processes[ 55 , 68 , 69 ]. With that said, insulin does not necessarily regulate glucose activity in neuronal cells after entering the brain.…”

Axonal Transport Of An Insulin-Like Peptide Mrna Promotes Stress Recovery InC. Elegans

“…The inability to recover from stress predisposes us to many neurological dysfunctions, such as post-traumatic brain injuries and neurodegeneration [reviewed in (Blázquez et al, 2014;Esch et al, 2002;Frey, 2013;Koenen et al, 2008;Zeng et al, 2016)]. Here we use the worm C. elegans to elucidate the mechanisms of stress adaptation and recovery, since the worm can switch its the nerve ring (NR) bundle ( Figure S1A), where the axons synapse to each other (White et al, 1986).…”

“…physiological state in response to stress [reviewed in (Riddle and Albert, 1997)]. Like in humans [(Blessing et al, 2017;Marcovecchio and Chiarelli, 2012); reviewed in (Bedse et al, 2015;Blázquez et al, 2014;Boucher et al, 2014;Frey, 2013;Zeng et al, 2016)], insulin-like peptides (ILPs) and their receptor enable the worms to endure and recover from stress (Kimura et al,…”