Aβ efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas

Impairment of vascular pathways of cerebral β-amyloid (Aβ) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aβ clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aβ co-deposits. LRP1-mediated Aβ transport across the blood-brain barrier and Aβ clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aβ deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aβ pathology

Mode of action of plant-derived natural insecticides

Most of the chemical insecticides are neurotoxic, acting on targets in the central nervous system such as the membrane ion channels (DDT, pyrethroids), the enzyme acetylcholinesterase (organophosphate, carbamate), and the receptors of neurotransmitters (avermectins, neonicotinoids). The recently introduced diamide group of insecticides target the novel ryanodine receptor in the nervous system. Since pests continue to evolve resistance to compounds currently in use, new compounds with new modes of action are needed. Natural products could be a promising source for novel pest control agents. The origin of many of the important insecticide classes is traceable to a natural source as in the case of pyrethroids, avermectins, spinosads, and neonicotinoids. Although insect control agents acting on targets other than the nervous system such as insect growth regulators (e.g., azadirachtin, JH analogues, ecdysone antagonists) have been developed, due to their lack of contact toxicity, they are not quite successful, but find a place in the integrated pest management. Recent progress in understanding the biology of insect olfaction and taste offers new strategies for developing selective pest control agents. Decalesides, recently discovered natural insecticides, represent a new class of plant-derived insecticides targeting the tarsal gustatory receptors. In this chapter, we focus on the toxicity and mode of action of natural insecticides