Angiopoietin-1 and ανβ3 integrin peptide promote the therapeutic effects of L-serine in an amyotrophic lateral sclerosis/Parkinsonism dementia complex model

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult disorder of neurodegeneration that manifests as the destruction of upper and lower motor neurons. Beta-N-methylamino-L-alanine (L-BMAA), an amino acid not present in proteins, was found to cause intraneuronal protein misfolding and to induce ALS/Parkinsonism dementia complex (PDC), which presents symptoms analogous to those of Alzheimer’s-like dementia and Parkinsonism. L-serine suppresses the erroneous incorporation of L-BMAA into proteins in the human nervous system. In this study, angiopoietin-1, an endothelial growth factor crucial for vascular development and angiogenesis, and the integrin αvβ3 binding peptide C16, which inhibits inflammatory cell infiltration, were utilized to improve the local microenvironment within the central nervous system of an ALS/PDC rodent model by minimizing inflammation. Our results revealed that L-serine application yielded better effects than C16+ angiopoietin-1 treatment alone for alleviating apoptotic and autophagic changes and improving cognition and electrophysiological dysfunction, but not for improving the inflammatory micro-environment in the central nerve system, while further advances in attenuating the functional disability and pathological impairment induced by L-BMAA could be achieved by co-treatment with C16 and angiopoietin-1 in addition to L-serine. Therefore, C16+ angiopoietin-1 could be beneficial as a supplement to promote the effects of L-serine treatment.

Novel nano-carriers with N-formylmethionyl-leucyl-phenylalanine-modified liposomes improve effects of C16-angiopoietin 1 in acute animal model of multiple sclerosis

“…The prerequisite for leukocytes to enter the CNS is the disruption and inflammation of the BBB, which can be initiated by ROS (Pierson et al., 2018 ). Several agents that aim to suppress the infiltration of leukocytes and the activation of macrophages/microglia in the CNS have been developed as potential therapies for MS (Cai et al., 2018 ). The effects of the compounds of C16 and Ang-1 on CNS inflammatory-related diseases have been confirmed using a variety of animal models (Han et al., 2010 ; Aarts et al., 2017 ; Chen et al., 2019 ; Nakazato et al., 2020 ; Fu et al., 2021 ).…”

Co-Application of C16 and Ang-1 Improves the Effects of Levodopa in Parkinson Disease Treatment

“…The targets of C16 and Ang-1 are ανβ3 integrin and Tie2, respectively. 28 C16 can competitively inhibit integrin αvβ3 signaling and inflammatory cell binding to the endothelium, preventing leukocyte transmigration.Furthermore, it can also act as an ανβ3 integrin agonist and promote endothelial cell angiogenesis. 25 Ang-1 can maintain the integrity of endothelial cells, enhance the survival of endothelial cells, and alleviate blood vessel leakage by activating the Ang-1-Tie2 system.…”

Microbial BMAA and the Pathway for Parkinson’s Disease Neurodegeneration

“…BMAA administration to rats was able to reproduce the neuronal phenotype of ALS, concomitantly with a strong expression of proinflammatory cytokines (Michaelson et al, 2017). Remarkably, BMAA was able to promote the upregulation of Glial Fibrillary Acidic Protein (GFAP) and, consequently, an evident astrogliosis in a rat model of ALS-PDC (Cai et al, 2018). Also, BMAA triggered cytotoxic effects in a RAW246.7 cell line and in BV-2 microglial cells (Takser et al, 2016), which confers potential immunomodulatory capacity to this neurotoxin.…”