Studies On The Pharmacodynamics Of A Polypeptide Specifically Recognizing β-amyloid

Alzheimer’s disease is a kind of neurodegenerative disease that characterizedclinically by global cognitive dysfunction, especially memory loss. AD is the mostcommon form of dementia. The neuropathological hallmarks of AD are extracellular senileplaques (SP) formed by Aβ deposits, and intracellular neurofibrillary tangles (NFT)composed of an abnormally hyperphosphorylated and aggregated form of tau protein, andcerebral atrophy caused by neuronal loss, gliosis and inflammation. Aβ plays a key role inthe cascade process of AD. As a natural product of metabolism, Aβ is derived fromproteolytic processing of the amyloid precursor protein (APP) by means of BACE1(β-secretase) and γ-secretase, consisting of39to42amino acid. Increasing evidenceindicates that the oligomers aggregated from β-amyloid(Aβ) monomers are the majorcausative agent in Alzheimer’s disease. Soluble Aβ oligomers generated from theaggregation of Aβ monomer is the major cause of neurotoxicity, and oxidative stress andinflammation are strongly linked to the mechanism of cytotoxicity induced by Aβ.Up to now, although it remains uncertainty as to whether oxidative stress is involvedat the onset of AD, it is believed to play a significant role during disease progression,particularly in cellular and tissue damage that occurs throughout AD. In oxidative stressreaction, the toxic Aβ aggregates that formed in AD can induce the overproduction ofreactive oxygen species (ROS), which may damage a variety of types of biologicalmolecules including proteins, lipids and DNA. Lipid peroxidation itself can directlydestroy structural integrity of cell membranes and lead to apoptosis and even cell deathwhile the lipid peroxidation product malondialdehyde (MDA) is also neuronal toxic, and inparticular may cause protein modification and impair protein functions. On the other way,it has been reported that some endogenous enzymes that detoxify ROS were decreased inthe brain of AD. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) arethe two main antioxidant enzymes involved in cellular protection against damages inducedby free radical. Moreover, the aggregates of Aβ can activate microglia and induce theproduction of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-a) andinterleukins1beta (IL-1β), which may promote the inflammatory cascade in thedownstream. Therefore, inhibiting Aβ42-induced neurotoxicity, and reducingAβ42-induced oxidative stress and the production of proinflammatory cytokine areattractive therapeutic and preventive strategies in the development of disease-modifyingdrugs for AD. Previously, we isolated a peptide, XD3, whicn target Aβ monomer, from a ringpeptide library after three rounds of screening, enrichment and elution by phage displaytechnology. Under the foundation of previous study, here, the pharmacodynamics of XD3in vivo and in vitro was investigated.The results indicate that XD3dose-dependently attenuates Aβ42-induced cytotoxicityin SH-SY5Y neuroblastoma cells, reduces Aβ42-induced oxidative stress reaction bydecreasing the formation of reactive oxygen species (ROS) and glutathione disulfide(GSSG), increasing the level of glutathione, enhancing the activities of super oxidedismutase (SOD) and glutathione peroxidase (GSH-Px), and suppresses inflammationresponse via decreasing the release of proinflammatory cytokines TNF-α and IL-1β inmicroglia.Moreover, XD3could improve cognitive function in APP+PS1mice, suppress glialinflammation by reducing gliosis in microglia and astroglia, and reduce senile plaqueburden and oxidative stress in the brain of APP+PS1transgeneic mice.Overall, these results suggest that this peptide, which specifically targets Aβ, may bea promising therapeatic for patients exhibiting cognitive impairment and increasedAβ burden.