ABSTRACT
Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid ß (Aß) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti-amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aß amyloid (for sequence recognition) was designed. The efficacy of the designed peptide, R8-Aß(25-35), on amyloid reduction and the improvement of cognitive functions were evaluated using APP/PS1 double transgenic mice. Daily intranasal administration of PEI-conjugated R8-Aß(25-35) peptide significantly reduced Aß amyloid accumulation and ameliorated the memory deficits of the transgenic mice. Intranasal administration is a feasible route for peptide delivery. The modular design combining polyR and aggregate-forming segments produced a desirable therapeutic effect and could be easily adopted to design therapeutic peptides for other proteinaceous aggregate-associated diseases.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/therapeutic use , Brain/drug effects , Cognitive Dysfunction/drug therapy , Peptide Fragments/therapeutic use , Peptides/therapeutic use , Administration, Intranasal , Alzheimer Disease/complications , Alzheimer Disease/pathology , Amyloid/antagonists & inhibitors , Amyloid/ultrastructure , Amyloid beta-Peptides/administration & dosage , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/ultrastructure , Animals , Brain/pathology , Cell Line , Cognition/drug effects , Cognitive Dysfunction/complications , Cognitive Dysfunction/pathology , Disease Models, Animal , Female , Memory Disorders/complications , Memory Disorders/drug therapy , Memory Disorders/pathology , Mice, Inbred C57BL , Peptide Fragments/administration & dosage , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/chemistry , Peptide Fragments/ultrastructure , Peptides/administration & dosage , Peptides/chemistryABSTRACT
Amyloid-ß (Aß) aggregation in the brain plays a central and initiatory role in pathogenesis and/or progression of Alzheimer's disease (AD). Inhibiting Aß aggregation is a potential strategy in the prevention of AD. A scavenger peptide, V24P(10-40), designed to decrease Aß accumulation in the brain, was conjugated to polyethylenimine (PEI) and tested as a preventive/therapeutic strategy for AD in this study. This PEI-conjugated V24P(10-40) peptide was delivered intranasally, as nasal drops, to four-month-old APP/PS1 double transgenic mice for four or eight months. Compared with control values, peptide treatment for four months significantly reduced the amount of GdnHCl-extracted Aß40 and Aß42 in the mice's hippocampus and cortex. After treatment for eight months, amyloid load, as quantified by Pittsburgh compound B microPET imaging, was significantly decreased in the mice's hippocampus, cortex, amygdala, and olfactory bulb. Our data suggest that this intranasally delivered scavenger peptide is effective in decreasing Aß accumulation in the brain of AD transgenic mice. Nasal application of peptide drops is easy to use and could be further developed to prevent and treat AD.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides , Peptide Fragments , Polyethyleneimine/administration & dosage , Administration, Intranasal , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Amyloid beta-Peptides/administration & dosage , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Aniline Compounds/pharmacokinetics , Animals , Benzothiazoles/pharmacokinetics , Cell Line, Tumor , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Mutation/genetics , Neuroblastoma/pathology , Peptide Fragments/administration & dosage , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Positron-Emission Tomography , Presenilin-1/genetics , Thiazoles/pharmacokineticsABSTRACT
This work describes the syntheses, crystal structures, photophysical properties, and electro-chemical analyses of benzo[k]fluoranthene-based linear acenes, together with ab initio density functional theory computations on them. The molecules were prepared in generally moderate to good yields through Pd-catalyzed cycloadditions between 1,8-diethynylnaphthalene derivatives and aryl iodides. This protocol is simpler and more efficient than conventional methods. The scope and limitations of this reaction were examined. The structures of compounds 4hb, 15ac, 17ab, 19ac, and 24je were determined by X-ray analysis; they are either bent or twisted, rather than planar. The photophysical and electrochemical properties of these cycloadducts were also investigated and compared with computational predictions based on density functional theory.
