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
Neprilysin (NEP) is the most important Aß-degrading enzyme. Its expression level decreases with age and inversely correlated with amyloid accumulation, suggesting its correlation with the late-onset of Alzheimer's disease. Recently, many reports showed that upregulating NEP level is a promising strategy in the prevention and therapy of Alzheimer's disease. Here, we used a sensitive fluorescence-based Aß digestion assay to screen 25 curcumin analogs for their ability to upregulate NEP activity. To our surprise, four compounds, dihydroxylated curcumin, monohydroxylated demethoxycurcumin, and mono- and di-hydroxylated bisdemethoxycurcumin, increased NEP activity, while curcumin did not. The ability of these polyhydroxycurcuminoids to upregulate NEP was further confirmed by mRNA and protein expression levels in the cell and mouse models. Finally, feeding monohydroxylated demethoxycurcumin (also named demethylcurcumin) or dihydroxylated bisdemethoxycurcumin (also named bisdemethylcurcumin) to APPswe/PS1dE9 double transgenic mice upregulated NEP levels in the brain and reduced Aß accumulation in the hippocampus and cortex. These polyhydroxycurcuminoids offer hope in the prevention of Alzheimer's disease.
Subject(s)
Alzheimer Disease/prevention & control , Amyloid beta-Peptides/metabolism , Curcumin/pharmacology , Neprilysin/biosynthesis , Up-Regulation/drug effects , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Peptides/genetics , Animals , Cell Line, Tumor , Curcumin/analogs & derivatives , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Neprilysin/geneticsABSTRACT
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.
