Amyloid-beta Protofibrils: Size, Morphology and Synaptotoxicity of an Engineered Mimic

• Structural and biochemical studies of the aggregation of the amyloid-beta peptide (A beta) are important to understand the mechanisms of Alzheimer's disease, but research is complicated by aggregate inhomogeneity and instability. We previously engineered a hairpin form of A beta called A beta cc, which forms stable protofibrils that do not convert into amyloid fibrils. Here we provide a detailed characterization of A beta(42)cc protofibrils. Like wild type A beta they appear as smooth rod-like particles with a diameter of 3.1 (+/- 0.2) nm and typical lengths in the range 60 to 220 nm when observed by atomic force microscopy. Non-perturbing analytical ultracentrifugation and nanoparticle tracking analyses are consistent with such rod-like protofibrils. A beta(42)cc protofibrils bind the ANS dye indicating that they, like other toxic protein aggregates, expose hydrophobic surface. Assays with the OC/A11 pair of oligomer specific antibodies put A beta(42)cc protofibrils into the same class of species as fibrillar oligomers of wild type A beta. A beta(42)cc protofibrils may be used to extract binding proteins in biological fluids and apolipoprotein E is readily detected as a binder in human serum. Finally, A beta(42)cc protofibrils act to attenuate spontaneous synaptic activity in mouse hippocampal neurons. The experiments indicate considerable structural and chemical similarities between protofibrils formed by A beta(42)cc and aggregates of wild type A beta(42). We suggest that A beta(42)cc protofibrils may be used in research and applications that require stable preparations of protofibrillar A beta.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biofysik (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biophysics (hsv//eng)

NATURVETENSKAP  -- Biologi -- Strukturbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Structural Biology (hsv//eng)

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

TEKNIK OCH TEKNOLOGIER  -- Industriell bioteknik -- Läkemedelsbioteknik (hsv//swe)

ENGINEERING AND TECHNOLOGY  -- Industrial Biotechnology -- Pharmaceutical Biotechnology (hsv//eng)

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