TY  - JOUR
AU  - Schlenzig, D.
AU  - Manhart, S.
AU  - Cinar, Y.
AU  - Willbold, D.
AU  - Funke, S. A.
AU  - Kleinschmidt, M.
AU  - Hause, G.
AU  - Schilling, S.
AU  - Demuth, H.-U.
TI  - Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. A driving force in different neurodegenerative disorders?
JO  - Biochemistry
VL  - 48
SN  - 0006-2960
CY  - Columbus, Ohio
PB  - American Chemical Society
M1  - PreJuSER-6518
SP  - 7072 - 7078
PY  - 2009
N1  - Record converted from VDB: 12.11.2012
AB  - N-Terminally truncated and pyroglutamate (pGlu) modified amyloid beta (Abeta) peptides are major constituents of amyloid deposits in sporadic and inherited Alzheimer's disease (AD). Formation of pGlu at the N-terminus confers resistance against cleavage by most aminopeptidases, increases toxicity of the peptides, and may seed Abeta aggregate formation. Similarly, the deposited amyloid peptides ABri and ADan, which cause a very similar histopathology in familial British dementia (FBD) and familial Danish dementia (FDD), are N-terminally blocked by pGlu. Triggered by the coincidence of pGlu-modified amyloid peptides and similar pathology in AD, FBD, and FDD, we investigated the impact of N-terminal pGlu on biochemical and biophysical properties of Abeta, ABri, and ADan. N-Terminal pGlu increases the hydrophobicity and changes the pH-dependent solubility profile, rendering the pGlu-modified peptides less soluble in the basic pH range. The pGlu residue increases the aggregation propensity of all amyloid peptides as evidenced by ThT fluorescence assays and dynamic light scattering. The far-UV CD spectroscopic analysis points toward an enhanced beta-sheet structure of the pGlu-Abeta. Importantly, changes in fibril morphology are clearly caused by the N-terminal pGlu, resulting in the formation of short fibers, which are frequently arranged in bundles. The effect of pGlu on the morphology is virtually indistinguishable between ABri, ADan, and Abeta. The data provide evidence for a comparable influence of the pGlu modification on the aggregation process of structurally different amyloid peptides, thus likely contributing to the molecularly distinct neurodegenerative diseases AD, FBD, and FDD. The main driving force for the aggregation is apparently an increase in the hydrophobicity and thus an accelerated seed formation.
KW  - Alzheimer Disease: metabolism
KW  - Amino Acid Sequence
KW  - Amyloid: chemistry
KW  - Amyloid: metabolism
KW  - Amyloid: ultrastructure
KW  - Circular Dichroism
KW  - Humans
KW  - Hydrogen-Ion Concentration
KW  - Microscopy, Electron
KW  - Molecular Sequence Data
KW  - Peptides: chemistry
KW  - Peptides: metabolism
KW  - Pyrrolidonecarboxylic Acid: metabolism
KW  - Solubility
KW  - Spectrophotometry, Ultraviolet
KW  - Amyloid (NLM Chemicals)
KW  - Peptides (NLM Chemicals)
KW  - Pyrrolidonecarboxylic Acid (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:19518051
UR  - <Go to ISI:>//WOS:000268175600035
DO  - DOI:10.1021/bi900818a
UR  - https://juser.fz-juelich.de/record/6518
ER  -