The aggregation of
misfolded proteins is a co
mmon feature underlying a wide range of age-related degenerative disorders, including Alzhei
mer鈥檚 and Parkinson鈥檚 diseases. A key aspect of understanding the
molecular origins of these conditions is to define the
manner in which specific types of protein aggregates influence disease pathogenesis through their interactions with cells. We de
monstrate how seleniu
m-enhanced electron
microscopy (SE-EM), co
mbined with to
mographic reconstruction
methods, can be used to i
mage, here at a resolution of 5鈥?0 n
m, the interaction with hu
man
macrophage cells of a
myloid aggregates for
med fro
m A尾
25鈥?6, a frag
ment of the A尾 peptide whose self-asse
mbly is associated with Alzhei
mer鈥檚 disease. We find that prefibrillar aggregates and
mature fibrils are distributed into distinct subcellular co
mpart
ments and undergo varying degrees of
morphological change over ti
me, observations that shed new light on the origins of their differential toxicity and the
mechanis
ms of their clearance. In addition, the results show that SE-EM provides a powerful and potentially widely applicable
means to define the nature and location of protein asse
mblies
in situ and to provide detailed and specific infor
mation about their partitioning and processing.
Keywords:
myloid+%CE%B2&qsSearchArea=searchText">amyloid 尾; neurodegeneration; cytotoxicity; microscopy&qsSearchArea=searchText">electron microscopy; macrophages&qsSearchArea=searchText">macrophages