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P4–016: Cellular prion protein protects against stress–induced amyloidogenic processing of the Alzheimer's amyloid precursor protein
Author(s) -
Parkin Edward T.,
Eckman Elizabeth A.,
Eckman Christopher B.,
Hussain Ishrut,
Watt Nicole T.,
Turner Anthony J.,
Hooper Nigel M.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1754
Subject(s) - senile plaques , peptide , amyloid precursor protein , intracellular , p3 peptide , chemistry , extracellular , amyloid precursor protein secretase , amyloid (mycology) , biochemistry of alzheimer's disease , cleavage (geology) , microbiology and biotechnology , protein precursor , endogeny , biochemistry , alzheimer's disease , biology , enzyme , medicine , pathology , disease , inorganic chemistry , paleontology , fracture (geology)
amyloid have deleterious effects on neuronal function and viability. To understand the role of different conformations of beta-amyloid in the disease process, we analyzed the neurotoxic features of well characterized fibrillar (Grace et al., 2002), and soluble oligomeric (Demuro et al., 2005) and ADDL (Lacor et al., 2004) forms of beta-amyloid in primary human cortical neurons in culture. The results show that different preparations of soluble beta-amyloid exert dissimilar effects on neuronal viability. Soluble beta-amyloid species appear to be targeted preferentially to synaptic sites as evident from triple colocalization of synaptophysin, PSD-95, and betaamyloid oligomer/ADDLs. Soluble beta-amyloid preparations induced a rapid reduction in mitochondrial membrane potential and intracellular ATP levels, and increased levels of activated caspase 3/7. These rapid changes are absent in fibrillar beta-amyloid treated cells. Oligomers induced significant cell loss by 24 hrs, while ADDLs at similar concentrations induced equivalent toxic changes over 5 to 7 days (5uM). Soluble beta-amyloid neurotoxicity was characterized by dramatic neuritic fragmentation and shrinking of cell bodies, consistent with neurotoxicity induced by sudden calcium influx (Demuro et al., 2005), possibly as a result of pore forming structures by soluble beta-amyloid species (Kayed et al., 2004). In contrast, the effect of fibrils was slower, requiring higher concentrations to produce a comparable effect on viability (20uM). Fibrils induced chronic dystrophic changes and neuritic retraction leading to progressive synaptic loss, consistent with the aberrant activation of focal adhesion signals involved in adaptive plasticity (Grace and Busciglio, 2003). These results indicate that beta-amyloid may promote neuronal dysfunction and degeneration by multiple mechanisms in the AD brain, therefore suggesting the development of a multi-modal therapeutic approach to reduce beta-amyloid-mediated neurotoxicity.