Key result
Deletion of flotillin 1 in APPPS1 mice resulted in a significant decrease in amyloid plaque formation to 76% of that measured in controls, with no further reduction in flotillin 1/2 double knockouts.
Absolute Event Rate: 76% vs 100%
Deletion of flotillin 1, with or without flotillin 2, leads to a small but significant reduction in Aβ levels and amyloid plaques in a mouse model of cerebral amyloidosis, suggesting a role for flotillins in APP processing.
Flotillin 1 deletion modestly attenuates plaques in APPPS1 mice; leaves open relevance to human Alzheimer's pathology.
Flotillin 1 and flotillin 2 associate in the plasma membrane to form microdomains that have roles in cell signaling, regulation of cell-cell contacts, membrane-cytoskeletal interactions, and endocytosis. They are thought to be involved in the trafficking and hence processing of the Amyloid Precursor Protein, APP. In this study we set out to obtain in vivo confirmation of a link between flotillins and cleavage of APP to release amyloidogenic Aβ peptide, and to generate tools that would allow us to ask whether flotillins are functionally redundant. We used a mouse model for Aβ-dependent cerebral amyloidosis, APPPS1 mice, combined with deletion of either flotillin 1 singly, or flotillin 1 and flotillin 2 together. There was a small but significant reduction in Aβ levels, and the abundance of congo-red stained plaques, in brains of 12 week old mice lacking flotillin 1. A similar reduction in Aβ levels was observed in the flotillin 1-/-, flotillin 2-/- double knockouts. We did not observe large effects on the clustering or endocytosis of APP in flotillin 1-/- mouse embryonic fibroblasts. We conclude that flotillins are likely to play some role in APP trafficking or processing, but the relevant cellular mechanisms require more investigation. The availability of flotillin 1-/-, flotillin 2-/- mice, which have no overt phenotypes, will facilitate research into flotillin function in vivo.
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Bitsikas et al. (2014) studied Aβ-dependent cerebral amyloidosis (Alzheimer's disease model). Deletion of flotillin 1 and/or flotillin 2 vs. Congenic control mice (APPPS1 with wild-type flotillins) was evaluated on Abundance of Congo Red stained amyloid plaques. Deletion of flotillin 1 in APPPS1 mice resulted in a significant decrease in amyloid plaque formation to 76% of that measured in controls, with no further reduction in flotillin 1/2 double knockouts.
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