Journal
BIOCHEMISTRY
Volume 46, Issue 7, Pages 1913-1924Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi062177x
Keywords
-
Categories
Funding
- NIA NIH HHS [AG025649] Funding Source: Medline
Ask authors/readers for more resources
There is increasing evidence that a class of cell membrane glycolipids, gangliosides, can mediate the fibrillogenesis and toxicity of Alzheimer's disease amyloid-beta peptide (A beta). Using lipid monolayers and vesicles as model membranes, we measured the insertion of A beta into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-ganglioside G(M1) monolayers to probe A beta-G(M1) interactions, imaged the effects of A beta insertion on monolayer morphology, and measured the rate of A beta fibril formation when incubated with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)-G(M1) vesicles. Furthermore, the location of A beta association in the monolayer was assessed by dual-probe fluorescence experiments. A beta exhibited direct and favorable interactions with G(M1) as A beta insertion monotonically increased with G(M1) concentration, despite increases in monolayer rigidity at low G(M1) levels. At low G(M1) concentrations, A beta preferentially inserted into the disordered, liquid expanded phase. At higher G(M1) concentrations, A beta inserted more uniformly into the monolayer, resulting in no detectable preferences for either the disordered or condensed phase. A beta insertion led to the disruption of membrane morphology, specifically to the expansion of the disordered phase at low G(M1) concentrations and significant disruption of the condensed domains at higher G(M1) concentrations. During incubation with POPC vesicles containing physiological levels of G(M1), the association of A beta with vesicles seeded the formation of A beta fibrils. In conclusion, favorable interactions between A beta and G(M1) in the cell membrane may provide a mechanism for A beta fibrillogenesis in vivo, and A beta-induced disruption of the cell membrane may provide a pathway by which A beta exerts toxicity.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available