Alzheimer''s disease (AD) is the most common type of dementia among elderly, but the mechanisms causing AD are still largely unknown. Cerebrovascular deposits of amyloid-beta (Ab) plaques and tau protein tangles have long been considered hallmarks of AD. However, although they are present in the brains of the diseased, it is becoming clear that the deposits themselves may not be toxic. On the contrary, these aggregates may provide a protective mechanism whereby the cell immobilizes toxic species of soluble Ab-oligomers. Ab is generated from cleavage of Ab precursor protein (APP). To understand the biology of APP, binding partners of APP binding protein 1 X11a (APPB1) was identified (Bredesen Lab, unpubl.), 22 of these with good homology to C. elegans proteins. In order to test these APPB1 binding proteins in an in vivo model, we RNAi inactivated these genes in a C. elegans model expressing human Ab42 in muscle, showing an age-related increase in Ab-aggregation and paralysis1. We found that inactivation of three of these genes dramatically alters toxicity in Ab-worms, but not in controls. Paralysis over time was greatly accelerated when these genes were inactivated and for one of the genes this was extremely severe. Interestingly, this gene also seems to play a role in the toxicity of protein aggregation in general, as is the case for several Ab-toxicity modulating genes, e.g.
hsf-1 and
hsp-70. When we inactivated the gene in a model for Parkinsons disease overexpressing a-synuclein in muscle cells, this lead to an increased formation of vesicles of a-synuclein, as previously reported in this model2. Complementing the RNAi analysis in the Ab-model, Western blots probed with anti-Ab42-antibody revealed large differences in the distribution of Ab-oligomers in RNAi treated animals compared to RNAi controls. We are currently investigating the Ab-distribution further using WB and immunostaining as well as investigating genetic pathways these candidate genes for Ab toxicity may operate in. 1: Link, C.D. 1995. PNAS 92: 9368-9372 2: van Ham, T.J. et al. 2008. PLoS Genet 4: 1-11.