The Alzheimer's disease (AD) is the most common neurodegenerative disorder and its symptoms include dementia, loss of memory and motor dysfunction. The main neuropathologic hallmarks of AD are the extracellular deposits of beta -amyloid (A beta ) plaques, insoluble aggregates of beta-amyloid peptide, and the intraneuronal fibrillary tangles, resulting from the hyperphosphorylation of the microtubule associated protein Tau. These aggregates both contribute to the loss of synapse functions and the consequent neuronal death. The major genetic risk factor in sporadic AD is represented by the E4 isoform of Apolipoprotein E (ApoE), ligand of the Low Density Lipoprotein-Related Proteins Receptors (LRPs), involved in a variety of functions, including cholesterol metabolism and cell signaling. LRPs intramembrane proteolysis is regulated by the ?-secretase cleavage and similarly the beta-amyloid peptide is the product of the Amyloid Precursor Protein (APP) ?-secretase cleavage. Moreover, Apo E affects A beta production and clearance and colocalizes with A beta in amyloid plaques. C.elegans presents the orthologs of human APP, ?-secretase presenilins and Tau (respectively
apl-1,
sel-12,
hop-1 and
ptl-1), and it has been extensively used to study AD, with several neurodegeneration models generated to investigate APP processing, A beta aggregation and Tau hyperphosphorylation. Neurodegeneration results in defects progressively increasing with aging, such as neuronal abnormalities (inclusions and varicosities in cell body), axonal degeneration (bulges, dilatation and collapse of axonal membrane), altered neurotransmission and uncoordinated movement (Kraemer et al., 2003). Considering the lack of informations about LRPs and its involvement in AD, we propose a new C.elegans model to study the correlation of human LRP8, the ApoE receptor, to APP and Tau. Several data led us to hypothesize that LRPs could affect APP processing and signaling (and vice versa) through ?-secretase, resulting in alteration of Tau phosphorylation levels. To test this hypothesis we generated transgenic worms expressing human LRP8 in all neurons and analyzed their phenotypes to determine whether LRP8 overexpression caused any defect similar to the one caused by Tau hyperphosphorylation or APP overexpression. Our preliminary results suggest that huLRP8 overexpression affects nematode locomotion, a defect that progressively worsen in aged worms, and lifespan. These results allow us to hypothesize an involvement of LRP8 in neuronal function and to investigate huLRP8 processing and its genetic interaction with APP.