Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques formed by accumulated Amyloid- beta peptide (A beta ) aggregates and neurofibrillary tangles, which are formed by aggregation of hypophosphorylated microtubule-associated protein TAU. We generated a new model of this disease by crossing existing A beta (CL2355) and TAU (BR5270, BR5271) pan-neuronal expressing transgenic strains of Caenorhabditis elegans. The lifespan and progeny viability of the double transgenic strain were significantly decreased compared with wild-type N2 (P<0.0001). We also observed that ectopic expression of these transgenes could interfere with neurotransmitter signaling pathways. Moreover, the double transgenic strain showed the most severe defects in chemotaxis associative learning when compared with other strains. In order to gain new insights into AD pathology mechanisms, we performed RNA-seq transcriptomic analysis. We observed 1053 genes to be regulated, of which 248 were up- and 805 were down-regulated in a comparison between the new AD model (UM0001, UM0002) and N2. Gene set enrichment analysis using David 6.7 indicated that up-regulated annotation clusters included UDP-Glucuronosyltransferase (5 genes, P<4.2E-4), PapD-like (4 genes, P<1.8E-2), aging (5 genes, P<8.1E-2) and down-regulated included nematode cuticle collagen (36 genes, P<1.5E-21), metabolic process (65 genes, P<1.9E-8). Comparing the list of regulated genes from C. elegans to the top 60 genes related to human AD confirmed an overlap of 9 genes: patched homolog 1, PTCH1 (
ptc-3), the Rab GTPase activating protein, TBC1D16 (
tbc-16), the WD repeat and FYVE domain-containing protein 3, WDFY3 (
wdfy-3), myosin IXA, MYO9A (
hum-7), ADP-ribosylation factor guanine nucleotide exchange factor 2, ARFGEF2 (
agef-1), Early B-cell Factor, EBF1 (
unc-3), D-amino-acid oxidase, DAO (
daao-1), glutamate receptor, metabotropic 1, GRM1 (
mgl-2), prolyl 4-hydroxylase subunit alpha 2, P4HA2 (
dpy-18 and
phy-2). Taken together, our C. elegans model provides insight on the fundamental toxic mechanisms underlying human AD and also provides some potential new therapeutic targets against TAU- and A beta -mediated proteotoxicity.