Accumulation of cerebral amyloid-beta (Abeta) has been implicated as a putative causal factor in the development of Alzheimer's disease (AD). Transgenic mice like the PDAPP line overexpress human mutant Amyloid Precursor Protein (hAPP) and recapitulate many features of AD, including amyloid neuropathology and cognitive deficits. Inhibition of the beta-site aspartyl cleaving enzyme (BACE1) enzyme responsible for the first proteolytic cleavage that ultimately generates Abeta has been proposed as a strategy for AD therapy. To assess the theoretical repercussions of beta-secretase activity reduction in an in vivo model of AD, BACE1(-/-) mice bred to the PDAPP line were examined in a series of behavioral tasks. Although BACE1 gene ablation abolished hAbeta accumulation, BACE1(-/-) mice had unexpected sensorimotor impairments, spatial memory deficits, and displayed seizures, phenotypes which were severe on the PDAPP background. These results suggest that while excess Abeta is functionally pathological, BACE1-mediated processing of APP and other substrates play a role in "normal" learning, memory and sensorimotor processes.