Alzheimer's disease (AD) etiological studies suggest that an elevation in amyloid-β peptides (Aβ) level contributes to aggregations of the peptide and subsequent development of the disease. The major constituent of these amyloid peptides is the 1 to 40–42 residue peptide (Aβ40？42) derived from amyloid protein precursor (APP). Most likely, reducing Aβ levels in the brain may block both its aggregation and neurotoxicity and would be beneficial for patients with AD. Among the several possible ways to lower Aβ accumulation in the cells, we have selectively chosen to target the primary step in the Aβ cascade, namely, to reduce APP gene expression. Toward this end, we engineered specific SOFA-HDV ribozymes, a new generation of catalytic RNA tools, to decrease APP mRNA levels. Additionally, we demonstrated that APP-ribozymes are effective at decreasing APP mRNA and protein levels as well as Aβ levels in neuronal cells. Our results could lay the groundwork for a new protective treatment for AD. 1. Introduction Alzheimer’s disease (AD) is a degenerative disorder of the human central nervous system (CNS). Its clinical and neuropathological features are defined by a progressive loss of cognitive function and by the onset of a slowly progressive impairment of memory during mid- to late-adult life. The neuropathological hallmarks of AD include the accumulation and aggregation of amyloid-β peptide (Aβ), neurofibrillary tangles, astrocytic gliosis, and reductions in the numbers of both neurons and synapses in many areas of the brain, particularly in the cerebral cortex and hippocampus [1]. Strong evidence from multiple studies suggests that defects in Aβ regulation are one of the central biochemical events leading to the development of AD [2]. The neurotoxic Aβ fragment originates from the amyloid protein precursor (APP) following sequential cleavages by β (BACE) and γ-secretases (presenilin complex). Observations on the physiological processing of APP and on the effects of pathogenic mutations in the APP and/or the presenilin genes have led to the hypothesis that aberrant processing of APP into Aβ peptides is linked to AD [3]. We have previously reported strong evidence indicating that the amyloid cascade is an early and critical event in the neurodegeneration associated with AD. For example, cell lines and/or transgenic mice expressing mutant presenilin 1 (PS1), presenilin 2 (PS2), or APP exhibit an accelerated rate of neurotoxic Aβ formation [4]. Thus, the three known genetic causes of familial AD affect Aβ metabolism. Moreover, the ε4 allele of apolipoprotein E, a
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