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AATF Inhibits Aberrant Production of Amyloid β Peptide 1-42 by Interacting Directly with Par-4*

Aggregation of the neurotoxic amyloid β peptide 1-42 (Aβ-(1-42)) in the brain is considered to be an early event in the pathogenesis of Alzheimer's disease (AD). Par-4 (prostate apoptosis response-4) is a leucine zipper protein that is pro-apoptotic and associated with neuronal degeneration in AD. Overexpression of Par-4 significantly increased production of Aβ-(1-42) after initiation of apoptotic cascades, indicating factors regulating apoptotic pathways may also affect processing of β-amyloid precursor protein (APP). AATF (apoptosis-antagonizing transcription factor) was recently identified as an interaction partner of DAP-like kinase (Dlk), a member of the DAP (death-associated protein) kinase family. AATF antagonizes apoptosis induced by Par-4, suggesting that AATF might directly or indirectly participate in regulation of Par-4 activity. We now report that AATF colocalizes with Par-4 in both cytoplasmic and nuclear compartments, and it interacts directly and selectively with Par-4 via the leucine zipper domain in neural cells. Par-4 induced an aberrant production and secretion of Aβ in neuroblastoma IMR-32 cells after apoptotic cascades are initiated. Co-expression of AATF completely blocked aberrant production and secretion of Aβ-(1-42) induced by Par-4, and AATF/Par-4 complex formation was essential for the inhibitory effect of AATF on aberrant Aβ secretion. These results indicate that AATF is an endogenous antagonist of Par-4 activity and an effective inhibitor of aberrant Aβ production and secretion under apoptotic conditions.