Heat Shock Protein 70 Participates in the Neuroprotective Response to Intracellularly Expressed β-Amyloid in Neurons

Intracellular beta-amyloid 42 (Abeta42) accumulation is increasingly recognized as an early event in the pathogenesis of Alzheimer's disease (AD). We have developed a doxycycline-inducible adenoviral-based system that directs intracellular Abeta42 expression and accumulation into the endoplasmic reticulum of primary neuronal cultures in a regulated manner. Abeta42 exhibited a perinuclear distribution in cell bodies and an association with vesicular compartments. Virally expressed intracellular Abeta42 was toxic to neuronal cultures 24 hr after induction in a dose-dependent manner. Abeta42 expression prompted the rapid induction of stress-inducible Hsp70 protein in neurons, and virally mediated Hsp70 overexpression rescued neurons from the toxic effects of intracellular Abeta accumulation. Together, these results implicate the cellular stress response as a possible modulator of Abeta-induced toxicity in neuronal cultures.