Neurofibrillary tangles and amyloid plaques are considered to be hallmarks of Alzheimer's disease (AD), and the toxic effects of amyloid-beta peptide (A beta) lead to activation of stress-related signaling and neuronal loss. The small heat shock protein Hsp27 is reported to be increased in AD brains and to accumulate in plaques, but whether this represents a potentially protective response to stress or is part of the disease process is not known. We hypothesized that increased expression of Hsp27 in neurons can promote neuronal survival and stabilize the cytoskeleton in the face of A beta exposure. By using neonatal rat cortical neurons, we investigated the potential role of Hsp27 in neuronal cultures in the presence or absence of A beta. We initially tested whether a heat stress (HS) would be sufficient to induce endogenous Hsp27 expression. HS not only did not result in neuronal Hsp27 up-regulation but made the cells more vulnerable to A beta exposure. We then used cDNA transfection to overexpress EGFP-Hsp27 (or the empty vector) in cultures and then assessed neuronal survival and growth. Transfected neurons appeared healthy and had robust neuritic outgrowth. A beta treatment induced significant cell death by 48-72 hr in nontransfected and empty-vector-expressing cultures. In contrast, cultures expressing Hsp27 did not display significant apoptosis. Our results show that Hsp27-expressing neurons were selectively protected against the deleterious effects of A beta treatment; neuronal degeneration was prevented, and A beta-induced alterations in mitochondrial size were attenuated. We also demonstrate that Hsp27 expression can enhance neurite growth in cortical neurons compared with control vector-transfected cells. Overall, our study provides new evidence that Hsp27 can provide a protective influence in primary cortical neurons in the face of toxic concentrations of amyloid.
(c) 2009 Wiley-Liss, Inc.