Calpain-mediated cleavage of DARPP-32 in Alzheimer's disease.

Toxicity induced by aberrant protein aggregates in Alzheimer's disease (AD) causes synaptic disconnection and concomitant progressive neurodegeneration that eventually impair cognitive function. cAMP-response element-binding protein (CREB) is a transcription factor involved in the molecular switch that converts short-term to long-term memory. Although disturbances in CREB function have been suggested to cause memory deficits in both AD and AD animal models, the mechanism of CREB dysfunction is still unclear. Here, we show that the dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP-32), a key inhibitor of protein phosphate-1 (PP-1) that regulates CREB phosphorylation, is cleaved by activated calpain in both AD brains and neuronal cells treated with amyloid-ß or okadaic acid, a protein phosphatase-2A inhibitor that induces tau hyperphosphorylation and neuronal death. We found that DARPP-32 is mainly cleaved at Thr(153) by calpain and that this cleavage of DARPP-32 reduces CREB phosphorylation via loss of its inhibitory function on PP1. Our results suggest a novel mechanism of DARPP-32-CREB signalling dysregulation in AD.

The growth of a low defect InAs HEMT structure on Si by using an AlGaSb buffer layer containing InSb quantum dots for dislocation termination.

It is found that the surface migration and nucleation behaviors of InSb quantum dots on AlSb/Si substrates, formed by molecular beam epitaxy in Stranski-Krastanov (SK) growth mode, are dependent on the substrate temperature. At relatively high temperatures above 430 degrees C, quantum dots are migrated and preferentially assembled onto the surface steps of high defect AlSb layers grown on Si substrates, while they are uniformly distributed on the surface at lower temperatures below 400 degrees C. It is also found that quantum dots located on the defect sites lead to effective termination of the propagation of micro-twin-induced structural defects into overlying layers, resulting in the low defect material grown on a largely mismatched substrate. The resulting 1.0 microm thick Al(x)Ga(1-x)Sb (x = 0.8) layer grown on the silicon substrate shows atomically flat (0.2 nm AFM mean roughness) surface and high crystal quality, represented by a narrow full width at half-maximum of 300 arc s in the x-ray rocking curve. The room-temperature electron mobility of higher than 16 000 cm(2) V(-1) s(-1) in InAs/AlGaSb FETs on the Si substrate is obtained with a relatively thin buffer layer, when a low defect density ( approximately 10(6) cm(-2)) AlGaSb buffer layer is obtained by the proposed method.