BACE inhibition-dependent repair of Alzheimer's pathophysiology.

Amyloid-ß (Aß) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aß is the ß-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aß levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aß surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aß, mechanistically linking Aß pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.

Rescue of long-range circuit dysfunction in Alzheimer's disease models.

Alzheimer's disease (AD) is associated with defects of synaptic connectivity. Such defects may not be restricted to local neuronal interactions but may extend to long-range brain activities, such as slow-wave oscillations that are particularly prominent during non-rapid eye movement (non-REM) sleep and are important for integration of information across distant brain regions involved in memory consolidation. There is increasing evidence that sleep is often impaired in AD, but it is unclear whether this impairment is directly related to amyloid-ß (Aß) pathology. Here we demonstrate that slow-wave activity is severely altered in the neocortex, thalamus and hippocampus in mouse models of AD amyloidosis. Most notably, our results reveal an Aß-dependent impairment of slow-wave propagation, which causes a breakdown of the characteristic long-range coherence of slow-wave activity. The finding that the impairment can be rescued by enhancing GABAAergic inhibition identifies a synaptic mechanism underlying Aß-dependent large-scale circuit dysfunction.

The potential role of c-Jun activation in patients with cutaneous lichen planus.

c-Jun, a component of the activating protein-1 transcription factor family, has been known to play an important role in the control of cell proliferation. It is also suspected to be a critical mediator of tumor promotion. However, investigations of c-Jun activation patterns in inflammatory and inflammatory transforming skin diseases have not been described so far. In this work, we show the c-Jun activation pattern in skin samples of patients with cutaneous lichen planus (LP), squamous cell carcinoma (SCC), psoriasis and normal skin using an immunohistochemical approach and Western blot analysis. In addition, we studied the c-Jun activation pattern in histological samples of three patients in whom LP transformed to SCC. We show that c-Jun is rarely activated in normal skin and psoriasis in contrast to LP and SCC. Our results suggest that c-Jun activation in human skin is involved in (1) proliferation and (2) could potentially participate in the transformation of LP from an inflammatory to a carcinogenic state. Nevertheless, JNK1/2, an important c-Jun activating kinase, was not found to be differentially regulated in LP and SCC compared with normal skin.