BACE inhibition-dependent repair of Alzheimer ́s pathophysiology

Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer ́s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE for which powerful inhibitors, already used in human clinical trials, have recently been developed. However, although BACE inhibition can reduce cerebral Aβ levels, it remains unclear whether it can also ameliorate neural circuit and memory impairments. By employing histochemistry, in vivo Ca2+-imaging and behavioral analyses in a mouse model of AD, we demonstrate that in addition to reducing pre fibrillary Aβ 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 Aβ, mechanistically linking Aβ pathology to neuronal and cognitive dysfunctions. These data highlight the potential benefits of BACE inhibition of the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments     «

Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer ́s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE for which powerful inhibitors, already used in human clinical trials, have recently been developed. However, although BACE inhibition can reduce cerebral Aβ levels, it remains unclear whether it can also ameliorate neural circuit and memory impairments. By employing histochemistry, in vivo Ca2+-imaging and behavioral analyses in a mous...     »