BACE inhibition-dependent repair of Alzheimer’s pathophysiology

Abstract

Significance The accumulation of amyloid-β (Aβ) proteins in the brain contributes to Alzheimer´s disease (AD). Reducing Aβ by inhibiting its production with a β-secretase (BACE) inhibitor represents a novel mechanism for treating AD; however, whether this therapeutic strategy is capable of repairing impaired brain circuits associated with AD is unknown. Here we demonstrate that BACE inhibition is beneficial to all levels of impairment in an AD mouse model: cellular, long-range circuitry, and memory. We provide evidence that the rescue is dependent on the reduction of soluble forms of Aβ surrounding amyloid plaques. These results have mechanistic and therapeutic implications for AD, including Aβ-related memory defects.