β‐secretase inhibition prevents structural spine plasticity deficits in AppNL‐G‐F mice

Abstract

AbstractBackgroundBACE1‐inhibitor trials for the treatment of Alzheimer´s Disease (AD) have failed due to insufficient efficacy or side effects like cognitive worsening. However, the scientific evidence to date suggests that BACE1‐inhibition could be an effective preventative measure if applied early enough and in the correct dose. Preclinical studies have associated strong BACE1‐inhibition with decreased dendritic spine density in the cerebral cortex of wildtype mice (GFP‐M) only.MethodWe investigated dose‐dependent effects of BACE1‐inhibition on hippocampal dendritic spine dynamics in the APP knock‐in mouse line for the first time. We conducted in vivo two‐photon microscopy in the stratum oriens of hippocampal CA1 neurons in 3.5‐month‐old AppNL‐G‐FGFP‐M mice over 6 weeks to monitor the effect of Bace1 inhibition (NB‐360) in low and high doses on dendritic spine plasticity.ResultsStructural spine plasticity is already impaired in CA1 neurons in untreated AppNL‐G‐F mice of this early age. Interestingly, prolonged high‐dose but not low‐dose BACE1‐inhibition was found to enhance spine formation and did not cause spine loss as observed in wildtype control mice.ConclusionIn an early stage of amyloid pathology in a transgenic beta‐amyloid mouse model, BACE1‐inhibition successfully holds the progressive changes in dendritic spine plasticity in hippocampal CA1 neurons.