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 have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aβ levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca 2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary 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 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.A lzheimer´s disease (AD) is the most common cause of dementia globally, with an increasing impact on aging societies (1). Therefore, the prevention and treatment of AD is a major unmet medical need. The amyloid hypothesis posits that the abnormal accumulation of amyloid-β (Aβ) peptides in the brain, and their aggregation, is an essential feature of AD (2, 3); however, results from clinical studies using several Aβ-targeting compounds have called into question the existence of a direct link between a reduction in Aβ and improvement of brain function, particularly in more advanced disease stages (4-6). In addition, recent evidence obtained in mouse models carrying genetic mutations that cause AD in humans revealed that immunotherapy with antibodies against Aβ worsened rather than reversed neuronal dysfunction (7). Despite reducing plaque burden, the anti-Aβ antibodies caused a massive increase in cortical hyperactivity and promoted abnormal synchrony of neurons in a subset of the treated mice. In this context, it is noteworthy that another recent mouse study found an increased risk of sudden death after anti-Aβ antibody treatment, which was attributed to enhanced excitatory neuronal activity culminating in fatal convulsive seizures (8).To clarify the causal relationship between Aβ and pathophysiology in vivo, we made use of a novel compound that reduces Aβ by inhibiting the β-secretase BACE, the rate-limiting enzyme for Aβ production (9). This approach allowed us to determine how the inhibition of Aβ production affects neural circuit and memory impairments in APP23xPS45 transgenic mice overexpressing mutant human amyloid precursor protein (APP) and presenilin 1 (PS1). The combination of histochemistry, in vivo Ca 2+ imaging, and behavioral analysis allowed us to directly link the treatment-related changes in brain Aβ levels to changes in neuronal and cognitive functions in individual mice. ResultsIn this study, we used 6-to 8-mo-old APP23xPS45 transgenic mice that exhibit severe cerebral Aβ pathology, neur...

Among the most promising approaches for treating Alzheimer's disease is immunotherapy with amyloid-β (Aβ)-targeting antibodies. Using in vivo two-photon imaging in mouse models, we found that two different antibodies to Aβ used for treatment were ineffective at repairing neuronal dysfunction and caused an increase in cortical hyperactivity. This unexpected finding provides a possible cellular explanation for the lack of cognitive improvement by immunotherapy in human studies.

Hyperactivity mediated by synaptotoxic β-amyloid (Aβ) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer’s disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aβ peptides prior to Aβ plaque formation. We demonstrate that an Aβ binding anticalin protein (Aβ-anticalin) can suppress early neuronal hyperactivity. Unexpectedly, the sole targeting of Aβ monomers was sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin. Biochemical and neurophysiological analysis suggest that Aβ-anticalin-dependent depletion of naturally secreted Aβ monomers interrupts aggregation to neurotoxic oligomers and, thereby, prevents synaptic dysfunction. Our results demonstrate that Aβ monomer scavenging can reverse early neuronal dysfunction and, thus, offers a promising strategy for the preventive treatment of AD.