Alzheimer's therapy targeting the β-secretase enzyme BACE1: Benefits and potential limitations from the perspective of animal model studies.
Accumulating evidence points to the amyloid-β (Aβ) peptide as the culprit in the pathogenesis of Alzheimer's disease (AD). β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a protease that is responsible for initiating Aβ production. Although precise mechanisms that trigger Aβ accumulation remain unclear, BACE1 inhibition undoubtedly represents an important intervention that may prevent and/or cure AD. Remarkably, animal model studies with knockouts, virus-delivered small interfering RNAs, immunization and bioavailable small-molecule agents that specifically inhibit BACE1 activity strongly support the idea for the therapeutic BACE1 inhibition. Meanwhile, a growing number of BACE1 substrates besides APP uncover new physiological roles of this protease, raising some concern regarding the safety of BACE1 inhibition. Here, I review recent progress in preclinical studies that have evaluated the efficacies and potential limitations of genetic/pharmacological inhibition of BACE1, with special focus on AD-associated phenotypes including synaptic dysfunction, neuron loss and memory deficits in animal models.
Center for Dementia Research, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA; Departments of Psychiatry, New York University Langone Medical Center, New York, NY 10016, USA. Electronic address: mohno@nki.rfmh.org.
Masuo
M
Ohno
D000544:Alzheimer Disease / Q000201:enzymology* / Q000628:therapy*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology
D018696:Neuroprotective Agents; D018697:Nootropic Agents; D053829:Amyloid Precursor Protein Secretases
Alzheimer’s disease; BACE1; Learning and memory; Mouse model; Synaptic function; β-Secretase