German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
Int J Mol Sci. 2023 Jul 31;24(15):12283. doi: 10.3390/ijms241512283.
β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is considered a therapeutic target to combat Alzheimer's disease by reducing β-amyloid in the brain. To date, all clinical trials involving the inhibition of BACE1 have been discontinued due to a lack of efficacy or undesirable side effects such as cognitive worsening. The latter could have been the result of the inhibition of BACE at the synapse where it is expressed in high amounts. We have previously shown that prolonged inhibition of BACE interferes with structural synaptic plasticity, most likely due to the diminished processing of the physiological BACE substrate Seizure protein 6 (Sez6) which is exclusively processed by BACE1 and is required for dendritic spine plasticity. Given that BACE1 has significant amino acid similarity with its homolog BACE2, the inhibition of BACE2 may cause some of the side effects, as most BACE inhibitors do not discriminate between the two. In this study, we used newly developed BACE inhibitors that have a different chemotype from previously developed inhibitors and a high selectivity for BACE1 over BACE2. By using longitudinal in vivo two-photon microscopy, we investigated the effect on dendritic spine dynamics of pyramidal layer V neurons in the somatosensory cortex in mice treated with highly selective BACE1 inhibitors. Treatment with those inhibitors showed a reduction in soluble Sez6 (sSez6) levels to 27% (elenbecestat, Biogen, Eisai Co., Ltd., Tokyo, Japan), 17% (Shionogi compound ) and 39% (Shionogi compound ), compared to animals fed with vehicle pellets. We observed a significant decrease in the number of dendritic spines with Shionogi compound after 21 days of treatment but not with Shionogi compound or with elenbecestat, which did not show cognitive worsening in clinical trials. In conclusion, highly selective BACE1 inhibitors do alter dendritic spine density similar to non-selective inhibitors if soluble (sSez6) levels drop too much. Low-dose BACE1 inhibition might be reasonable if dosing is carefully adjusted to the amount of Sez6 cleavage, which can be easily monitored during the first week of treatment.
β-淀粉样前体蛋白裂解酶 1（BACE1）被认为是通过减少大脑中的β-淀粉样蛋白来治疗阿尔茨海默病的治疗靶点。迄今为止，由于缺乏疗效或认知恶化等不良副作用，所有涉及 BACE1 抑制的临床试验都已停止。后者可能是由于在突触处 BACE 的抑制，而突触处大量表达 BACE。我们之前曾表明，BACE 的长期抑制会干扰结构突触可塑性，这很可能是由于生理 BACE 底物 Seizure protein 6（Sez6）的处理减少所致，而 Sez6 仅由 BACE1 处理，是树突棘可塑性所必需的。鉴于 BACE1 与它的同源物 BACE2 具有显著的氨基酸相似性，BACE2 的抑制可能会引起一些副作用，因为大多数 BACE 抑制剂不能区分两者。在这项研究中，我们使用了新开发的 BACE 抑制剂，这些抑制剂具有与以前开发的抑制剂不同的化学型，并且对 BACE1 具有比 BACE2 更高的选择性。通过使用纵向体内双光子显微镜，我们研究了在接受高度选择性 BACE1 抑制剂治疗的小鼠体感皮层 V 层锥体神经元的树突棘动力学的影响。与给予载体丸剂的动物相比，用这些抑制剂处理可将可溶性 Sez6（sSez6）水平降低到 27%（elenbecestat，Biogen，Eisai Co.，Ltd.，东京，日本），17%（Shionogi 化合物）和 39%（Shionogi 化合物）。我们观察到 Shionogi 化合物治疗 21 天后树突棘数量明显减少，但 Shionogi 化合物或 elenbecestat 则没有，这两种药物在临床试验中均未表现出认知恶化。总之，如果可溶性（sSez6）水平下降过多，高度选择性的 BACE1 抑制剂会像非选择性抑制剂一样改变树突棘密度。如果剂量调整到 Sez6 切割的量，则低剂量的 BACE1 抑制可能是合理的，这可以在治疗的第一周内轻松监测。
