BACE1 inhibition in injured peripheral nerve and a neuropathy mouse models

描述（由申请人提供）：周围神经损伤和疾病是常见的健康问题，经常导致长期功能缺陷。幼龄啮齿动物神经损伤或疾病后，外周轴突可以再生和再支配目标组织。然而，人类轴突再生非常缓慢，失神经的雪旺细胞（为再生提供了一个允许的微环境）和目标组织都有萎缩和死亡的风险，阻碍了功能的恢复。这种情况强调了对加速轴突再生以恢复功能的药物的迫切需要。促进轴突再生的主要候选是抑制β -淀粉样蛋白切割酶（BACE1）。最近，我们发现基因缺失和药物抑制BACE1可显著促进小鼠损伤周围神经的轴突再生。然而，目前尚不清楚抑制BACE1如何促进神经再生。我们假设加速神经再生是由于阻断BACE1切割两种不同的BACE1底物。这两种底物分别是轴突上的淀粉样前体蛋白（APP）和巨噬细胞上的肿瘤坏死因子受体1 (TNFR1)，巨噬细胞浸润受损神经并清除抑制性髓磷脂碎片。我们将系统地探索这两种底物的基因操作，以加速BACE1 KO小鼠的轴突再生和髓鞘碎片的快速清除。同样重要的是，我们建议对一种新的非常有吸引力的治疗方法（例如，药理抑制BACE1）进行批判性评估，以加速临床前啮齿动物模型的神经再生。作为实验模型，我们将采用小鼠周围神经损伤和化疗诱导的周围神经病变。为了评估BACE1抑制剂作为神经损伤和化疗引起的周围神经病变的治疗方法，我们计划采取形态学、电生理和行为学研究相结合的方法。拟议的研究是高度相关的，因为与BACE1抑制相关的更快的生长速度可能有助于加速人类条件下的神经再生。

DESCRIPTION (provided by applicant): Peripheral nerve damage and diseases are common health problems that often result in long-term functional deficits. Peripheral axons can regenerate and reinnervate target tissue following nerve injury or disease in young rodent animals. However, human axonal regeneration is very slow and both denervated Schwann cells, which provide a permissive micro-environment for regeneration, and target tissues are at risk for undergoing atrophy and death, precluding functional recover. This situation underscores the critical need for agents that can speed up axonal regeneration to restore function. A prime candidate for enhancing axonal regeneration is inhibition of Beta -Amyloid Cleaving Enzyme (BACE1). Recently, we show that genetic deletion and pharmacological inhibition of BACE1 markedly accelerate axonal regeneration in the injured peripheral nerves of mice. However, it is unclear how inhibition of BACE1 improves nerve regeneration. We postulate that accelerated nerve regeneration is due to blockade of BACE1 cleavage of two different BACE1 substrates. The two proposed substrates are the amyloid precursor protein (APP) in axons and tumor necrosis factor receptor 1 (TNFR1) on macrophages, which infiltrate injured nerves and clear the inhibitory myelin debris. We will systematically explore genetic manipulations of these two substrates in regard to accelerated axonal regeneration and rapid myelin debris removal seen in BACE1 KO mice. Equally importantly, we propose critical evaluations of a new and very attractive therapeutic approach (e.g. pharmacological inhibition of BACE1) to accelerate nerve regeneration in preclinical rodent models. As experimental models, we will employ peripheral nerve injury and chemotherapy-induced peripheral neuropathy in mice. To evaluate BACE1 inhibitors as a therapy for nerve damage and chemotherapy-induced peripheral neuropathy, we plan to take combined approaches of morphological, electrophysiological and behavioral studies. The proposed studies are highly relevant because faster rate of outgrowth associated with BACE1 inhibition could be useful in speeding nerve regeneration in human conditions.