BACKGROUND In addition to cognitive deficits, Alzheimer's disease (AD) is associated with other neuropsychiatric symptoms, including severe depression. Indeed, depression often precedes cognitive deficits in patients with AD. Unfortunately, the field has seen only minimal therapeutic advances, underscoring the critical need for new treatments. P7C3 aminopropyl carbazoles promote neuronal survival by enhancing nicotinamide adenine dinucleotide flux in injured neurons. Neuroprotection with P7C3 compounds has been demonstrated in preclinical models of neurodegeneration by virtue of promoting neuronal survival independently of early disease-specific pathology, resulting in protection from cognitive deficits and depressive-like behavior. We hypothesize that P7C3 compounds might be uniquely applicable to patients with AD, given the comorbid presentation of depression and cognitive deficits. METHODS Aging male and female wild-type and TgF344-AD rats, a well-characterized preclinical AD model, were administered (-)-P7C3-S243 daily for 9 and 18 months, beginning at 6 months of age. Behavioral phenotypes related to cognition and depression were assessed at 15 and 24 months, and brain pathology and biochemistry were assessed at 24 months. RESULTS (-)-P7C3-S243 safely protected aging male and female wild-type and TgF344-AD rats from cognitive deficits and depressive-like behavior. Depressive-like behavior occurred earlier than cognitive deficits in TgF344-AD rats, consistent with AD in many patients. Treatment with (-)-P7C3-S243 blocked neurodegeneration in TgF344-AD rats, without altering amyloid deposition or indicators of neuroinflammation. CONCLUSIONS Neuronal cell death-specific treatment approaches, such as P7C3 compounds, may represent a new treatment approach for patients experiencing the combination of cognitive deficits and depression associated with AD.

中文翻译：

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(-)-P7C3-S243 保护阿尔茨海默病大鼠模型免受神经精神缺陷和神经变性的影响，而不改变淀粉样蛋白沉积或反应性胶质细胞

背景除了认知缺陷之外，阿尔茨海默病（AD）还与其他神经精神症状有关，包括严重的抑郁症。事实上，抑郁症往往先于 AD 患者的认知缺陷。不幸的是，该领域的治疗进展微乎其微，突显出对新疗法的迫切需求。P7C3 氨基丙基咔唑通过增强受损神经元中的烟酰胺腺嘌呤二核苷酸通量来促进神经元存活。P7C3 化合物的神经保护作用已在神经退行性变的临床前模型中得到证实，它可以独立于早期疾病特异性病理学促进神经元存活，从而防止认知缺陷和抑郁样行为。我们假设 P7C3 化合物可能特别适用于 AD 患者，鉴于抑郁症和认知缺陷的共存表现。方法 衰老的雄性和雌性野生型和 TgF344-AD 大鼠，一种充分表征的临床前 AD 模型，从 6 个月大时开始，每天施用 (-)-P7C3-S243，持续 9 和 18 个月。在 15 个月和 24 个月时评估与认知和抑郁相关的行为表型，并在 24 个月时评估大脑病理学和生物化学。结果 (-)-P7C3-S243 可以安全地保护衰老的雄性和雌性野生型和 TgF344-AD 大鼠免受认知缺陷和抑郁样行为的影响。在 TgF344-AD 大鼠中，抑郁样行为发生的时间早于认知缺陷，这与许多患者的 AD 一致。(-)-P7C3-S243 治疗阻止了 TgF344-AD 大鼠的神经变性，而不会改变淀粉样蛋白沉积或神经炎症指标。