Medina-Vera Dina, López-Gambero Antonio J, Verheul-Campos Julia, Navarro Juan A, Morelli Laura, Galeano Pablo, Suárez Juan, Sanjuan Carlos, Pacheco-Sánchez Beatriz, Rivera Patricia, Pavon-Morón Francisco J, Rosell-Valle Cristina, Fonseca Fernando Rodríguez de
Grupo de Neuropsicofarmacología, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Unidades Clínicas de Neurología y Salud Mental, 29010 Málaga, Spain.
Facultad de Ciencias, Universidad de Málaga, 29010 Málaga, Spain.
Nutrients. 2024 Dec 4;16(23):4186. doi: 10.3390/nu16234186.
BACKGROUND/OBJECTIVES: Alzheimer's disease (AD), a leading cause of dementia, lacks effective long-term treatments. Current therapies offer temporary relief or fail to halt its progression and are often inaccessible due to cost. AD involves multiple pathological processes, including amyloid beta (Aβ) deposition, insulin resistance, tau protein hyperphosphorylation, and systemic inflammation accelerated by gut microbiota dysbiosis originating from a leaky gut. Given this context, exploring alternative therapeutic interventions capable of addressing the multifaceted components of AD etiology is essential.
This study suggests D-Pinitol (DPIN) as a potential treatment modifier for AD. DPIN, derived from carob pods, demonstrates insulin-sensitizing, tau hyperphosphorylation inhibition, and antioxidant properties. To test this hypothesis, we studied whether chronic oral administration of DPIN (200 mg/kg/day) could reverse the AD-like disease progression in the 5×FAD mice.
Results showed that treatment of 5×FAD mice with DPIN improved cognition, reduced hippocampal Aβ and hyperphosphorylated tau levels, increased insulin-degrading enzyme (IDE) expression, enhanced pro-cognitive hormone circulation (such as ghrelin and leptin), and normalized the PI3K/Akt insulin pathway. This enhancement may be mediated through the modulation of cyclin-dependent kinase 5 (CDK5). DPIN also protected the gut barrier and microbiota, reducing the pro-inflammatory impact of the leaky gut observed in 5×FAD mice. DPIN reduced bacterial lipopolysaccharide (LPS) and LPS-associated inflammation, as well as restored intestinal proteins such as Claudin-3. This effect was associated with a modulation of gut microbiota towards a more balanced bacterial composition.
These findings underscore DPIN's promise in mitigating cognitive decline in the early AD stages, positioning it as a potential disease modifier.
背景/目的：阿尔茨海默病（AD）是痴呆的主要病因，缺乏有效的长期治疗方法。目前的疗法只能提供暂时缓解，或无法阻止其进展，且由于成本问题往往难以获得。AD涉及多种病理过程，包括淀粉样β（Aβ）沉积、胰岛素抵抗、tau蛋白过度磷酸化以及由肠道渗漏引起的肠道微生物群失调加速的全身炎症。在此背景下，探索能够解决AD病因多方面因素的替代治疗干预措施至关重要。
本研究提出D-松醇（DPIN）作为AD的一种潜在治疗调节剂。DPIN源自角豆荚，具有胰岛素增敏、抑制tau过度磷酸化和抗氧化特性。为了验证这一假设，我们研究了长期口服DPIN（200mg/kg/天）是否能逆转5×FAD小鼠的AD样疾病进展。
结果表明，用DPIN治疗5×FAD小鼠可改善认知，降低海马Aβ和过度磷酸化tau水平，增加胰岛素降解酶（IDE）表达，增强促认知激素循环（如胃饥饿素和瘦素），并使PI3K/Akt胰岛素信号通路正常化。这种增强作用可能是通过调节细胞周期蛋白依赖性激酶5（CDK5）介导的。DPIN还保护肠道屏障和微生物群，减少5×FAD小鼠中观察到的肠道渗漏的促炎影响。DPIN降低了细菌脂多糖（LPS）和与LPS相关的炎症，并恢复了如Claudin-3等肠道蛋白。这种作用与肠道微生物群向更平衡的细菌组成的调节有关。
这些发现强调了DPIN在减轻AD早期认知衰退方面的前景，使其成为一种潜在的疾病调节剂。
