Institute of Neuroscience of the CNR, Via G. Moruzzi 1, 56124, Pisa, Italy.
Department of Neuroscience, Psychology, Drug Research, Child Health (NEUROFARBA), Florence University, Florence, Italy.
Aging Clin Exp Res. 2021 May;33(5):1223-1238. doi: 10.1007/s40520-020-01646-5. Epub 2020 Jul 16.
A decrease in brain-derived neurotrophic factor (BDNF), a neurotrophin essential for synaptic function, plasticity and neuronal survival, is evident early in the progression of Alzheimer's disease (AD), being apparent in subjects with mild cognitive impairment or mild AD, and both proBDNF and mature BDNF levels are positively correlated with cognitive measures. BDNF delivery is, therefore, considered of great interest as a potentially useful therapeutic strategy to contrast AD. Invasive BDNF administration has indeed been recently used in animal models of AD with promising results in rescuing memory deficits, synaptic density and cell loss. Here, we tested whether non-invasive intranasal administration of different BDNF concentrations after the onset of cognitive and anatomical deficits (6 months of age) could rescue neuropathological and memory deficits in AD11 mice, a model of NGF deprivation-induced neurodegeneration. In addition to AD hallmarks, we investigated BDNF effects on microglia presence in the brain of AD11 mice, since alterations in microglia activation have been associated with ageing-related cognitive decline and with the progression of neurodegenerative diseases, including AD. We found that intranasal delivery of 42 pmol BDNF (1 μM), but not PBS, was sufficient to completely rescue performance of AD11 mice both in the object recognition test and in the object context test. No further improvement was obtained with 420 pmol (10 μM) BDNF dose. The strong improvement in memory performance in BDNF-treated mice was not accompanied by an amelioration of AD-like pathology, Aβ burden, tau hyperphosphorylation and cholinergic deficit, but there was a dramatic decrease of CD11b immunoreactive brain microglia. These results reinforce the potential therapeutic uses of BDNF in AD and the non-invasive intranasal route as an effective delivery strategy of BDNF to the brain. They also strengthen the connection between neuroinflammation and neurodegenerative dementia and suggest microglia as a possible mediator of BDNF therapeutic actions in the brain.
脑源性神经营养因子（BDNF）减少，这种神经营养因子对突触功能、可塑性和神经元存活至关重要，在阿尔茨海默病（AD）的进展早期就很明显，在轻度认知障碍或轻度 AD 患者中表现明显，而且 proBDNF 和成熟 BDNF 水平与认知测量呈正相关。因此，BDNF 传递被认为是一种很有前途的治疗策略，可以对抗 AD。事实上，最近已经在 AD 动物模型中使用了侵入性 BDNF 给药，在挽救记忆缺陷、突触密度和细胞丢失方面取得了有希望的结果。在这里，我们测试了在认知和解剖缺陷（6 个月大）出现后，用不同浓度的非侵入性鼻内给予 BDNF 是否可以挽救 AD11 小鼠（一种 NGF 剥夺诱导的神经退行性变模型）的神经病理学和记忆缺陷。除了 AD 的特征外，我们还研究了 BDNF 对 AD11 小鼠大脑中小胶质细胞存在的影响，因为小胶质细胞激活的改变与与年龄相关的认知能力下降以及神经退行性疾病（包括 AD）的进展有关。我们发现，鼻内给予 42pmol BDNF（1μM），而不是 PBS，足以完全挽救 AD11 小鼠在物体识别测试和物体环境测试中的表现。用 420pmol（10μM）BDNF 剂量没有进一步改善。在 BDNF 治疗的小鼠中，记忆性能的显著改善并没有伴随着 AD 样病理学、Aβ 负担、tau 过度磷酸化和胆碱能缺陷的改善，但大脑中 CD11b 免疫反应性小胶质细胞明显减少。这些结果加强了 BDNF 在 AD 中的潜在治疗用途，以及非侵入性鼻内途径作为将 BDNF 有效递送至大脑的策略。它们还加强了神经炎症与神经退行性痴呆之间的联系，并表明小胶质细胞可能是 BDNF 在大脑中治疗作用的一个可能介导物。
