ACS Nano

Nature communications

Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy.

Nature Reviews Neurology

当下，减缓阿尔茨海默病 (AD) 的进一步发展可能是我们这个时代最大且未被满足的医疗需求。尽管目前已有AD 疗法获得了 FDA加速批准（存在争议），我们仍迫切需要更有效和更容易获得的疗法。当前的共识是，为了在 AD 发展过程中进行有意义的治疗，治疗干预必须在疾病的早期阶段（临床前期或前驱期）开始。虽然已经开发出了针对这样的早期临床试验的方法，但识别和招募无症状或症状轻微的被试过程非常费时费力。

例如，在无症状AD患者的抗淀粉样蛋白治疗试验中（首例AD临床前期III 期临床试验），需要3.5 年时间和超过5,900 多种筛查来招募1,169 名参与者，并且为了提高招募效率并加速AD治疗进展，需要新的临床试验基础设施。北美、欧洲和亚洲正在合作通过建立临床前期和前驱期 AD 个体的试验就绪队列来解决这个问题。这些合作正在采用创新方法吸引目标人群，评估大脑淀粉样蛋白积累风险，选择参与者进行生物标志物研究并确定参与试验的资质。将来，这些计划可以提供有效的工具在早期阻止AD的发病进程。本文回顾了从 AD 试验就绪队列成立至今吸取的经验教训，旨在为当前和将来的试验招募工作提供更加高效、经济的信息。

Slowing the progression of Alzheimer disease (AD) might be the greatest unmet medical need of our time. Although one AD therapeutic has received a controversial accelerated approval from the FDA, more effective and accessible therapies are urgently needed. Consensus is growing that for meaningful disease modification in AD, therapeutic intervention must be initiated at very early (preclinical or prodromal) stages of the disease. Although the methods for such early-stage clinical trials have been developed, identification and recruitment of the required asymptomatic or minimally symptomatic study participants takes many years and requires substantial funds. As an example, in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Trial (the first phase III trial to be performed in preclinical AD), 3.5 years and more than 5,900 screens were required to recruit and randomize 1,169 participants. A new clinical trials infrastructure is required to increase the efficiency of recruitment and accelerate therapeutic progress. Collaborations in North America, Europe and Asia are now addressing this need by establishing trial-ready cohorts of individuals with preclinical and prodromal AD. These collaborations are employing innovative methods to engage the target population, assess risk of brain amyloid accumulation, select participants for biomarker studies and determine eligibility for trials. In the future, these programmes could provide effective tools for pursuing the primary prevention of AD. Here, we review the lessons learned from the AD trial-ready cohorts that have been established to date, with the aim of informing ongoing and future efforts towards efficient, cost-effective trial recruitment.