美国伊利诺大学芝加哥分校Orly Lazarov团队近日取得一项新成果。经过不懈努力，他们的最新研究提出了成年期、衰老和阿尔茨海默病过程中的人类海马神经发生。该项研究成果发表在2026年2月25日出版的《自然》上。

在这里，课题组研究人员研究了从不同队列中获得的人类死后海马：具有完整记忆的年轻人，没有认知障碍的老年人，具有非凡记忆容量的老年人（超级老年人），具有临床前中间病理的成年人或患有AD的成年人。使用多组单细胞测序（单核RNA测序和单核转座酶可及染色质测序），该课题组人员分析了从海马体样本中分离的355997个细胞核的特征，并鉴定了神经干细胞、神经母细胞和未成熟颗粒神经元。神经发生失调在很大程度上与染色质可及性的改变有关。

对转录因子和靶基因特征的分析显示，临床前阿尔茨海默病患者神经源性细胞的染色质可及性在早期发生了改变，这种变化在阿尔茨海默病患者的样本中更为明显。研究小组在超级老人中发现了一种独特的神经发生特征，这可能反映了一种“弹性特征”。最后，星形胶质细胞和CA1神经元的改变控制着衰老海马的认知功能。总之，他们的研究指出了海马体的多组分子特征，该特征区分了认知弹性和认知衰退随年龄的增长。

据悉，人类海马神经发生的存在一直存在争议，其与认知的相关性仍然未知。最近的研究已经证实，在阿尔茨海默病（AD）中存在增殖祖细胞和未成熟神经元，并且后者减少。然而，它们的起源和调节神经发生和功能的分子网络知之甚少。

附：英文原文

Title: Human hippocampal neurogenesis in adulthood, ageing and Alzheimer’s disease

Author: Disouky, Ahmed, Sanborn, Mark A., Sabitha, K. R., Mostafa, Mostafa M., Ayala, Ivan Alejandro, Bennett, David A., Lu, Yisha, Zhou, Yi, Keene, C. Dirk, Weintraub, Sandra, Gefen, Tamar, Mesulam, M.-Marsel, Geula, Changiz, Maienschein-Cline, Mark, Rehman, Jalees, Lazarov, Orly

Issue&Volume: 2026-02-25

Abstract: The existence of human hippocampal neurogenesis has long been disputed1,2,3,4,5,6,7,8,9,10,11,12 and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer’s disease (AD)11,13. However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with intact memory, aged adults with no cognitive impairments, aged adults with extraordinary memory capacity (SuperAgers)14,15, adults with preclinical intermediate pathology or adults with AD. Using multiomic single-cell sequencing (single-nucleus RNA sequencing and single-nuclei assay for transposase-accessible chromatin with sequencing), we analysed the profiles of 355,997 nuclei isolated from the hippocampus samples and identified neural stem cells, neuroblasts and immature granule neurons. Dysregulated neurogenesis was largely associated with changes in chromatin accessibility. Analyses of transcription factors and target gene signatures that distinguished each of the groups revealed early alterations in chromatin accessibility of neurogenic cells from individuals with preclinical AD, and such changes were even more evident in samples from individuals with AD. We identified a distinct profile of neurogenesis in SuperAgers that may reflect a ‘resilience signature’. Finally, alterations in the profile of astrocytes and CA1 neurons govern cognitive function in the ageing hippocampus. Together, our study points to a multiomic molecular signature of the hippocampus that distinguishes cognitive resilience and deterioration with ageing.

DOI: 10.1038/s41586-026-10169-4

Source: https://www.nature.com/articles/s41586-026-10169-4