Cortical neurodegeneration caused by Psen1 mutations is independent of Aβ

• 成果类型: Article
• 署名作者: Yan, Kuo; Zhang, Chen; Kang, Jongkyun; Montenegro, Paola; Shen, Jie
• 署名单位: Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Harvard University; Harvard Medical School; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12797
• DOI: 10.1073/pnas.2409343121
• 发表日期: 2024-08-20
• 关键词: familial alzheimers-disease; gamma-secretase activity; synaptic plasticity; presenilin function; missense mutations; gene; hypothesis; knockout; release; plaques

摘要

Mutations in the PSEN genes are the major cause of familial Alzheimer's disease, and presenilin (PS) is the catalytic subunit of gamma- secretase, which cleaves type I trans- membrane proteins, including the amyloid precursor protein (APP) to release A f3 peptides. While PS plays an essential role in the protection of neuronal survival, PSEN mutations also increase the ratio of Af342/Af340. Thus, it remains unresolved whether PSEN mutations cause AD via a loss of its essential function or increases of Af342/ Af340. Here, we test whether the knockin (KI) allele of Psen1 L435F, the most severe FAD mutation located closest to the active site of gamma- secretase, causes age- dependent cortical neurodegeneration independent of A f3 by crossing various Psen mutant mice to the App- null background. We report that removing A f3 completely through APP deficiency has no impact on the age- dependent neurodegeneration in Psen mutant mice, as shown by the absence of effects on the reduced cortical volume and decreases of cortical neurons at the ages of 12 and 18 mo. The L435F KI allele increases Af342/ Af340 in the cerebral cortex while decreasing de novo production and steady- state levels of Af342 and Af340 in the presence of APP. Furthermore, APP deficiency does not alleviate elevated apoptotic cell death in the cerebral cortex of Psen mutant mice at the ages of 2, 12, and 18 mo, nor does it affect the progressive microgliosis in these mice. Our findings demonstrate that Psen1 mutations cause age- dependent neurodegeneration independent of Af3, providing further support for a loss- of- function pathogenic mechanism underlying PSEN mutations.