Premature cognitive decline in a mouse model of tuberous sclerosis.

IF 8 1区医学 Q1 CELL BIOLOGY

Aging Cell Pub Date : 2024-08-27 DOI:10.1111/acel.14318

J Krummeich, L Nardi, C Caliendo, D Aschauer, V Engelhardt, A Arlt, J Maier, F Bicker, M D Kwiatkowski, K Rolski, K Vincze, R Schneider, S Rumpel, S Gerber, M J Schmeisser, S Schweiger

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Abstract

Little is known about the influence of (impaired) neurodevelopment on cognitive aging. We here used a mouse model for tuberous sclerosis (TS) carrying a heterozygous deletion of the Tsc2 gene. Loss of Tsc2 function leads to mTOR hyperactivity in mice and patients. In a longitudinal behavioral analysis, we found premature decline of hippocampus-based cognitive functions together with a significant reduction of immediate early gene (IEG) expression. While we did not detect any morphological changes of hippocampal projections and synaptic contacts, molecular markers of neurodegeneration were increased and the mTOR signaling cascade was downregulated in hippocampal synaptosomes. Injection of IGF2, a molecule that induces mTOR signaling, could fully rescue cognitive impairment and IEG expression in aging Tsc2^+/- animals. This data suggests that TS is an exhausting disease that causes erosion of the mTOR pathway over time and IGF2 is a promising avenue for treating age-related degeneration in mTORopathies.

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结节性硬化症小鼠模型的认知能力早衰。

人们对神经发育（受损）对认知老化的影响知之甚少。在这里，我们使用了一种携带 Tsc2 基因杂合性缺失的结节性硬化症（TS）小鼠模型。Tsc2 功能的缺失会导致小鼠和患者的 mTOR 功能亢进。在一项纵向行为分析中，我们发现基于海马体的认知功能过早衰退，同时即时早期基因（IEG）表达显著减少。虽然我们没有检测到海马突起和突触接触的任何形态学变化，但神经变性的分子标记物增加了，海马突触体中的mTOR信号级联下调了。注射诱导 mTOR 信号转导的分子 IGF2 可以完全缓解老化的 Tsc2+/- 动物的认知障碍和 IEG 表达。这些数据表明，TS是一种耗竭性疾病，会随着时间的推移导致mTOR通路的侵蚀，而IGF2是治疗mTOR病中与年龄相关的退化的一种有希望的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology

自引率

2.60%

发文量

212

期刊介绍： Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.