Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease

被引：24

作者：

Shulman, Dana ^{[1
,2
,3
]}

Dubnov, Serafima ^{[1
,2
]}

Zorbaz, Tamara ^{[2
]}

Madrer, Nimrod ^{[1
,2
]}

Paldor, Iddo ^{[4
]}

Bennett, David A. ^{[5
]}

Seshadri, Sudha ^{[6
]}

Mufson, Elliott J. ^{[7
]}

Greenberg, David S. ^{[1
,2
]}

Loewenstein, Yonatan ^{[1
,8
,9
,10
]}

Soreq, Hermona ^{[1
,2
,11
]}

机构：

[1] Hebrew Univ Jerusalem, Edmond & Lily Safra Ctr Brain Sci, Jerusalem, Israel

[2] Hebrew Univ Jerusalem, Inst Life Sci, Jerusalem, Israel

[3] Hebrew Univ Jerusalem, Rachel & Selim Benin Sch Comp Sci & Engn, Jerusalem, Israel

[4] Shaare Zedek Med Ctr, Neurosurg Dept, Jerusalem, Israel

[5] Rush Univ, Rush Alzheimers Dis Ctr, Med Ctr, Chicago, IL USA

[6] UT Hlth Med Arts & Res Ctr, San Antonio, TX USA

[7] St Josephs Med Ctr, Barrow Neurol Inst, Phoenix, AZ USA

[8] Hebrew Univ Jerusalem, Dept Neurobiol, Jerusalem, Israel

[9] Hebrew Univ Jerusalem, Dept Cognit Sci, Jerusalem, Israel

[10] Federmann Ctr Study Rat, Jerusalem, Israel

[11] Hebrew Univ Jerusalem, Inst Life Sci, Edmond J Safra Campus, IL-9190401 Jerusalem, Israel

来源：

ALZHEIMERS & DEMENTIA | 2023年 / 19卷 / 11期

基金：

美国国家卫生研究院; 以色列科学基金会;

关键词：

Alzheimer's disease; bioinformatics; cholinergic system; cognitive impairment; sex-differences; tRNA fragments (tRFs); MILD COGNITIVE IMPAIRMENT; SINGLE-CELL; NEURONS; EXPRESSION; MEMORY; DIFFERENTIATION; ORGANIZATION; PROJECTIONS; PROGRESSION; DIAGNOSIS;

D O I：

10.1002/alz.13095

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

IntroductionFemales with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in transfer RNS (tRNA) fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). MethodsWe analyzed small RNA-sequencing (RNA-Seq) data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. ResultsNAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single-cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. DiscussionOur findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

引用

页码：5159 / 5172

页数：14

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