期刊
NEUROBIOLOGY OF DISEASE
卷 166, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2022.105655
关键词
Alzheimer 's disease; Astrocytes; Hierarchical clustering; MCI; Mitochondria; Perisynaptic astrocyte processes; RNA seq
资金
- Fundacio Marato-TV3 [201414-30]
- Grup de Recerca en demencias [SGR2017547]
- Generalitat de Catalunya
- Rotary Coins for Alzheimer's Research Trust Fund
- Woodruff School of Mechanical Engineering at Georgia Tech
- National Institutes of Health Cell and Tissue Engineering Biotechnology Training Grant [T32GM008433]
- NIA [P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949]
- NINDS [R01 NS080820]
- CurePSP Foundation
- Mayo Foundation
- National Institute of Neurological Disorders and Stroke (National Brain and Tissue Resource for Parkinson's Disease and Related Disorders) [U24 NS072026]
- National Institute on Aging (Arizona Alzheimer's Disease Core Center) [P30 AG19610]
- Arizona Department of Health Services (Arizona Alzheimer's Research Center) [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
- Michael J. Fox Foundation for Parkinson's Research
- NIA grants [P30AG10161, R01AG15819, R01AG17917, RC2AG036547, R01AG36836, R01AG48015, RF1AG57473, U01AG32984, U01AG46152, U01AG46161, U01AG61356]
- Illinois Department of Public Health (ROSMAP)
- Translational Genomics Research Institute (genomic)
The phenotypic transformation of astrocytes in Alzheimer's disease is still not well understood. This study reveals the molecular heterogeneity of individuals with the same clinical diagnosis and highlights the down-regulation of neuronal genes and up-regulation of astrocytic genes. These findings provide insights into the mechanism of astrocytic transformation in Alzheimer's disease.
The phenotypic transformation of astrocytes in Alzheimer's disease (AD) is still not well understood. Recent analyses based on single-nucleus RNA sequencing of postmortem Alzheimer's disease (AD) samples are limited by the low number of sequenced astrocytes, small cohort sizes, and low number of differentially expressed genes detected. To optimize the detection of astrocytic genes, we employed a novel strategy consisting of the localization of pre-determined astrocyte and neuronal gene clusters in publicly available whole-brain transcriptomes. Specifically, we used cortical transcriptomes from 766 individuals, including cognitively normal subjects (Controls), and people diagnosed with mild cognitive impairment (MCI) or dementia due to AD. Samples came from three independent cohorts organized by the Mount Sinai Hospital, the Mayo Clinic, and the Religious Order Study/Memory and Aging Project (ROSMAP). Astrocyte-and neuron-specific gene clusters were generated from human brain cell-type specific RNAseq data using hierarchical clustering and cell-type enrichment scoring. Genes from each cluster were manually annotated according to cell-type specific functional Categories. Gene Set Variation Analysis (GSVA) and Principal Component Analysis (PCA) were used to establish changes in these functional categories among clinical cohorts. We highlight three novel findings of the study. First, individuals with the same clinical diagnosis were molecularly heterogeneous. Particularly in the Mayo Clinic and ROSMAP cohorts, over 50% of Controls presented down-regulation of genes encoding synaptic proteins typical of AD, whereas 30% of patients diagnosed with dementia due to AD presented Control-like transcriptomic profiles. Second, down-regulation of neuronal genes related to synaptic proteins coincided, in astrocytes, with up regulation of genes related to perisynaptic astrocytic processes (PAP) and down-regulation of genes encoding endolysosomal and mitochondrial proteins. Third, down-regulation of astrocytic mitochondrial genes inversely correlated with the disease stages defined by Braak and CERAD scoring. Finally, we interpreted these changes as maladaptive or adaptive from the point of view of astrocyte biology in a model of the phenotypical transformation of astrocytes in AD. The main prediction is that early malfunction of the astrocytic endolysosomal system, associated with progressive mitochondrial dysfunction, contribute to Alzheimer's disease. If this prediction is correct, therapies preventing organelle dysfunction in astrocytes may be beneficial in preclinical and clinical AD.
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