Multi-transcriptomic analysis points to early organelle dysfunction in human astrocytes in Alzheimer’s disease

Abstract

BackgroundOur understanding of the impact of astrocytes in Alzheimer’s disease (AD) is hindered by the lack of astrocyte-specific omics data from patients diagnosed with dementia due to AD. Studies aiming to profile human AD astrocytes—including single-nucleus RNA sequencing—were limited by the low number of differentially expressed genes detected, and by the small size of cohorts. We improved on prior studies with a novel systems-biology-based approach.Methods Human astrocytic and neuronal gene clusters were generated from RNA sequencing data from isolated healthy human brain cells using a cell-type enrichment score and clustering. The cell-specific gene clusters were localized in 766 subjects from three AD whole-brain transcriptomes generated by the Mount Sinai Hospital, the Mayo Clinic, and the Religious Order Study/Memory and Aging Project (ROSMAP), which also contains subjects with mild cognitive impairment (MCI). Gene clusters were organized into functional categories and subcategories using manual curation. Functional changes among subject groups were determined by gene set variation analysis (GSVA) and principal component analysis (PCA).Results Hierarchical clustering of transcriptomic data revealed molecular heterogeneity in individuals with the same clinical diagnosis. Particularly in the Mayo Clinic and ROSMAP cohorts, over 50% of Controls presented massive down-regulation of genes encoding for synaptic proteins, as widely documented in AD, suggesting that these subjects might have been at a preclinical stage at the time of death. Conversely, approximately 30% of AD patients showed preservation of neuronal genes as if they were non demented subjects, suggesting that they were resilient to AD pathology (present, according to CERAD and Braak scoring), but developed dementia due to comorbidities. The astrocytic gene profiles in AD patients presenting down-regulation of neuronal genes were termed ‘AD astrocytes’. According to GSVA and PCA, AD astrocytes showed down-regulation of genes encoding for mitochondrial and endolysosomal proteins, and up-regulation of genes related to perisynaptic astrocytic processes (PAP), and survival and stress responses.Discussion Astrocytes undergo a profound transcriptional change in a remarkable percentage of Control, MCI and AD subjects, affecting organelles and astrocyte-neuron interactions. We argue that therapies preventing organelle dysfunction in astrocytes may protect neural circuits in preclinical and clinical AD.

Bridging metabolic syndrome and cognitive dysfunction: role of astrocytes

“…In summary, it has been elaborated that astrocytes are susceptible to morphologically and functionally responsive changes in metabolically disturbed environments. Reactive astrocytes are involved in pathological processes such as neuroinflammation, energy metabolic homeostasis, and crossbarrier transport of nutrients and amyloid in MetS-associated cognitive dysfunction (165,194).…”

Plasma Proteomic Signature of Mucolipidosis Type IV

“…This analysis was conducted using the GSVA package (v1.44.5) available in R through Bioconductor with the relative protein expression values. Significant differences in gene set enrichment scores between the two groups were determined via gene set permutation analysis, as we have done before (24). Gene labels were randomly shuffled, and GSVA was recalculated.…”

Neuroinflammation: The Abused Concept

“…For example, "neuroinflammation" is, for some authors, the reactive astrocytosis detected by immunohistochemical and imaging approaches in Alzheimer's disease (Harada et al, 2022). What a more detailed analysis of the existing data shows is that amyloid-β damages astrocytes, particularly their endolysosomal system and mitochondria, resulting in the disruption of energy metabolism and ROS homeostasis in astrocyte-neuronal circuits, among other alterations (reviewed in Galea et al, 2022). There is no evidence in human brains that reactive astrocytes are first "neuroprotective" and then "neurotoxic".…”

“…These are simplistic classifications that do not reflect the complex mix of adaptive and maladaptive changes occurring in any phenotypical transformation (Escartin et al, 2021). Rather, based on correlations between gene expression and scoring of disease stages in Alzheimer's disease, astrocytes seem to evolve from doing badly to doing worse (Galea et al, 2022). This is a case of astrocytopathy and not innate immunity going rogue.…”