Bhatnagar, A. | Search bioRxiv

bioRxiv2020

Transcriptome analysis uncovers distinct modes of epigenetic gene changes in early versus late stages of amyloid-β induced Alzheimer's disease pathology

Alzheimers disease (AD) is an age-related neurodegenerative disorder hallmarked by amyloid-{beta} (A{beta}) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferases (HAT) Tip60 and increased histone deacetylase 2 (HDAC2) levels, can directly contribute to AD pathology. However, whether such AD-associated neuroepigenetic alterations occur in response to A{beta} peptide production and can be protected against by increasing Tip60 levels over the course of neurodegenerative progression remains unknown. Here we profile Tip60 HAT/HDAC2 dynamics and transcriptome-wide changes across early and late stage AD pathology in the Drosophila brain produced solely by human amyloid-{beta}42. We show that early A{beta}42 induction leads to disruption of Tip60 HAT/HDAC2 balance during early neurodegenerative stages preceding A{beta} plaque accumulation that persists into late AD stages. Correlative transcriptome-wide studies reveal alterations in biological processes we classified as transient (early-stage only), late-onset (late-stage only), and constant (both). Increasing Tip60 HAT levels in the A{beta}42 fly brain protects against AD functional pathologies that include A{beta} plaque accumulation, neural cell death, cognitive deficits, and shorter life-span. Strikingly, Tip60 protects against A{beta}42-induced transcriptomic alterations via distinct mechanisms during early and late stages of neurodegeneration. Our findings reveal distinct modes of neuroepigenetic gene changes and Tip60 neuroprotection in early versus late stages in AD that can serve as early biomarkers for AD, and support the therapeutic potential of Tip60 over the course of AD progression.

neuroscience↗

bioRxiv2019

Skap2 Regulates Atherosclerosis through Macrophage Polarization and Efferocytosis

RationaleAtherosclerosis causes more deaths than any other pathophysiologic process. It has a well-established inflammatory, macrophage-mediated component, but important and potentially protective intracellular macrophage processes in atherosclerosis remain enigmatic. Src Kinase-Associated Phosphoprotein 2 (Skap2) is a macrophage-predominant adaptor protein critical for cytoskeletal reorganization, and thereby, for macrophage migration and chemotaxis. The role of macrophage Skap2 in atherosclerosis is unknown and deserves exploration. ObjectiveTo establish the critical role of Skap2 in macrophage-mediated atherosclerotic plaque homeostasis. ResultsIn human arterial gene expression analysis, Skap2 expression is enriched in macrophage-containing areas of human atheroma, and the transcript level varies with plaque characteristics. We have discovered that deletion of Skap2 accelerates atherosclerosis by threefold in ApoE-/- mice on standard diet. Skap2 expression is switched on only as monocytes differentiate into macrophages, so Skap2-/- monocytes have no defect in infiltrating the atheroma. On the other hand, once they fully differentiate, Skap2-deficient macrophages cannot polarize efficiently into alternatively-activated, regulatory cells, and instead they preferentially polarize toward the classical pro-inflammatory phenotype both ex vivo and within the developing atheroma. This defect extends to polarized effector functions, as ex vivo analysis of macrophage phagocytosis of dying foam cells indicates that Skap2 is required for the regulatory process of efferocytosis. ConclusionsTaken together, our findings support a model in which Skap2 drives a regulatory, efferocytic mode of behavior to quell atherosclerosis. CONDENSED ABSTRACT / SUMMARYSkap2--a macrophage protein found in the human atheroma--is atheroprotective. Skap2-null mice, whose foam cells do not migrate well due to a defect in integrin-induced cytoskeletal rearrangement, have accelerated atherosclerosis. Skap2 is not expressed in monocytes but becomes important once they reach the atheroma and become macrophage foam cells, at which point it drives toward a regulatory, anti-inflammatory polarization state required for efficient efferocytosis of dying foam cells. Thus, Skap2 drives a protective, regulatory mode of behavior, supporting the fact that macrophages are not solely deleterious in atherosclerosis, and further pointing to efferocytosis as a target for therapy. There are no relationships to disclose.

cell biology↗